The FASEB Journal • SRC Commentary
Retinoids Are Back Li-Na Wei*,1 and Ethan Dmintrovsky† *Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota; and †Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, and Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Attendees of the FASEB Summer Research Conference, 2nd Annual Conference on Retinoids (June 1–6, 2014), Itasca, IL, USA.
IN JUNE 1–6, 2014, A GROUP of researchers, clinicians, and drug developers convened for the 2014 FASEB Scientific Research Conference (SRC) on Retinoids, jointly held with the 2nd International Retinoid Conference, in the Eaglewood resort of Itasca, IL, USA. In addition to continuing the longstanding tradition of FASEB SRC on Retinoids, which is to review, update, and project future research on basic biologic aspects of retinoids, this joint meeting incorporated several new and exciting developments in the field. This notably included use of retinoids in molecular therapeutics. After the meeting concluded, all of the participants agreed that studies of retinoids are relevant both scientifically and clinically. Retinoids are especially important in oncology, immunity, metabolism, and neurological disorders. As an innovation of this FASEB SRC on Retinoids, the meeting kicked off with a roundtable panel discussion consisting of 8 panelists—W. Blaner (Columbia University, New York, NY, USA), E. Dmitrovsky (MD Anderson Cancer Center, Houston, TX, USA), E. Harrison (Ohio State University, Columbus, OH, USA), J. Napoli (University of California–Berkeley, Berkeley, CA, USA), N. Noy (Case Western Reserve University, Cleveland, OH, USA), 0892-6638/15/0029-1131 © FASEB
C. Rochette-Egly (IGBMC, Illkirch Cedex, France), X.-K. Zhang (Xiamen University, Fujian, China), led by A. C. Ross (Penn State University, State College, PA, USA)— who provided their expert views on major questions that are intriguing to address. With regard to new retinoids, the leading retinoid X receptor (RXR) agonist (rexinoid) currently in the clinic is bexarotene (targretin), a U.S. Food & Drug Administration-approved retinoid for treating cutaneous T cell lymphoma. It is under clinical testing for a number of other applications. There are ample opportunities for further modifying retinoid structures to create novel compounds that may have greater activity or specificity, with lesser off-target effects than currently existing agents. Retinoids also have the potential in treating neurodegenerative disorders, including Alzheimer’s disease for which clinical trials are underway. With regard to signaling, there is still much to be learned concerning the architecture of 1
Correspondence: Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church St., S.E., Minneapolis, MN 55455. E-mail: [email protected] doi: 10.1096/fj.15-0402ufm
1131
receptor-DNA (chromatin) interactions, as well as noncanonical signaling pathways, which may involve receptor modification or other receptor-interacting proteins. Despite decades of research on vitamin A and retinoid metabolism, the panelists concurred that much still needs to be learned and that some basic premises require refinement if not substantial revision. A concern was raised that public health decisions may be made based on outdated understanding of retinoid metabolism. For instance, a long-known plasma transport protein, retinol-binding protein (RBP4), may play a role outside of delivering retinol to cells, and the RBP4 receptor, STRA6, may have functions beyond those described originally. There is also a need for a better understanding of how retinoids affect energy balance and adipogenesis and how they interact with fatty acids in terms of intracellular signaling. Attention was drawn to the possibility that human carotenoid metabolism may generate compounds that either are additional sources of vitamin A or that interact with the vitamin A metabolic or signaling systems. It is important to study the b-carotene cleavage enzymes BCO-1 and BCO-2, which catalyze central and eccentric b-carotene cleavage, and whether novel carotenoids (some known to be present in foods) are bioactive compounds in humans and other species. Finally, there is excitement in immunology concerning retinoids as important functional factors in the context of an appropriate cytokine environment for the differentiation of T regulatory cells, a T cell subset with immunosuppressive/ immunoregulatory properties. Retinoids also promote B cell development and the functions of antigen-presenting cells. In the future, there are possibilities for use of synthetic retinoids to promote an optimal balance of immune functions in the intestine, lung, and other organs. After the roundtable discussion, a total of 8 symposia were held: Retinoid/Carotenoid Signaling (receptor biology), chaired by X.-K. Zhang (Xiamen University); Retinoid Enzymology, chaired by N. Kedishvili (University of Alabama–Birmingham, Birmingham, AL, USA); Retinoid Metabolism, chaired by L. Quadro (Rutgers University, New Brunswick, NJ, USA); Translation-Oriented Symposium 1—Retinoids and Disease, chaired by E. Dmitrovsky (MD Anderson Cancer Center); Translation-Oriented Symposium 2—Immunity and Metabolic Disorders, chaired by U. Hammerling (Sloan-Kettering Institute for Cancer Research, New York, NY, USA); Translation-Oriented Symposium 3—Nervous System and Other Applications, chaired by S. Kojima (RIKEN, Saitama, Japan); Retinoid/ Carotenoid Chemical Biology and Therapeutics, chaired by H. Gronemeyer (IGBMC); and Retinoids in Development and Stem Cell Biology, chaired by D. Soprano (Temple University, Philadelphia, PA, USA). Two poster sections were held on the second and third days and were judged by a panel of experts led by M. Kane (University of Maryland, College Park, MD, USA). A business meeting was held on the fifth day to elect the next coorganizer, N. Kedishvili. After the 8 scientific symposia, on the final day, the conference recognized 6 poster awards and concluded with a new “Meet the Expert” panel, presided over by P. Maruvada [National Institute of Diabetes and Digestive and Kidney Diseases, U.S. National Institutes of Health (NIH), Bethesda, MD, USA], where academic, clinical, and industrial leaders provided their experience 1132
Vol. 29
April 2015
and recommendations for the next generation of scientists. The conclusions and discussions of these symposia and special sections are summarized. The symposium on Retinoid/Carotenoid Signaling was kicked off by C. Rochette-Egly (IGBMC). She described retinoic acid receptor (RAR) phosphorylation and its nongenomic effects, such as activating kinase cascades, and demonstrated that phosphorylation induces receptor’s conformational change to affect partner protein recruitment and DNA binding. E. Harrison (Ohio State University) reported oxidative cleavage of b-carotene and lycopene by two oxygenases (BCO1 and BCO2), forming apocarotenoids, and showed that these apocarotenoids act as antagonists of retinoid receptors via promoting the formation of transcriptionally silent RXR tetramers. X.-K. Zhang (Xiamen University) showed that abnormal cleavage of RXR in cancer cells produces an N-terminally truncated extranuclear protein that can promote cell growth and survival. His group found that nonsteroidal anti-inflammatory drugs, such as sulindac and its analogs, inhibit these effects via inducing tetramerization of truncated RXRa. These findings shed light on new strategies for RXR-based therapeutics. There were 3 additional short talks. D. Levesque (Universitaire sur le Medicament, Qu´ebec, QC, Canada) reported a new bioluminescence resonance energy transfer assay for ligands of the NuR/RXR dimer. H. Sakai (Gifu University, Gifu City, Japan) described aberrant phosphorylation of RXRa in liver carcinogenesis. L. Levi (Case Western Reserve University) showed that in certain cells retinoids can be delivered to peroxisome proliferator-activated receptor d via fatty acid binding protein 5 (FABP5) to promote cell growth and survival. This indicated cross-talk between these two important dietary components: long chain fatty acids and vitamin A. In the Retinoid Enzymology symposium, J. Napoli (University of California–Berkeley) reported that FoxO1 and all-trans-retinoic acid (ATRA) stimulate gluconeogenesis and that FoxO1 increases ATRA biosynthesis via inducing Rdh expression. Insulin suppresses FoxO1 activity, thereby suppressing gluconeogenesis and ATRA biosynthesis through decreasing Rdh1 and Rdh10 transcription and mRNA stability. These data suggest dysregulation of Rdh expression in diabetes. N. Kedishvili (University of Alabama–Birmingham) presented evidence for the mutually activating relationship among members of the short-chain dehydrogenase/reductase superfamily, retinol dehydrogenase 10 (RDH10) and retinaldehyde reductase DHRS3, and proposed a novel model for the regulation of retinoic acid biosynthesis through proteinprotein interactions between RDH10 and DHRS3. M. Kane (University of Maryland) reiterated the importance of quantifying retinoid metabolites and described current developments in chromatography and mass spectrometry-based analytical strategies to improve retinoid detection. Three short talks were given by N. Isoherranen (University of Washington, Seattle, WA, USA), T. Matsuura (Jikei University, Tokyo, Japan), and A. Moise (University of Kansas, Lawrence, KS, USA). N. Isoherranen presented evidence for substrate channeling between cellular retinoic acid binding proteins I and II (CRABPI/II) and CYP26B1. T. Matsuura showed that human stem cells express both lecithin retinol acyltransferase (LRAT) and cellular retinol-binding protein
The FASEB Journal x www.fasebj.org
SRC COMMENTARY
(CRBP) to store vitamin, which could contribute to the development of portal fibrogenesis in patients with viral hepatitis. A. Moise described developmental and biochemical defects associated with Dhrs3 deficiency in mice (which is consistent with Kedishvili group’s finding), supporting a critical role for Dhrs3 in retinoid metabolism. In the Retinoid Metabolism symposium, A. C. Ross (Penn State University) first addressed the issue of dietary retinoid distribution into various tissues, which depends on the vitamin A status, in a neonatal model. W. S. Blaner (Columbia University) focused on retinoid metabolism in adipose tissue in relation to the development of the metabolic syndrome. L. Quadro (Rutgers University) talked about b-carotene metabolism, the most abundant dietary vitamin A precursor, during mammalian embryogenesis, with a particular emphasis on the role played by the asymmetric cleavage pathway. N. Noy (Case Western Reserve University) discussed the role of Stra6 in cancer biology. Two short talks were presented by C. Breen and D. Martin (National University of Ireland–Maynooth, Kildare, Ireland). C. Breen described identification of STRA6-interacting proteins, and D. Martin presented structural insights into STRA6. There is a continuing and growing interest in understanding STRA6 biology. Translation-Oriented Symposium 1 focused on use of retinoids in cancer therapy and prevention. E. Dmitrovsky (MD Anderson Cancer Center) reported that rexinoids induce targeted cyclin D1 degradation. It was successfully used in treating non–small cell lung cancer in combination with an epidermal growth factor receptor, tyrosine kinase inhibitor such as erlotinib. S. Waxman (Mount Sinai Medical School, New York, NY, USA) reported that the ability to induce RARb1 and decrease RARg expression was associated with differentiation and loss of tumor stem cell markers in triple negative breast cancer cells. P. Brown (MD Anderson Cancer Center) showed that estrogen receptor-negative (ER2) breast cancer could be prevented by using a rexinoid alone or in combination with other nuclear hormone receptor ligands. This suggested that future clinical trials can be conducted with rexinoids alone or in combination with other drugs for the prevention of ER2 breast cancer. Two short talks were given by Y. Shirakami (Gifu University) and H. B. Everts (Ohio State University). Y. Shirakamik described a synthetic retinoid inhibiting diethylnitrosamineinduced liver tumor formation in obese and diabetic mice, and H. B. Everts discussed how short-term UV exposure could alter retinoid-metabolizing proteins in SKH-1 hairless mice. Taken together, these findings indicate the renewed and increased use of retinoids in treating cancers, especially in the treatment with receptor isoform-specific agonists and antagonists in combination with chemotherapy, epigenetic modifying agents, and specific components of signal transduction pathways. Future work should translate these preclinical findings into the clinic. Translation-Oriented Symposium 2 focused on immunity and metabolic diseases. R. Jones (Johns Hopkins University, Baltimore, MD, USA) highlighted the role of retinaldehyde dehydrogenase and ATRA for the determination of self-renewal versus differentiation of hematopoietic stem cells. L. Purton (University of Melbourne, Melbourne, Australia) discussed the regulation of the homeobox gene HOXA1 because it pertains to the myeolodysplastic syndrome. U. Hammerling (Sloan-Kettering Institute for RETINOIDS ARE BACK
Cancer Research) introduced a model of how energy homeostasis is maintained by vitamin A-dependent signaling via protein kinase Cd. Three short talks were presented by B. Lee (University of Minnesota, Minneapolis, MN, USA), D. Schwartz (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH), and E. Shabrova (Sloan-Kettering Institute for Cancer Research), respectively. B. Lee presented new findings on the synergistic or cooperative actions of ATRA and interleukin-4 on the regulation of the arginase 1 gene, particularly in the context of anti-inflammatory macrophage activation. D. Schwart discussed retinoid-mediated control of regulatory T cells via Foxp3-dependent and -independent mechanisms. E. Shabrova followed on Hammerling’s discussion about the dysregulation of protein kinase Cd signaling by the long-term oversupply of vitamin A, which can promote obesity and type 2 diabetes in mice. Translation-Oriented Symposium 3 focused on the nervous system and other applications. R. Chandraratna (Io Therapeutics Inc., Santa Ana, CA, USA) presented work on IRX4204, a second-generation, highly selective panRXR agonist, and proposed that this drug will not have clinically adverse events related to RAR activation. In addition, IRX4204 proved to be effective in reversing pathologic Th17/Treg cell imbalance, reducing myeloid dendritic cells and CD4+ T cells to protect against multiple sclerosis, by promoting remyelination. S. W. Park (University of Minnesota) discussed retinoid-triggered epigenetic control of the family of opioid receptor genes during neuronal differentiation and maturation. It is noteworthy that all of these neuronal genes did not contain retinoic acid-responsive elements. Retinoid-triggered epigenetic control mechanisms appear to involve specific chromatin remodelers and highly orchestrated genomic and nongenomic actions of retinoid-elicited signaling molecules. S. Kojima (RIKEN) presented evidence for genomic and nongenomic actions of acyclic retinoid (ACR), a chemoprevention drug undergoing phases 2 and 3 trials to reduce liver cancer. ACR selectively kills hepatocellular carcinoma and its progenitor cells through both caspase- and transglutaminase-dependent pathways. ACR also inhibits angiogenesis via inhibiting phosphorylation of vascular endothelial growth factor receptor 2 and mitogen-activated protein kinases (MAPKs). Three short talks were presented by M. M. Holley (Case Western Reserve University), Robin D. Clugston (Columbia University), and Philip T. Liu (UCLA, Los Angeles, CA, USA), respectively. M. Holley presented evidence that bexarotene improves cognitive function by reducing intraneuronal amyloid precursor protein/amyloid. R. D. Clugston discussed how long-term alcohol consumption alters retinoid homeostasis in intrascapular brown adipose tissue and how this in turn impairs thermogenesis. P. T. Liu examined the therapeutic effects of retinoids against Mycobacterium tuberculosis, which depend on Niemann-Pick disease type C2 (NPC2). The symposium on Retinoid/Carotenoid Chemical Biology and Therapeutics presented evidence for the development and chemical synthesis of multiple novel types of retinoids and their application to systems biology-based approaches. H. Kagechika (Tokyo Medical and Dental University, Tokyo, Japan) reminded the audience that the RARa-selective agonist AM80 was approved in Japan in 2005 for treating patients who have relapsed with acute promyelocytic leukemia and reported the synthesis of 1133
new retinoids with novel substitutions in the hydrophobic domain of the ligand and of carborane-based retinoids, with potent RAR and RXR activities. K. Zhang (Tarrex Biopharema, Xiamen, China) reported on TX803, a ligand targeting the truncated RXR, originally described by X.-K. Zhang (Sanford-Burnham Medical Research Institute, La Jolla, CA, USA), and discussed nongenomic activity of truncated RXR. H. Gronemeyer (IGBMC) elucidated studies of complex system biology analysis of ATRA and RAR isoform-selective synthetic retinoids using an integrated approach to define the temporal patterns of RAR-RXR heterodimer binding to chromatin and corresponding changes in the epigenome. In comparing natural and synthetic retinoids, it was noted that none of the examined synthetic retinoids was able to exert the full spectrum of gene regulation elicited by the natural ligand ATRA. Four short presentations were given by X.-Y. Qin (RIKEN), M, Ishigami-Yuasa (Tokyo Medical and Dental University), B. C. Das (University of Kansas Medical Center), and Marco Mendoza-Parra (IGBMC), respectively. Qin reported on novel acyclic retinoids and vitamin K2 derivatives in inhibiting hepatocellular carcinoma, and Ishigami-Yuasa reported on a new class of store-operated calcium entry inhibitors that have retinoidlike structures. B. C. Das reported synthesis and application of boron-containing retinoids for treating brain cancers. M. Mendoza-Parra followed on Gronemeyer’s presentation to describe a novel bioinformatics-based tool for the quality control of ChIP-seq data sets and provided information on a freely available Next Generation Sequencing Quality Control (NGS-QC) Generator that can be used to define the quality indicators of ChIP-seq data sets (www.ngs-qc.org). The symposium on Retinoids in Development and Stem Cell Biology discussed the molecular mechanism of action of retinoids during the differentiation of specific types of stem cells and tumor cells. L. Gudas (Weill-Cornell University Medical School, New York, NY, USA) described epigenetic changes associated with the binding of different histone deacetylases to regulatory elements in retinoid-responsive genes during the differentiation of embryonic stem cells. A. Yen summarized a novel retinoid-dependent pathway involving hyperactive MAPK signaling that leads to nuclear translocation of Raf that phosphorylates transcription factors. D. Soprano (Temple University) discussed a retinoiddependent coupling of transcription and RNA splicing of weak 59-splice sites in RNAs transcribed from retinoic acidresponsive elements-containing genes by the serine-argininerich (SR)-related protein acinus. Three short talks were presented in turn by A. C. Green (St. Vincent’s Institute, Melbourne, Australia), C. Hogarth (Washington State University, Spokane, WA, USA), and S. Sugii (Duke-NUS Medical School, Singapore, Singapore). A. Green reported the action of RAR ligands to inhibit and/or potentiate osteoblastic differentiation from mesenchymal progenitor cells. C. Hogarth described retinoids’ action in spermatogenesis, and S. Sugii reported how RA contributes to depot specificity of adipose-derived stem cells. There were 49 posters presented in two poster sections. The organizers recognized 6 poster awardees, judged by an expert panel of 5 senior investigators. Each awardee was presented with a certificate of achievement, a gift, and a monetary prize. The young scientists who were recognized were as follows: Shawna Persaud (University of Minnesota), Marco-Antonio Mendoza-Parra (IGBMC– 1134
Vol. 29
April 2015
CERBM), Bomi Lee (University of Minnesota), Alanna Green (St. Vincent’s Institute), Robin Clugston (Columbia University), and Thais Acquafreda (Temple University). Finally, an additional new session to this conference was a “Meet the Expert” panel (E. Dmitrovsky, J. Napoli, L. Gudas, and H. Gronemeyer, presided over by P. Maruvada) held on the final day of the conference. The goal was to facilitate a forum and dialogue between senior and junior researchers and among academic, industrial, and clinical experts in order to engage junior researchers in an informal and interactive exchange on the subject of career development. The panelists first described their career paths and shared their perspectives on how they were able to build a productive career. This was followed by questions from the audience, and an open discussion was held on the skills needed to excel in independent scientific careers. All panelists emphasized the need for interdisciplinary collaborations. H. Gronemeyer discussed the need for open mindedness and skills from various fields. E. Dmitrovsky stressed the importance of pursuing the public interest in any career. L. Gudas discussed the importance of patience and maintaining the family and work life balance as critical factors in achieving success in a scientific career. J. Napoli emphasized research passion. Furthermore, critical qualities were identified, such as management, communication, and networking skills, as well as research integrity and honesty. This session concluded the 2014 FASEB SRC on Retinoids and provided a forum for active participation of junior investigators to learn about strategies for building independent research careers. Conference attendees of this meeting were struck by the genuine enthusiasm of investigators in the field for their continued work in this exciting field. A vote was cast by the meeting attendees in the business meeting to determine whether to continue this meeting series in the future, and it was unanimously and enthusiastically agreed to continue this meeting in the summer of 2016. That conference will be chaired by E. Dmitrovsky (MD Anderson) and cochaired by N. Kedishvili (University of Alabama). On a final note, it is important to emphasize the collaborative (both national and international) spirit of this conference that has provided a vital venue to connect the 2014 FASEB SRC on Retinoids and the 2nd International Retinoid Conference. As seen in many scientific disciplines, different biological and therapeutic topics have been showcased at each of these previous conferences. For retinoid research, after a few drug trials that did not meet their anticipated end points, interest in this field had waned. However, as reported in this meeting, it is clear that retinoids as therapeutic agents have gained intense interest especially in the areas of metabolism, immunology, and cancer biology. From a physiologic standpoint, it is now recognized that retinoids can also signal through noncanonical and nongenomic pathways. The conventional, “receptor-centered” view of retinoid action requires a re-evaluation. There is a broad interest in studying retinoids as a group of essential nutrients, hormones, and potential therapeutic agents. More work is needed especially at the basic and translational levels to understand and better use retinoids in biology and therapy. The 2014 FASEB SRC on retinoids stirred enthusiasm for the field. This fulfilled the major goal that was sought in organizing this meeting. That was to highlight the latest insights into basic retinoid biology that could be translated eventually into clinical benefits.
The FASEB Journal x www.fasebj.org
SRC COMMENTARY
The authors thank A. C. Ross, C. Rochette-Egly, N. Kedishvili, L. Quadro, S. Waxman, U. Hammerling, H. Gronemeyer, D. Soprano, M. Kane, and P. Maruvada for providing valuable meeting records. This work was supported by the U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grants R13DK102355, DK54733, DK60521, DK54733-11S, DK6052112S1, and DA001583 (to L.N.W.); the Dean’s Commitment
and the Distinguished McKnight University Professorship of the University of Minnesota; the NIH National Cancer Institute Grants R01-CA087546, R01-CA190722, and R01CA062275 (to E.D.); a Samuel Waxman Cancer Research Foundation award (to E.D.); by a UT-STARS award (to E.D.); and by an American Cancer Society Clinical Research Professorship provided by a generous gift from the F.M. Kirby Foundation (to E.D.).
The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to [email protected].
RETINOIDS ARE BACK
1135
Copyright of FASEB Journal is the property of Federation of American Society for Experimental Biology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Retinoids Are Back Li-Na Wei*,1 and Ethan Dmintrovsky† *Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota; and †Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, and Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Attendees of the FASEB Summer Research Conference, 2nd Annual Conference on Retinoids (June 1–6, 2014), Itasca, IL, USA.
IN JUNE 1–6, 2014, A GROUP of researchers, clinicians, and drug developers convened for the 2014 FASEB Scientific Research Conference (SRC) on Retinoids, jointly held with the 2nd International Retinoid Conference, in the Eaglewood resort of Itasca, IL, USA. In addition to continuing the longstanding tradition of FASEB SRC on Retinoids, which is to review, update, and project future research on basic biologic aspects of retinoids, this joint meeting incorporated several new and exciting developments in the field. This notably included use of retinoids in molecular therapeutics. After the meeting concluded, all of the participants agreed that studies of retinoids are relevant both scientifically and clinically. Retinoids are especially important in oncology, immunity, metabolism, and neurological disorders. As an innovation of this FASEB SRC on Retinoids, the meeting kicked off with a roundtable panel discussion consisting of 8 panelists—W. Blaner (Columbia University, New York, NY, USA), E. Dmitrovsky (MD Anderson Cancer Center, Houston, TX, USA), E. Harrison (Ohio State University, Columbus, OH, USA), J. Napoli (University of California–Berkeley, Berkeley, CA, USA), N. Noy (Case Western Reserve University, Cleveland, OH, USA), 0892-6638/15/0029-1131 © FASEB
C. Rochette-Egly (IGBMC, Illkirch Cedex, France), X.-K. Zhang (Xiamen University, Fujian, China), led by A. C. Ross (Penn State University, State College, PA, USA)— who provided their expert views on major questions that are intriguing to address. With regard to new retinoids, the leading retinoid X receptor (RXR) agonist (rexinoid) currently in the clinic is bexarotene (targretin), a U.S. Food & Drug Administration-approved retinoid for treating cutaneous T cell lymphoma. It is under clinical testing for a number of other applications. There are ample opportunities for further modifying retinoid structures to create novel compounds that may have greater activity or specificity, with lesser off-target effects than currently existing agents. Retinoids also have the potential in treating neurodegenerative disorders, including Alzheimer’s disease for which clinical trials are underway. With regard to signaling, there is still much to be learned concerning the architecture of 1
Correspondence: Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church St., S.E., Minneapolis, MN 55455. E-mail: [email protected] doi: 10.1096/fj.15-0402ufm
1131
receptor-DNA (chromatin) interactions, as well as noncanonical signaling pathways, which may involve receptor modification or other receptor-interacting proteins. Despite decades of research on vitamin A and retinoid metabolism, the panelists concurred that much still needs to be learned and that some basic premises require refinement if not substantial revision. A concern was raised that public health decisions may be made based on outdated understanding of retinoid metabolism. For instance, a long-known plasma transport protein, retinol-binding protein (RBP4), may play a role outside of delivering retinol to cells, and the RBP4 receptor, STRA6, may have functions beyond those described originally. There is also a need for a better understanding of how retinoids affect energy balance and adipogenesis and how they interact with fatty acids in terms of intracellular signaling. Attention was drawn to the possibility that human carotenoid metabolism may generate compounds that either are additional sources of vitamin A or that interact with the vitamin A metabolic or signaling systems. It is important to study the b-carotene cleavage enzymes BCO-1 and BCO-2, which catalyze central and eccentric b-carotene cleavage, and whether novel carotenoids (some known to be present in foods) are bioactive compounds in humans and other species. Finally, there is excitement in immunology concerning retinoids as important functional factors in the context of an appropriate cytokine environment for the differentiation of T regulatory cells, a T cell subset with immunosuppressive/ immunoregulatory properties. Retinoids also promote B cell development and the functions of antigen-presenting cells. In the future, there are possibilities for use of synthetic retinoids to promote an optimal balance of immune functions in the intestine, lung, and other organs. After the roundtable discussion, a total of 8 symposia were held: Retinoid/Carotenoid Signaling (receptor biology), chaired by X.-K. Zhang (Xiamen University); Retinoid Enzymology, chaired by N. Kedishvili (University of Alabama–Birmingham, Birmingham, AL, USA); Retinoid Metabolism, chaired by L. Quadro (Rutgers University, New Brunswick, NJ, USA); Translation-Oriented Symposium 1—Retinoids and Disease, chaired by E. Dmitrovsky (MD Anderson Cancer Center); Translation-Oriented Symposium 2—Immunity and Metabolic Disorders, chaired by U. Hammerling (Sloan-Kettering Institute for Cancer Research, New York, NY, USA); Translation-Oriented Symposium 3—Nervous System and Other Applications, chaired by S. Kojima (RIKEN, Saitama, Japan); Retinoid/ Carotenoid Chemical Biology and Therapeutics, chaired by H. Gronemeyer (IGBMC); and Retinoids in Development and Stem Cell Biology, chaired by D. Soprano (Temple University, Philadelphia, PA, USA). Two poster sections were held on the second and third days and were judged by a panel of experts led by M. Kane (University of Maryland, College Park, MD, USA). A business meeting was held on the fifth day to elect the next coorganizer, N. Kedishvili. After the 8 scientific symposia, on the final day, the conference recognized 6 poster awards and concluded with a new “Meet the Expert” panel, presided over by P. Maruvada [National Institute of Diabetes and Digestive and Kidney Diseases, U.S. National Institutes of Health (NIH), Bethesda, MD, USA], where academic, clinical, and industrial leaders provided their experience 1132
Vol. 29
April 2015
and recommendations for the next generation of scientists. The conclusions and discussions of these symposia and special sections are summarized. The symposium on Retinoid/Carotenoid Signaling was kicked off by C. Rochette-Egly (IGBMC). She described retinoic acid receptor (RAR) phosphorylation and its nongenomic effects, such as activating kinase cascades, and demonstrated that phosphorylation induces receptor’s conformational change to affect partner protein recruitment and DNA binding. E. Harrison (Ohio State University) reported oxidative cleavage of b-carotene and lycopene by two oxygenases (BCO1 and BCO2), forming apocarotenoids, and showed that these apocarotenoids act as antagonists of retinoid receptors via promoting the formation of transcriptionally silent RXR tetramers. X.-K. Zhang (Xiamen University) showed that abnormal cleavage of RXR in cancer cells produces an N-terminally truncated extranuclear protein that can promote cell growth and survival. His group found that nonsteroidal anti-inflammatory drugs, such as sulindac and its analogs, inhibit these effects via inducing tetramerization of truncated RXRa. These findings shed light on new strategies for RXR-based therapeutics. There were 3 additional short talks. D. Levesque (Universitaire sur le Medicament, Qu´ebec, QC, Canada) reported a new bioluminescence resonance energy transfer assay for ligands of the NuR/RXR dimer. H. Sakai (Gifu University, Gifu City, Japan) described aberrant phosphorylation of RXRa in liver carcinogenesis. L. Levi (Case Western Reserve University) showed that in certain cells retinoids can be delivered to peroxisome proliferator-activated receptor d via fatty acid binding protein 5 (FABP5) to promote cell growth and survival. This indicated cross-talk between these two important dietary components: long chain fatty acids and vitamin A. In the Retinoid Enzymology symposium, J. Napoli (University of California–Berkeley) reported that FoxO1 and all-trans-retinoic acid (ATRA) stimulate gluconeogenesis and that FoxO1 increases ATRA biosynthesis via inducing Rdh expression. Insulin suppresses FoxO1 activity, thereby suppressing gluconeogenesis and ATRA biosynthesis through decreasing Rdh1 and Rdh10 transcription and mRNA stability. These data suggest dysregulation of Rdh expression in diabetes. N. Kedishvili (University of Alabama–Birmingham) presented evidence for the mutually activating relationship among members of the short-chain dehydrogenase/reductase superfamily, retinol dehydrogenase 10 (RDH10) and retinaldehyde reductase DHRS3, and proposed a novel model for the regulation of retinoic acid biosynthesis through proteinprotein interactions between RDH10 and DHRS3. M. Kane (University of Maryland) reiterated the importance of quantifying retinoid metabolites and described current developments in chromatography and mass spectrometry-based analytical strategies to improve retinoid detection. Three short talks were given by N. Isoherranen (University of Washington, Seattle, WA, USA), T. Matsuura (Jikei University, Tokyo, Japan), and A. Moise (University of Kansas, Lawrence, KS, USA). N. Isoherranen presented evidence for substrate channeling between cellular retinoic acid binding proteins I and II (CRABPI/II) and CYP26B1. T. Matsuura showed that human stem cells express both lecithin retinol acyltransferase (LRAT) and cellular retinol-binding protein
The FASEB Journal x www.fasebj.org
SRC COMMENTARY
(CRBP) to store vitamin, which could contribute to the development of portal fibrogenesis in patients with viral hepatitis. A. Moise described developmental and biochemical defects associated with Dhrs3 deficiency in mice (which is consistent with Kedishvili group’s finding), supporting a critical role for Dhrs3 in retinoid metabolism. In the Retinoid Metabolism symposium, A. C. Ross (Penn State University) first addressed the issue of dietary retinoid distribution into various tissues, which depends on the vitamin A status, in a neonatal model. W. S. Blaner (Columbia University) focused on retinoid metabolism in adipose tissue in relation to the development of the metabolic syndrome. L. Quadro (Rutgers University) talked about b-carotene metabolism, the most abundant dietary vitamin A precursor, during mammalian embryogenesis, with a particular emphasis on the role played by the asymmetric cleavage pathway. N. Noy (Case Western Reserve University) discussed the role of Stra6 in cancer biology. Two short talks were presented by C. Breen and D. Martin (National University of Ireland–Maynooth, Kildare, Ireland). C. Breen described identification of STRA6-interacting proteins, and D. Martin presented structural insights into STRA6. There is a continuing and growing interest in understanding STRA6 biology. Translation-Oriented Symposium 1 focused on use of retinoids in cancer therapy and prevention. E. Dmitrovsky (MD Anderson Cancer Center) reported that rexinoids induce targeted cyclin D1 degradation. It was successfully used in treating non–small cell lung cancer in combination with an epidermal growth factor receptor, tyrosine kinase inhibitor such as erlotinib. S. Waxman (Mount Sinai Medical School, New York, NY, USA) reported that the ability to induce RARb1 and decrease RARg expression was associated with differentiation and loss of tumor stem cell markers in triple negative breast cancer cells. P. Brown (MD Anderson Cancer Center) showed that estrogen receptor-negative (ER2) breast cancer could be prevented by using a rexinoid alone or in combination with other nuclear hormone receptor ligands. This suggested that future clinical trials can be conducted with rexinoids alone or in combination with other drugs for the prevention of ER2 breast cancer. Two short talks were given by Y. Shirakami (Gifu University) and H. B. Everts (Ohio State University). Y. Shirakamik described a synthetic retinoid inhibiting diethylnitrosamineinduced liver tumor formation in obese and diabetic mice, and H. B. Everts discussed how short-term UV exposure could alter retinoid-metabolizing proteins in SKH-1 hairless mice. Taken together, these findings indicate the renewed and increased use of retinoids in treating cancers, especially in the treatment with receptor isoform-specific agonists and antagonists in combination with chemotherapy, epigenetic modifying agents, and specific components of signal transduction pathways. Future work should translate these preclinical findings into the clinic. Translation-Oriented Symposium 2 focused on immunity and metabolic diseases. R. Jones (Johns Hopkins University, Baltimore, MD, USA) highlighted the role of retinaldehyde dehydrogenase and ATRA for the determination of self-renewal versus differentiation of hematopoietic stem cells. L. Purton (University of Melbourne, Melbourne, Australia) discussed the regulation of the homeobox gene HOXA1 because it pertains to the myeolodysplastic syndrome. U. Hammerling (Sloan-Kettering Institute for RETINOIDS ARE BACK
Cancer Research) introduced a model of how energy homeostasis is maintained by vitamin A-dependent signaling via protein kinase Cd. Three short talks were presented by B. Lee (University of Minnesota, Minneapolis, MN, USA), D. Schwartz (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH), and E. Shabrova (Sloan-Kettering Institute for Cancer Research), respectively. B. Lee presented new findings on the synergistic or cooperative actions of ATRA and interleukin-4 on the regulation of the arginase 1 gene, particularly in the context of anti-inflammatory macrophage activation. D. Schwart discussed retinoid-mediated control of regulatory T cells via Foxp3-dependent and -independent mechanisms. E. Shabrova followed on Hammerling’s discussion about the dysregulation of protein kinase Cd signaling by the long-term oversupply of vitamin A, which can promote obesity and type 2 diabetes in mice. Translation-Oriented Symposium 3 focused on the nervous system and other applications. R. Chandraratna (Io Therapeutics Inc., Santa Ana, CA, USA) presented work on IRX4204, a second-generation, highly selective panRXR agonist, and proposed that this drug will not have clinically adverse events related to RAR activation. In addition, IRX4204 proved to be effective in reversing pathologic Th17/Treg cell imbalance, reducing myeloid dendritic cells and CD4+ T cells to protect against multiple sclerosis, by promoting remyelination. S. W. Park (University of Minnesota) discussed retinoid-triggered epigenetic control of the family of opioid receptor genes during neuronal differentiation and maturation. It is noteworthy that all of these neuronal genes did not contain retinoic acid-responsive elements. Retinoid-triggered epigenetic control mechanisms appear to involve specific chromatin remodelers and highly orchestrated genomic and nongenomic actions of retinoid-elicited signaling molecules. S. Kojima (RIKEN) presented evidence for genomic and nongenomic actions of acyclic retinoid (ACR), a chemoprevention drug undergoing phases 2 and 3 trials to reduce liver cancer. ACR selectively kills hepatocellular carcinoma and its progenitor cells through both caspase- and transglutaminase-dependent pathways. ACR also inhibits angiogenesis via inhibiting phosphorylation of vascular endothelial growth factor receptor 2 and mitogen-activated protein kinases (MAPKs). Three short talks were presented by M. M. Holley (Case Western Reserve University), Robin D. Clugston (Columbia University), and Philip T. Liu (UCLA, Los Angeles, CA, USA), respectively. M. Holley presented evidence that bexarotene improves cognitive function by reducing intraneuronal amyloid precursor protein/amyloid. R. D. Clugston discussed how long-term alcohol consumption alters retinoid homeostasis in intrascapular brown adipose tissue and how this in turn impairs thermogenesis. P. T. Liu examined the therapeutic effects of retinoids against Mycobacterium tuberculosis, which depend on Niemann-Pick disease type C2 (NPC2). The symposium on Retinoid/Carotenoid Chemical Biology and Therapeutics presented evidence for the development and chemical synthesis of multiple novel types of retinoids and their application to systems biology-based approaches. H. Kagechika (Tokyo Medical and Dental University, Tokyo, Japan) reminded the audience that the RARa-selective agonist AM80 was approved in Japan in 2005 for treating patients who have relapsed with acute promyelocytic leukemia and reported the synthesis of 1133
new retinoids with novel substitutions in the hydrophobic domain of the ligand and of carborane-based retinoids, with potent RAR and RXR activities. K. Zhang (Tarrex Biopharema, Xiamen, China) reported on TX803, a ligand targeting the truncated RXR, originally described by X.-K. Zhang (Sanford-Burnham Medical Research Institute, La Jolla, CA, USA), and discussed nongenomic activity of truncated RXR. H. Gronemeyer (IGBMC) elucidated studies of complex system biology analysis of ATRA and RAR isoform-selective synthetic retinoids using an integrated approach to define the temporal patterns of RAR-RXR heterodimer binding to chromatin and corresponding changes in the epigenome. In comparing natural and synthetic retinoids, it was noted that none of the examined synthetic retinoids was able to exert the full spectrum of gene regulation elicited by the natural ligand ATRA. Four short presentations were given by X.-Y. Qin (RIKEN), M, Ishigami-Yuasa (Tokyo Medical and Dental University), B. C. Das (University of Kansas Medical Center), and Marco Mendoza-Parra (IGBMC), respectively. Qin reported on novel acyclic retinoids and vitamin K2 derivatives in inhibiting hepatocellular carcinoma, and Ishigami-Yuasa reported on a new class of store-operated calcium entry inhibitors that have retinoidlike structures. B. C. Das reported synthesis and application of boron-containing retinoids for treating brain cancers. M. Mendoza-Parra followed on Gronemeyer’s presentation to describe a novel bioinformatics-based tool for the quality control of ChIP-seq data sets and provided information on a freely available Next Generation Sequencing Quality Control (NGS-QC) Generator that can be used to define the quality indicators of ChIP-seq data sets (www.ngs-qc.org). The symposium on Retinoids in Development and Stem Cell Biology discussed the molecular mechanism of action of retinoids during the differentiation of specific types of stem cells and tumor cells. L. Gudas (Weill-Cornell University Medical School, New York, NY, USA) described epigenetic changes associated with the binding of different histone deacetylases to regulatory elements in retinoid-responsive genes during the differentiation of embryonic stem cells. A. Yen summarized a novel retinoid-dependent pathway involving hyperactive MAPK signaling that leads to nuclear translocation of Raf that phosphorylates transcription factors. D. Soprano (Temple University) discussed a retinoiddependent coupling of transcription and RNA splicing of weak 59-splice sites in RNAs transcribed from retinoic acidresponsive elements-containing genes by the serine-argininerich (SR)-related protein acinus. Three short talks were presented in turn by A. C. Green (St. Vincent’s Institute, Melbourne, Australia), C. Hogarth (Washington State University, Spokane, WA, USA), and S. Sugii (Duke-NUS Medical School, Singapore, Singapore). A. Green reported the action of RAR ligands to inhibit and/or potentiate osteoblastic differentiation from mesenchymal progenitor cells. C. Hogarth described retinoids’ action in spermatogenesis, and S. Sugii reported how RA contributes to depot specificity of adipose-derived stem cells. There were 49 posters presented in two poster sections. The organizers recognized 6 poster awardees, judged by an expert panel of 5 senior investigators. Each awardee was presented with a certificate of achievement, a gift, and a monetary prize. The young scientists who were recognized were as follows: Shawna Persaud (University of Minnesota), Marco-Antonio Mendoza-Parra (IGBMC– 1134
Vol. 29
April 2015
CERBM), Bomi Lee (University of Minnesota), Alanna Green (St. Vincent’s Institute), Robin Clugston (Columbia University), and Thais Acquafreda (Temple University). Finally, an additional new session to this conference was a “Meet the Expert” panel (E. Dmitrovsky, J. Napoli, L. Gudas, and H. Gronemeyer, presided over by P. Maruvada) held on the final day of the conference. The goal was to facilitate a forum and dialogue between senior and junior researchers and among academic, industrial, and clinical experts in order to engage junior researchers in an informal and interactive exchange on the subject of career development. The panelists first described their career paths and shared their perspectives on how they were able to build a productive career. This was followed by questions from the audience, and an open discussion was held on the skills needed to excel in independent scientific careers. All panelists emphasized the need for interdisciplinary collaborations. H. Gronemeyer discussed the need for open mindedness and skills from various fields. E. Dmitrovsky stressed the importance of pursuing the public interest in any career. L. Gudas discussed the importance of patience and maintaining the family and work life balance as critical factors in achieving success in a scientific career. J. Napoli emphasized research passion. Furthermore, critical qualities were identified, such as management, communication, and networking skills, as well as research integrity and honesty. This session concluded the 2014 FASEB SRC on Retinoids and provided a forum for active participation of junior investigators to learn about strategies for building independent research careers. Conference attendees of this meeting were struck by the genuine enthusiasm of investigators in the field for their continued work in this exciting field. A vote was cast by the meeting attendees in the business meeting to determine whether to continue this meeting series in the future, and it was unanimously and enthusiastically agreed to continue this meeting in the summer of 2016. That conference will be chaired by E. Dmitrovsky (MD Anderson) and cochaired by N. Kedishvili (University of Alabama). On a final note, it is important to emphasize the collaborative (both national and international) spirit of this conference that has provided a vital venue to connect the 2014 FASEB SRC on Retinoids and the 2nd International Retinoid Conference. As seen in many scientific disciplines, different biological and therapeutic topics have been showcased at each of these previous conferences. For retinoid research, after a few drug trials that did not meet their anticipated end points, interest in this field had waned. However, as reported in this meeting, it is clear that retinoids as therapeutic agents have gained intense interest especially in the areas of metabolism, immunology, and cancer biology. From a physiologic standpoint, it is now recognized that retinoids can also signal through noncanonical and nongenomic pathways. The conventional, “receptor-centered” view of retinoid action requires a re-evaluation. There is a broad interest in studying retinoids as a group of essential nutrients, hormones, and potential therapeutic agents. More work is needed especially at the basic and translational levels to understand and better use retinoids in biology and therapy. The 2014 FASEB SRC on retinoids stirred enthusiasm for the field. This fulfilled the major goal that was sought in organizing this meeting. That was to highlight the latest insights into basic retinoid biology that could be translated eventually into clinical benefits.
The FASEB Journal x www.fasebj.org
SRC COMMENTARY
The authors thank A. C. Ross, C. Rochette-Egly, N. Kedishvili, L. Quadro, S. Waxman, U. Hammerling, H. Gronemeyer, D. Soprano, M. Kane, and P. Maruvada for providing valuable meeting records. This work was supported by the U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grants R13DK102355, DK54733, DK60521, DK54733-11S, DK6052112S1, and DA001583 (to L.N.W.); the Dean’s Commitment
and the Distinguished McKnight University Professorship of the University of Minnesota; the NIH National Cancer Institute Grants R01-CA087546, R01-CA190722, and R01CA062275 (to E.D.); a Samuel Waxman Cancer Research Foundation award (to E.D.); by a UT-STARS award (to E.D.); and by an American Cancer Society Clinical Research Professorship provided by a generous gift from the F.M. Kirby Foundation (to E.D.).
The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to [email protected].
RETINOIDS ARE BACK
1135
Copyright of FASEB Journal is the property of Federation of American Society for Experimental Biology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
