G Model

ARTICLE IN PRESS

YSCBI 1186 1–6

Seminars in Cancer Biology xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer

Review

1

ER stress and hexosamine pathway during tumourigenesis: A pas de deux?

2

3

4

Q1

Sophie Vasseur a,b,c,d , Serge N. Manié e,f,g,∗

5

Q2

a

INSERM U1068, Centre de Recherche en Cancérologie de Marseille, France Institut Paoli-Calmettes, France CNRS, UMR7258, F-13009 Marseille, France d Université Aix-Marseille, F-13284 Marseille, France e INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France f Université de Lyon, Université Lyon 1, F-69000 Lyon, France g Centre Léon Bérard, F-69008 Lyon, France b

6

c

7 8 9 10 11 12

13 20

a r t i c l e

i n f o

a b s t r a c t

14

19

Keywords: UPR Nutrient shortage Metabolism HBP

21

1. Introduction

15 16 17 18

Both the hexosamine biosynthetic pathway (HBP) and the endoplasmic reticulum (ER) are considered sensors for the nutritional state of the cell. The former is a branch of the glucose metabolic pathway that provides donor molecules for glycosylation processes, whereas the second requires co-translational N-glycosylation to ensure proper protein folding. It has become clear that the microenvironment of solid tumours, characterised by poor oxygen and nutrient supply, challenges optimal functions of the ER and the HBP. Here, we review recent advances demonstrating that the ER stress (ERS) response and HBP pathways are interconnected to promote cell viability. We then develop the idea that communication between ER and HBP is a survival feature of neoplastic cells that plays a prominent role during tumourigenesis. © 2015 Published by Elsevier Ltd.

Q3 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

Over the past decade, the study of metabolism has been the subject of renewed interest at the forefront of cancer research [1]. Not only do malignant cells boost their metabolism, including a higher avidity for glucose and glutamine in order to meet the necessary nutrients needs for biomass synthesis and abnormal proliferation, but the notion of a tumourigenic role for metabolic reprogramming has also started to be appreciated [2,3]. However, enhanced utilisation of nutrient metabolism often exceeds the capacity of the vascular bed. In addition to this is added a strong desmoplastic reaction within the tumour, i.e. the growth of fibrous or connective tissue, which further limits proper vascularisation/oxygenation of malignant cells. Consequently, solid tumours eventually experience decreased access to nutrients and oxygen. How cells survive periods of potentially lethal metabolic and hypoxic stress remains a critical and unanswered question in the progression of cancer therapies [4].

∗ Corresponding author at: Cancer Research Center of Lyon, Inserm UMR 1052 CNRS 5286, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon, France. Tel.: +33 04 69 16 66 21; fax: +33 04 69 16 66 60. E-mail address: [email protected] (S.N. Manié).

A major consequence of transformation-associated glucose shortage or hypoxia is the disruption of ER homeostasis, resulting in ER stress (ERS) [5–7]. The ER can therefore be viewed as a sensor of the nutritional fluctuations in the cellular microenvironment. ER homeostasis disruption activates an integrated signal transduction pathway termed the unfolded protein response (UPR), mediated by three ER transmembrane sensors: IRE1␣ (inositol requiring enzyme 1␣), PERK (PKR-like endoplasmic reticulum kinase), and ATF6␣ (activating transcription factor 6␣) (Fig. 1; reviewed in [8]). UPR induces global changes in gene expression to restore ER homeostasis and can trigger apoptosis when ERS cannot be alleviated. Chronic UPR activation is well documented in tumourigenesis and the emerging view is that UPR signalling is neither fully tumour supporting nor tumour suppressive (Fig. 1; reviewed in [9]). For example, increased expression of the pro-apoptotic transcription factor CHOP that is controlled largely by the PERK pathway, represses tumour initiation in mouse models of lung cancer [6] and hepatocellular carcinoma [10]. On the other hand, the PERK pathway can also promote c-Myc-induced transformation [11] or tumour cell survival during hypoxia [12] through the up-regulation of autophagy-related genes. The control of this dual function of the PERK pathway may depend on the intensity of the ERS or on the cellular context that integrates different survival or death signalling pathways. Alternatively, the UPR outcome may depend on the developmental stage of the tumour, since the tumour-suppressive

http://dx.doi.org/10.1016/j.semcancer.2015.04.001 1044-579X/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: Vasseur S, Manié SN. ER stress and hexosamine pathway during tumourigenesis: A pas de deux? Semin Cancer Biol (2015), http://dx.doi.org/10.1016/j.semcancer.2015.04.001

38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

G Model YSCBI 1186 1–6 2

ARTICLE IN PRESS S. Vasseur, S.N. Manié / Seminars in Cancer Biology xxx (2015) xxx–xxx

Fig. 1. The ERS in cancer. Both intrinsic factors triggered by oncogenic signalling and extrinsic factors triggered by the tumour microenvironment can induce a chronic ER stress (ERS). In response to ERS, the three unfolded protein response (UPR) transducers, IRE1␣, ATF6 ␣ and PERK, are activated. Depending on the modulation of UPR signalling integration by factors including UPR intensity, cellular context or the developmental stage of tumours, the UPR signalling outcome can exert either protective or deleterious effects on malignant cell survival. Recent findings suggest that UPR signalling may function as a “double-edged sword” by repressing cancer initiation and supporting more advanced cancer cells that thrive in a stressful environment.

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92

role of CHOP [6,10] strongly suggests that premalignant cells need to suppress UPR-induced apoptosis to overcome an early ERS barrier to malignancy. In this later scenario, only premalignant cells that have successfully adapted to chronic ERS can benefit from the protective features of UPR and will contribute to tumour progression. The hexosamine biosynthetic pathway (HBP) is considered another sensor for the nutritional state of the cell, as this metabolic pathway integrates glucose, the amino acid glutamine, fatty acids and uridine [13]. Approximately 2–3% of the total glucose that enters the cell is used to fuel this pathway that provides UDPN-acetylglucosamine (UDP-GlcNAc), the monosaccharide donor molecules for O-GlcNAcylation or N-glycosylation (Fig. 2). The latter is necessary for ER homeostasis and aids in tertiary structure adoption and protein sorting to achieve proper protein folding in the ER [14]. These post-translational modifications linked to Asn- or Ser/Thr residues of proteins, are often strongly activated in tumour cells. In particular, aberrant glycosylation of glycosphingolipids and glycoproteins expressed in tumour cells has been implicated as one of the essential mechanisms in malignant transformation and metastatic dissemination [15,16]. Similarly, elevated O-GlcNAcylation that stabilises the expression of certain oncogenes has been described in various cancers (reviewed in [17]). Hence, oncogenic and metastatic features of tumour cells seem to be dependent on the stimulation of HBP. However, the mechanism by which O-GlcNAcylation and N-glycosylation becomes stimulated in cancer cells has not been well defined. In pancreatic tumours, it is known to result from elevated levels of certain HBP enzymes such as glutamine:fructose-6P aminotransferase (GFPT), which catalyses the first committed step of HBP [18,19].

Within the harsh tumour microenvironment, optimal functions of both the ER and the HBP are challenged by unreliable and limited supply of nutrients and oxygen. Interestingly, HBP and UPR appear to be functionally linked, with HBP recently shown to be directly activated by the UPR and the HBP in turn providing protective mechanisms upon ERS [20,21]. In this review, we argue that the malignant process pulls ERS and HBP into a dance duet necessary to sustain tumourigenesis. 2. HBP flux limitation triggers ERS The reduced availability of oxygen, glucose and glutamine in the tumoural microenvironment can affect ER homeostasis by interfering directly or indirectly with the production of UDP-GlcNAc, the HBP end product. Glucose is transferred into cells by glucose transporters where it fuels three pathways: the pentose phosphate pathway (PPP), the glycolytic pathway and the HBP. Although early studies demonstrated that glucose deprivation can lead to UPR activation [22], it was unclear which of the three glucose-utilizing pathways was primarily responsible for ERS activation during glucose shortage. A chief role for PPP was possible since PPP-dependent production of NADPH maintains the cellular redox potential of the ER lumen, which is necessary for proper protein folding [23]. Similarly, glycolysis was a very strong contender as productive protein folding requires extensive ATP production that is generated in large part through the glycolytic pathway [24]. It is only recently that the shortage of glucose in HBP fuelling was conclusively demonstrated to be primarily responsible for triggering ERS. Nascent polypeptide chains entering the ER require UDP-GlcNAc for N-linked

Please cite this article in press as: Vasseur S, Manié SN. ER stress and hexosamine pathway during tumourigenesis: A pas de deux? Semin Cancer Biol (2015), http://dx.doi.org/10.1016/j.semcancer.2015.04.001

93 94 95 96 97 98 99 100

101

102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120

G Model YSCBI 1186 1–6

ARTICLE IN PRESS S. Vasseur, S.N. Manié / Seminars in Cancer Biology xxx (2015) xxx–xxx

3

Fig. 2. The hexosamine biosynthetic pathway (HBP). Upon entering the cell, glucose is rapidly phosphorylated and then isomerised to fructose 6-P. Approximately 2–5% of fructose 6-P is diverted to HBP by GFPT that catalyses the formation of glucosamine 6-P with glutamine as an amine donor. Subsequent modifications of HBP metabolites link lipid and nucleotide metabolism with HBP. UDP-N-acetylglucosamine (UDP-GlcNAc) is the major end product of HBP. Exogenous or endogenous GlcNAc can provide an alternative source of UDP-GlcNAc. UDP-GlcNAc is the common donor molecule for N-glycan branching in the ER or the Golgi and for O-GlucNAcylation in the cytoplasm.

121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157

glycosylation, which is required for the correct tertiary structure adoption of proteins. It is of note that only 5% of the total cellular UPD-GlcNAc level suffices to provide enough UDP-GlcNAc for Nlinked glycosylation [25]. Disruption of this glycosylation leads to the accumulation of unfolded proteins in the ER lumen and induces the UPR. This is best exemplified by the effect of tunicamycin, one of the most commonly used mechanisms to experimentally induce ERS. This compound inhibits DPAGT1, the enzyme driving UDPGlcNAc into the N-glycosylation pathway [26]. The extent to which UDP-GlcNAc flux limitation is responsible for glucose-shortage mediated UPR activation has been demonstrated by the ability of GlcNAc supplementation to strongly reduce the expression of UPR markers and prevent UPR-induced cell death in glucose-deprived cells [6,27]. GlcNAc supplementation specifically enters the HBP and provides a source of UDP-GlcNAc, but is unable to enter glycolysis or other carbon metabolic pathways [28]. Thus, the shortage of HBP products is an important determinant of UPR activation when glucose becomes scarce. As with glucose, increased glutamine uptake is under the control of oncogenic signalling pathways. Glutamine is a major nutrient source for tumour cells and diverse cancer cell types depend on extracellular glutamine for survival [1]. It has been known for many years that glutamine levels are almost undetectable in solid tumours when compared with the normal homologous tissues [29]. This suggests that malignant cells also face glutamine shortage during tumour development. Given that the first committed step of HBP, catalysed by GFPT, requires glutamine to generate the first HBP metabolite, i.e. glucosamine-6P, a significant glutamine shortage may also contribute to reduce HBP flux and impact ER homeostasis. Direct evidence for this possibility deserves further study. In contrast, hypoxia appears to promote activation of the HBP. It has been reported that hypoxia increases transcription of GFPT as well as levels of protein O-GlcNAcylation in pancreatic adenocarcinoma [19]. It is tempting to speculate that upon glucose shortage, hypoxia may help malignant cells to optimise the uptake of residual environmental glucose through an efficient redirection of glucose towards HBP, thereby limiting UPR activation. However, at the

same time, hypoxia increases intracellular reactive oxygen species (ROS) that induce UPR [7]. Hence, the effect exerted by hypoxia on UPR may be more complex than previously anticipated.

3. UPR triggers HBP Recently, a mechanistic link between the UPR and the HBP was discovered. When activated, the UPR initiates transcriptional and translational programmes that maintain a productive ER protein-folding environment. For example, expression of numerous UPR-regulated genes, such as BiP or Grp90 chaperones, is increased to manage the accumulation of unfolded proteins in the ER. It would thus be expected that a simultaneous production of UDP-GlcNAc would occur to ensure sufficient N-glycosylation for proper protein folding, which is supported by the finding that correct N-linked glycosylation requires a balance between the synthesis of polypeptides in the ER lumen and the synthesis of preformed glycans [30]. Indeed, this appears to be one of the roles of the XBP1s transcription factor controlled by the IRE1 branch of the UPR. XBP1s directly promotes transcription of three enzyme-encoding genes within the HBP, including GFPT [21]. The authors demonstrated a causal link between the expression of XBP1s and the activation of the HBP flux and O-GlcNAcylation of proteins. In addition, they reported that stimulation of O-GlcNAcylation antagonises the detrimental effects of ERS observed during ischaemia/reperfusion. In a related study, using the Caenorhabditis elegans model, Denzel and colleagues found that a gain-of-function mutant of gfat-1, an orthologue of the mammalian GFPT, suppressed tunicamycin toxicity and led to extended life span [20]. These effects were independent of O-GlcNAcylation, suggesting a general improvement of cellular protein folding capacity via N-glycosylation in this model. It is therefore conceivable that both O- and N-glycosylation contribute to protection from ERS damage. These findings reveal that HBP activation is integral to UPR and that HBP flux mediates alleviation of ERS in a feedback loop.

Please cite this article in press as: Vasseur S, Manié SN. ER stress and hexosamine pathway during tumourigenesis: A pas de deux? Semin Cancer Biol (2015), http://dx.doi.org/10.1016/j.semcancer.2015.04.001

158 159 160

161

162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191

G Model YSCBI 1186 1–6 4

ARTICLE IN PRESS S. Vasseur, S.N. Manié / Seminars in Cancer Biology xxx (2015) xxx–xxx

Fig. 3. ERS and HBP interplay may promote tumourigenesis. Hypoxia stimulates ERS in part through the increased production of intracellular reactive oxygen species (ROS). Glucose shortage stimulates ERS mainly through an inhibition of HBP flux that reduces the availability of glycans required for N-glycosylation and proper folding of proteins. In a feedback loop, UPR-dependant increase in expression of XBP1␣, should up-regulate HBP flux to counterbalance glycan shortage and alleviate ERS. HBP stimulation also concomitantly increases O-GlcNAcylations that displays tumour-promoting functions through direct O-GlcNAcylation of oncogenes or tumour suppressor genes leading to their stabilisation or inhibition respectively. Alternative sources of glucose and glutamine that help fuel the HBP during periods of nutrient shortage may include transferred material from cell to cell through exosomes, stimulated micropinocytosis and autophagy. Dashed lines indicate hypotheses that have not yet been addressed experimentally. 192

193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217

4. HBP and ERS, a pas de deux promoting tumourigenesis? In the context of malignancies, the following model can thus be drawn: under nutrient-limiting conditions, a reduction of metabolite flux into HBP activates the UPR program, which in turn stimulates HBP to force the production of HBP products as a feed forward mechanism to attenuate long-term ERS (Fig. 3). This model may also hold true upon oncogene-induced UPR activation, independently of nutrient shortage. For example, unregulated protein synthesis has been linked to activation of the UPR in cancer cells that exhibit dysregulated mTORC1 activation [31], and an UPRstimulated HBP likely balances the synthesis of glycans with that of nascent polypeptides [30]. Such a pas de deux between ERS and HBP is predicted to promote tumourigenesis through two distinct mechanisms: It may help alleviate excessive and therefore potentially detrimental ERS, since a high level of prolonged ERS clearly sensitises both normal and cancer cells to programmed cell death [32]. Thus, there would be a selective advantage for malignant cells to attenuate ERS in order to reach sustainable levels of chronic UPR signalling pathways. The concept of sustainable levels of chronic UPR in malignant cells is supported by the therapeutic use of the proteasome inhibitor bortezomib that is believed to augment ERS to tip the balance towards apoptosis [33]. In the light of the above findings, increasing N-glycosylation in the ER lumen is likely part of the mechanism allowing cancer cell adaptation to long-term UPR within the hostile microenvironment. This hypothesis is further

reinforced by the observation that the ER enzyme ENTPD5, promoting N-glycosylation and folding, is up-regulated in PTEN negative prostate cancer and protects those cells from ERS [34]. Similarly, down-regulation of tumour suppressor candidate 3 (TUSC3) that represses N-glycosylation has been reported to alleviate ERS and UPR [35]. On the other hand, an increase in UDP-GlcNAc level stimulates the activity of the O-GlcNAc transferase (OGT) [36] and therefore directly translates into an increased O-GlcNAcylation of proteins. This will strengthen the case for tumour-promoting functions of O-GlcNAcylation that has recently received much attention. For instance, Onodera and colleagues have found that stimulation of O-GlcNAcylation, but not N-linked glycosylation, leads to a malignant-like phenotype in non-malignant breast cells cultured in a 3D structure [3]. Similarly, in a mouse model of pancreatic ductal adenocarcinoma, it was uncovered that oncogenic Kras plays a prominent role in maintaining the flux of glucose into the HBP to sustain protein O-GlcNAcylation during tumour development [18]. At the molecular level, these posttranslational modifications affect oncogenes, tumour suppressors and other proteins involved in oncogenic signalling pathways. For example, O-GlcNAcylation stabilises hypoxia-inducible factor 1␣ in breast cancer cells, thereby regulating metabolic reprogramming and survival stress signalling [37]. Likewise, O-GlcNAcylation regulates the stability of the transcription factor c-Myc, a key regulator of cancer cell metabolism, in human prostate cancer cells [38].

Please cite this article in press as: Vasseur S, Manié SN. ER stress and hexosamine pathway during tumourigenesis: A pas de deux? Semin Cancer Biol (2015), http://dx.doi.org/10.1016/j.semcancer.2015.04.001

218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244

G Model YSCBI 1186 1–6

ARTICLE IN PRESS S. Vasseur, S.N. Manié / Seminars in Cancer Biology xxx (2015) xxx–xxx

245 246 247 248 249 250

251

The aforementioned mechanisms describe that the interplay between chronic UPR and ERS should provide a means to malignant cells, not only to survive their harsh microenvironment by promoting ERS protective N-glycosylation, but also to further fuel the transformation process through the stimulation of tumourpromoting functions of O-GlcNAcylation. 5. Alternative sources of nutrients to fuel the HBP

276

Due to the heterogeneity of the microenvironment of solid tumours, cancer cells are not synchronously deprived of nutrients and oxygen within the tumour mass. For some cells, UPR-mediated up-regulation of HBP enzymes will conceivably promote active channelling of scarce metabolites into HBP. Others can also enhance degradation of glycogen stores to increase intracellular glucose pools and fuel HBP [39]. However, many cells will have to turn to alternative sources of nutrients during excessive shortage to ensure the maintenance of metabolite supply. When embedded in a dense desmoplastic reaction close to stromal cells, tumour cells can rely on a metabolic dialogue with activated fibroblasts and/or immune cells. Nanovesicles such as exosomes, transfer material from cell to cell and are part of tumour adaptive mechanisms to overcome microenvironmental stress, such as hypoxia [40,41]. Hence, trafficking of exosomes between stromal cells and tumour cells might help the latter to overcome nutrient deprivation. Tumour cells can also rely on stimulated micropinocytosis, allowing massive endocytosis of surrounding protein and metabolites that are used for their growth [42]. Moreover, tumour cells also enhance the recycling of organelles and protein aggregates through autophagy when they need to coordinate their metabolic demand and supply [43] (Fig. 3). Therefore, in their harsh microenvironment, malignant cells can develop several adaptive processes that may help fuel the HBP to replenish levels of UDP-GlcNAc before they reach unbearable levels of ERS.

277

6. Conclusions

252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275

293

Advances in cancer research over recent years have witnessed a renewed appreciation of the shift in metabolism to sustain tumour growth, particularly in the harsh tumour microenvironment with limited supply of nutrients. The studies discussed here position both ER and HBP as sensitive sensors of nutrient scarcity. They provide support for the proposal that their interplay has a prominent role in neoplastic cell survival facing microenvironmental challenges during tumourigenesis. Indeed, adaptive capacities of tumour cells to nutrient deprivation not only rely on their metabolic flexibility to simply meet their metabolic demand, but also on their capacity to overcome an “ERS checkpoint” by activating specific pathways such as HBP. This interaction between ERS and HBP illustrates another facet of the metabolic control of the cell fate under stress conditions, which may represent a critical metabolic vulnerability that could be exploited therapeutically to target cancer cells.

294

Conflict of interest

278 279 280 281 282 283 284 285 286 287 288 289 290 291 292

295

296

The authors declare that there are no conflicts of interest. Acknowledgements

We apologise to all colleagues whose work could not be cited owing to space limitations. This work was funded by grants from 298 Q4 Institut National du Cancer (INCA-7981), Ligue Nationale Contre le 299 Cancer (Comité du rhône) and Fondation ARC pour la recherche sur 300 le cancer (PJA20131200334) to SM and Plan Cancer 2013, Fondation 301 297

5

de France, Cancéropôle PACA and Ligue Nationale contre le Cancer to SV.

References [1] Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012;21:297–308. [2] Sebastian C, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 2012;151:1185–99. Q5 [3] Onodera Y, et al. Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. J Clin Investig 2014;124:367–84. [4] Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 2009;23:537–48. [5] Bi M, et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 2005;24:3470–81. [6] Huber AL, et al. p58(IPK)-mediated attenuation of the proapoptotic PERKCHOP pathway allows malignant progression upon low glucose. Mol Cell 2013;49:1049–59. [7] Liu L, et al. Hypoxic reactive oxygen species regulate the integrated stress response and cell survival. J Biol Chem 2008;283:31153–62. [8] Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519–29. [9] Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer 2014;14:581–97. [10] Nakagawa H, et al. ER stress cooperates with hypernutrition to trigger TNFdependent spontaneous HCC development. Cancer Cell 2014;26:331–43. [11] Hart LS, et al. ER stress-mediated autophagy promotes Myc-dependent transQ6 formation and tumor growth. J Clin Investig 2012. [12] Rouschop KM, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Investig 2010;120:127–41. [13] Zachara NE, Hart GW. O-GlcNAc a sensor of cellular state: the role of nucleocytoplasmic glycosylation in modulating cellular function in response to nutrition and stress. Biochim Biophys Acta 2004;1673:13–28. [14] Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 2004;73:1019–49. [15] Hauselmann I, Borsig L. Altered tumor-cell glycosylation promotes metastasis. Front Oncol 2014;4:28. [16] Radhakrishnan P, et al. Immature truncated O-glycophenotype of cancer directly induces oncogenic features. Proc Natl Acad Sci U S A 2014;111:E4066–75. [17] Fardini Y, et al. O-GlcNAcylation: a new cancer hallmark? Front Endocrinol 2013;4:99. [18] Ying H, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012;149:656–70. [19] Guillaumond F, et al. Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc Natl Acad Sci U S A 2013;110:3919–24. [20] Denzel MS, et al. Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 2014;156:1167–78. [21] WangF Z.V., et al. Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 2014;156:1179–92. [22] Lee AS. Mammalian stress response: induction of the glucose-regulated protein family. Curr Opin Cell Biol 1992;4:267–73. [23] Lavery GG, et al. Deletion of hexose-6-phosphate dehydrogenase activates the unfolded protein response pathway and induces skeletal myopathy. J Biol Chem 2008;283:8453–61. [24] Kaufman RJ, et al. The unfolded protein response in nutrient sensing and differentiation. Nat Rev Mol Cell Biol 2002;3:411–21. [25] Boehmelt G, et al. Decreased UDP-GlcNAc levels abrogate proliferation control in EMeg32-deficient cells. EMBO J 2000;19:5092–104. [26] Bretthauer RK. Structure, expression, and regulation of UDP-GlcNAc: dolichol phosphate GlcNAc-1-phosphate transferase (DPAGT1). Curr Drug Targets 2009;10:477–82. [27] Palorini R, et al. Glucose starvation induces cell death in K-ras-transformed cells by interfering with the hexosamine biosynthesis pathway and activating the unfolded protein response. Cell Death Dis 2013;4:e732. [28] Wellen KE, et al. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev 2010;24:2784–99. [29] Roberts E, Frankel S. Free amino acids in normal and neoplastic tissues of mice as studied by paper chromatography. Cancer Res 1949;9:645–8, 643 pl. [30] Shang J, et al. Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux. J Cell Biol 2007;176:605–16. [31] Ozcan U, et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 2008;29:541–51. [32] Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 2011;13:184–90. [33] Obeng EA, et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006;107:4907–16. [34] Shen Z, et al. ENTPD5, an endoplasmic reticulum UDPase, alleviates ER stress induced by protein overloading in AKT-activated cancer cells. Cold Spring Harb Symp Quant Biol 2011;76:217–23.

Please cite this article in press as: Vasseur S, Manié SN. ER stress and hexosamine pathway during tumourigenesis: A pas de deux? Semin Cancer Biol (2015), http://dx.doi.org/10.1016/j.semcancer.2015.04.001

302 303

304

305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383

G Model YSCBI 1186 1–6 6 384 385 386 387 388 389 390 391 392 393

ARTICLE IN PRESS S. Vasseur, S.N. Manié / Seminars in Cancer Biology xxx (2015) xxx–xxx

[35] Horak P, et al. TUSC3 loss alters the ER stress response and accelerates prostate cancer growth in vivo. Sci Rep 2014;4:3739. [36] Kreppel LK, Hart GW. Regulation of a cytosolic and nuclear O-GlcNAc transferase. Role of the tetratricopeptide repeats. J Biol Chem 1999;274: 32015–22. [37] Ferrer CM, et al. O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol Cell 2014;54: 820–31. [38] Itkonen HM, et al. O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells. Cancer Res 2013;73:5277–87.

[39] Pelletier J, et al. Glycogen synthesis is induced in hypoxia by the hypoxiainducible factor and promotes cancer cell survival. Front Oncol 2012;2:18. [40] King HW, et al. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 2012;12:421. [41] Kucharzewska P, et al. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci U S A 2013;110:7312–7. [42] Commisso C, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 2013;497:633–7. [43] Lee JM, et al. Nutrient-sensing nuclear receptors coordinate autophagy. Nature 2014;516:112–5.

Please cite this article in press as: Vasseur S, Manié SN. ER stress and hexosamine pathway during tumourigenesis: A pas de deux? Semin Cancer Biol (2015), http://dx.doi.org/10.1016/j.semcancer.2015.04.001

394 395 396 397 398 399 400 401 402 403 404

ER stress and hexosamine pathway during tumourigenesis: A pas de deux?

Both the hexosamine biosynthetic pathway (HBP) and the endoplasmic reticulum (ER) are considered sensors for the nutritional state of the cell. The fo...
1MB Sizes 1 Downloads 5 Views