G Model
ARTICLE IN PRESS
DNAREP-1949; No. of Pages 2
DNA Repair xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
DNA Repair journal homepage: www.elsevier.com/locate/dnarepair
Letter to the Editor
The hMTH1 paradox: mended in cancer?
Antioxidants
recom-
Human mutT homologue protein hMTH1 (also known as NUDT1) plays an important role in protecting cells against oxidative-stress-induced DNA damage [1]. Two papers recently published elegantly highlight the important role played by hMTH1 in the biology of cancer [2,3]. Elevated levels of reactive oxygen species (ROS) may cause oxidative damage to DNA, either directly or by oxidizing free bases in the cell and mitochondrial deoxynucleoside triphosphate (dNTP) pool. To offset oxidative damage to nucleic acids, cells are equipped with antioxidant enzymes like hMTH1. This protein is able to eliminate oxidized dNTPs before they can be incorporated into DNA, i.e., by converting these molecules into their monophosphate forms. Because the dNTP pool is a critical target of intracellular ROS and because oxidized dNTP nucleotides, unless continuously eliminated, can rapidly induce cell senescence, hMTH1 is needed to prevent this process and thus has important implications in aging [4]. The results of these two mentioned papers [2,3], however, provide support for an apparently different role of this protein in cancer as a serious disease associated with the human aging process. Despite the antioxidant role of this enzyme, hMTH1 inhibition eradicates cancer by preventing clean-up of the dNTP pool, thereby avoiding the incorporation of oxidized nucleotides into DNA, a process that could provoke mutations and cell death [5,6]. Many people take antioxidant vitamins based on the strong belief that their antioxidant properties, among other health benefits, will prevent cancer onset and/or spread [7]. Paradoxically, the results of the two papers on hMTH1 [2,3], as well as those of clinical trials, rather indicate the opposite: that antioxidants might actually increase the risk of some forms of cancer [8,9]. Despite mitigating oxidative stress and consequently DNA damage, these compounds have been observed to decrease the expression of the key tumor suppressor protein p53, accelerating lung cancer progression in mice [10]. In addition, the dual role of p38 mitogenactivated protein kinase-␣ (p38␣) in colon cancer has been recently revealed [11]. This kinase, which is activated by oxidative stress and inflammation, suppresses inflammation-associated epithelial damage and tumor development, but once the disease is established, it causes the proliferation and survival of tumor cells adding to the disease burden [11]. While the cancer-preventing benefits of ingesting antioxidants are still under scrutiny, the discovery of the role of hMHT1 inhibition in cancer suppression has two important implications, apart from the obvious potential of this enzyme as a candidate target for new anti-cancer drugs. First, it could provide insight into the way in which antioxidants act in cancer prevention/development and thus offer a scientific rationale for adequate lifestyle interventions
against this disease, especially with regard to dietary habits and the intake of vitamins or other supplements. And second, it could unveil the mechanisms underlying interplay between aging and cancer development, by resolving the apparent paradox that inhibition of an anti-oxidant enzyme suppresses tumorigenesis, when DNA damage is in fact a hallmark of the aging process [12]. Conflicts of interest The authors declare no conflicts of interest. References [1] C.K. Youn, J.Y. Jun, J.W. Hyun, G. Hwang, B.R. Lee, M.H. Chung, I.Y. Chang, H.J. You, hMTH1 depletion promotes oxidative-stress-induced apoptosis through a Noxa- and caspase-3/7-mediated signaling pathway, DNA Repair (Amst) 7 (2008) 1809–1823. [2] H. Gad, T. Koolmeister, A.S. Jemth, S. Eshtad, S.A. Jacques, C.E. Strom, L.M. Svensson, N. Schultz, T. Lundback, B.O. Einarsdottir, A. Saleh, C. Gokturk, P. Baranczewski, R. Svensson, R.P. Berntsson, R. Gustafsson, K. Stromberg, K. Sanjiv, M.C. Jacques-Cordonnier, M. Desroses, A.L. Gustavsson, R. Olofsson, F. Johansson, E.J. Homan, O. Loseva, L. Brautigam, L. Johansson, A. Hoglund, A. Hagenkort, T. Pham, M. Altun, F.Z. Gaugaz, S. Vikingsson, B. Evers, M. Henriksson, K.S. Vallin, O.A. Wallner, L.G. Hammarstrom, E. Wiita, I. Almlof, C. Kalderen, H. Axelsson, T. Djureinovic, J.C. Puigvert, M. Haggblad, F. Jeppsson, U. Martens, C. Lundin, B. Lundgren, I. Granelli, A.J. Jensen, P. Artursson, J.A. Nilsson, P. Stenmark, M. Scobie, U.W. Berglund, T. Helleday, MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool, Nature (2014). [3] K.V. Huber, E. Salah, B. Radic, M. Gridling, J.M. Elkins, A. Stukalov, A.S. Jemth, C. Gokturk, K. Sanjiv, K. Stromberg, T. Pham, U.W. Berglund, J. Colinge, K.L. Bennett, J.I. Loizou, T. Helleday, S. Knapp, G. Superti-Furga, Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy, Nature (2014). [4] P. Rai, T.T. Onder, J.J. Young, J.L. McFaline, B. Pang, P.C. Dedon, R.A. Weinberg, Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence, Proc. Natl. Acad. Sci. U.S.A. 106 (2009) 169–174. [5] S. Oka, M. Ohno, D. Tsuchimoto, K. Sakumi, M. Furuichi, Y. Nakabeppu, Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs, EMBO J. 27 (2008) 421–432. [6] J. Ichikawa, D. Tsuchimoto, S. Oka, M. Ohno, M. Furuichi, K. Sakumi, Y. Nakabeppu, Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death, DNA Repair (Amst) 7 (2008) 418–430. [7] J. Kaiser, Biomedical research. Antioxidants could spur tumors by acting on cancer gene, Science 343 (2014) 477. [8] G.M. DeNicola, F.A. Karreth, T.J. Humpton, A. Gopinathan, C. Wei, K. Frese, D. Mangal, K.H. Yu, C.J. Yeo, E.S. Calhoun, F. Scrimieri, J.M. Winter, R.H. Hruban, C. Iacobuzio-Donahue, S.E. Kern, I.A. Blair, D.A. Tuveson, Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis, Nature 475 (2011) 106–109. [9] R.M. Perera, N. Bardeesy, Cancer: when antioxidants are bad, Nature 475 (2011) 43–44. [10] V.I. Sayin, M.X. Ibrahim, E. Larsson, J.A. Nilsson, P. Lindahl, M.O. Bergo, Antioxidants accelerate lung cancer progression in mice, Sci. Transl. Med. 6 (2014), 221ra215. [11] J. Gupta, I. Del Barco Barrantes, A. Igea, S. Sakellariou, I.S. Pateras, V.G. Gorgoulis, A.R. Nebreda, Dual Function of p38alpha MAPK in colon cancer: suppression of colitis-associated tumor initiation but requirement for cancer cell survival, Cancer Cell (2014). [12] C. Lopez-Otin, M.A. Blasco, L. Partridge, M. Serrano, G. Kroemer, The hallmarks of aging, Cell 153 (2013) 1194–1217.
http://dx.doi.org/10.1016/j.dnarep.2014.04.010 1568-7864/© 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: F. Sanchis-Gomar, et al., The hMTH1 paradox: Antioxidants recommended in cancer? DNA Repair (2014), http://dx.doi.org/10.1016/j.dnarep.2014.04.010
G Model DNAREP-1949; No. of Pages 2 2
ARTICLE IN PRESS Letter to the Editor / DNA Repair xxx (2014) xxx–xxx
Fabian Sanchis-Gomar ∗ Helios Pareja-Galeano Department of Physiology, Faculty of Medicine, University of Valencia, Fundación Investigación Hospital Clínico Universitario/INCLIVA. Av. Blasco Iba˜ nez 15, Valencia 46010, Spain Alejandro Lucía Universidad Europea and Research Institute of Hospital 12 de Octubre (‘i+12 ), C/Tajo S/N, Urbanización El Bosque, 28670 Villaviciosa de Odón, Madrid, Spain
∗ Corresponding author. E-mail addresses: [email protected] (F. Sanchis-Gomar), [email protected] (H. Pareja-Galeano), [email protected] (A. Lucía).
17 April 2014 Available online xxx
Please cite this article in press as: F. Sanchis-Gomar, et al., The hMTH1 paradox: Antioxidants recommended in cancer? DNA Repair (2014), http://dx.doi.org/10.1016/j.dnarep.2014.04.010
ARTICLE IN PRESS
DNAREP-1949; No. of Pages 2
DNA Repair xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
DNA Repair journal homepage: www.elsevier.com/locate/dnarepair
Letter to the Editor
The hMTH1 paradox: mended in cancer?
Antioxidants
recom-
Human mutT homologue protein hMTH1 (also known as NUDT1) plays an important role in protecting cells against oxidative-stress-induced DNA damage [1]. Two papers recently published elegantly highlight the important role played by hMTH1 in the biology of cancer [2,3]. Elevated levels of reactive oxygen species (ROS) may cause oxidative damage to DNA, either directly or by oxidizing free bases in the cell and mitochondrial deoxynucleoside triphosphate (dNTP) pool. To offset oxidative damage to nucleic acids, cells are equipped with antioxidant enzymes like hMTH1. This protein is able to eliminate oxidized dNTPs before they can be incorporated into DNA, i.e., by converting these molecules into their monophosphate forms. Because the dNTP pool is a critical target of intracellular ROS and because oxidized dNTP nucleotides, unless continuously eliminated, can rapidly induce cell senescence, hMTH1 is needed to prevent this process and thus has important implications in aging [4]. The results of these two mentioned papers [2,3], however, provide support for an apparently different role of this protein in cancer as a serious disease associated with the human aging process. Despite the antioxidant role of this enzyme, hMTH1 inhibition eradicates cancer by preventing clean-up of the dNTP pool, thereby avoiding the incorporation of oxidized nucleotides into DNA, a process that could provoke mutations and cell death [5,6]. Many people take antioxidant vitamins based on the strong belief that their antioxidant properties, among other health benefits, will prevent cancer onset and/or spread [7]. Paradoxically, the results of the two papers on hMTH1 [2,3], as well as those of clinical trials, rather indicate the opposite: that antioxidants might actually increase the risk of some forms of cancer [8,9]. Despite mitigating oxidative stress and consequently DNA damage, these compounds have been observed to decrease the expression of the key tumor suppressor protein p53, accelerating lung cancer progression in mice [10]. In addition, the dual role of p38 mitogenactivated protein kinase-␣ (p38␣) in colon cancer has been recently revealed [11]. This kinase, which is activated by oxidative stress and inflammation, suppresses inflammation-associated epithelial damage and tumor development, but once the disease is established, it causes the proliferation and survival of tumor cells adding to the disease burden [11]. While the cancer-preventing benefits of ingesting antioxidants are still under scrutiny, the discovery of the role of hMHT1 inhibition in cancer suppression has two important implications, apart from the obvious potential of this enzyme as a candidate target for new anti-cancer drugs. First, it could provide insight into the way in which antioxidants act in cancer prevention/development and thus offer a scientific rationale for adequate lifestyle interventions
against this disease, especially with regard to dietary habits and the intake of vitamins or other supplements. And second, it could unveil the mechanisms underlying interplay between aging and cancer development, by resolving the apparent paradox that inhibition of an anti-oxidant enzyme suppresses tumorigenesis, when DNA damage is in fact a hallmark of the aging process [12]. Conflicts of interest The authors declare no conflicts of interest. References [1] C.K. Youn, J.Y. Jun, J.W. Hyun, G. Hwang, B.R. Lee, M.H. Chung, I.Y. Chang, H.J. You, hMTH1 depletion promotes oxidative-stress-induced apoptosis through a Noxa- and caspase-3/7-mediated signaling pathway, DNA Repair (Amst) 7 (2008) 1809–1823. [2] H. Gad, T. Koolmeister, A.S. Jemth, S. Eshtad, S.A. Jacques, C.E. Strom, L.M. Svensson, N. Schultz, T. Lundback, B.O. Einarsdottir, A. Saleh, C. Gokturk, P. Baranczewski, R. Svensson, R.P. Berntsson, R. Gustafsson, K. Stromberg, K. Sanjiv, M.C. Jacques-Cordonnier, M. Desroses, A.L. Gustavsson, R. Olofsson, F. Johansson, E.J. Homan, O. Loseva, L. Brautigam, L. Johansson, A. Hoglund, A. Hagenkort, T. Pham, M. Altun, F.Z. Gaugaz, S. Vikingsson, B. Evers, M. Henriksson, K.S. Vallin, O.A. Wallner, L.G. Hammarstrom, E. Wiita, I. Almlof, C. Kalderen, H. Axelsson, T. Djureinovic, J.C. Puigvert, M. Haggblad, F. Jeppsson, U. Martens, C. Lundin, B. Lundgren, I. Granelli, A.J. Jensen, P. Artursson, J.A. Nilsson, P. Stenmark, M. Scobie, U.W. Berglund, T. Helleday, MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool, Nature (2014). [3] K.V. Huber, E. Salah, B. Radic, M. Gridling, J.M. Elkins, A. Stukalov, A.S. Jemth, C. Gokturk, K. Sanjiv, K. Stromberg, T. Pham, U.W. Berglund, J. Colinge, K.L. Bennett, J.I. Loizou, T. Helleday, S. Knapp, G. Superti-Furga, Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy, Nature (2014). [4] P. Rai, T.T. Onder, J.J. Young, J.L. McFaline, B. Pang, P.C. Dedon, R.A. Weinberg, Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence, Proc. Natl. Acad. Sci. U.S.A. 106 (2009) 169–174. [5] S. Oka, M. Ohno, D. Tsuchimoto, K. Sakumi, M. Furuichi, Y. Nakabeppu, Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs, EMBO J. 27 (2008) 421–432. [6] J. Ichikawa, D. Tsuchimoto, S. Oka, M. Ohno, M. Furuichi, K. Sakumi, Y. Nakabeppu, Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death, DNA Repair (Amst) 7 (2008) 418–430. [7] J. Kaiser, Biomedical research. Antioxidants could spur tumors by acting on cancer gene, Science 343 (2014) 477. [8] G.M. DeNicola, F.A. Karreth, T.J. Humpton, A. Gopinathan, C. Wei, K. Frese, D. Mangal, K.H. Yu, C.J. Yeo, E.S. Calhoun, F. Scrimieri, J.M. Winter, R.H. Hruban, C. Iacobuzio-Donahue, S.E. Kern, I.A. Blair, D.A. Tuveson, Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis, Nature 475 (2011) 106–109. [9] R.M. Perera, N. Bardeesy, Cancer: when antioxidants are bad, Nature 475 (2011) 43–44. [10] V.I. Sayin, M.X. Ibrahim, E. Larsson, J.A. Nilsson, P. Lindahl, M.O. Bergo, Antioxidants accelerate lung cancer progression in mice, Sci. Transl. Med. 6 (2014), 221ra215. [11] J. Gupta, I. Del Barco Barrantes, A. Igea, S. Sakellariou, I.S. Pateras, V.G. Gorgoulis, A.R. Nebreda, Dual Function of p38alpha MAPK in colon cancer: suppression of colitis-associated tumor initiation but requirement for cancer cell survival, Cancer Cell (2014). [12] C. Lopez-Otin, M.A. Blasco, L. Partridge, M. Serrano, G. Kroemer, The hallmarks of aging, Cell 153 (2013) 1194–1217.
http://dx.doi.org/10.1016/j.dnarep.2014.04.010 1568-7864/© 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: F. Sanchis-Gomar, et al., The hMTH1 paradox: Antioxidants recommended in cancer? DNA Repair (2014), http://dx.doi.org/10.1016/j.dnarep.2014.04.010
G Model DNAREP-1949; No. of Pages 2 2
ARTICLE IN PRESS Letter to the Editor / DNA Repair xxx (2014) xxx–xxx
Fabian Sanchis-Gomar ∗ Helios Pareja-Galeano Department of Physiology, Faculty of Medicine, University of Valencia, Fundación Investigación Hospital Clínico Universitario/INCLIVA. Av. Blasco Iba˜ nez 15, Valencia 46010, Spain Alejandro Lucía Universidad Europea and Research Institute of Hospital 12 de Octubre (‘i+12 ), C/Tajo S/N, Urbanización El Bosque, 28670 Villaviciosa de Odón, Madrid, Spain
∗ Corresponding author. E-mail addresses: [email protected] (F. Sanchis-Gomar), [email protected] (H. Pareja-Galeano), [email protected] (A. Lucía).
17 April 2014 Available online xxx
Please cite this article in press as: F. Sanchis-Gomar, et al., The hMTH1 paradox: Antioxidants recommended in cancer? DNA Repair (2014), http://dx.doi.org/10.1016/j.dnarep.2014.04.010
