Endoplazmik Retikulum Stresi ve Pankreas Kanseri

Year 2015, Volume: 16 Issue: 1, 20 - 24, 01.04.2015

Kemal Ergin Esra Gökmen

Abstract

Endoplazmik retikulum (ER) stres, farklı uyaranlar sonucu gelişen önemli hücresel bir olaydır. ER strese farklı yanıt türleri vardır. Bunlardan biri evrimsel olarak korunmuş katlanmamış protein cevabıdır (UPR). UPR’nin moleküllerin sonraki aktivasyonu için üç sensörü vardır. Bu sensörler inozitol gerektiren enzim 1 (IRE1), aktive edici transkripsiyon faktörü 6 (ATF6) ve protein kinaz RNA (PKR)-benzeri ER kinaz (PERK). ER stresin olmadığı durumlarda bu sensörler inaktif durumda tutulurlar. Ancak ER stres durumunda aktif hale gelirler ve yolaktaki alt basamak hedeflerini indüklerler. ER stresin sonucunda hücre ya canlı kalabilir ya da ölebilir. Pek çok çalışmada ER stresin farklı tipte hastalıklarla; örneğin diyabet, Alzheimer hastalığı, prion hastalığı, kanser vb; bağlantılı olduğu gösterilmiştir. Bir kanser türü olarak pankreas kanserinin de ER stres ile ilişkili olduğu gösterilmiştir. Pankreas kanseri geç tanısı ile birlikte düşük tedavi edilebilme potansiyeline sahiptir. Pankreas kanserinin ER stres ile olan ilişkisi yeni bir tedavi yaklaşımı olarak görülmektedir. Bu derlemenin amacı ER stresin tetiklediği mekanizmalar üzerine ve patogenezinde etkili olduğu hastalıklardan biri olan pankreas kanseri ile olan ilişkisine genel bir bakış yapmaktır

Keywords

Endoplazmik retikulum, pankreas kanseri, stres

Endoplasmic Reticulum Stress and Pancreatic Cancer

Abstract

Endoplasmic reticulum (ER) stress, which results from different stimuli, is an important cellular event. There are different types of response to ER stress. One of them is evolutionarily conserved unfolded protein response (UPR). UPR has three sensors for further activation of molecules. These sensors are inositol-requiring enzyme 1 (IRE1), activated transcription factor 6 (ATF6), and ER-resident protein kinase RNA (PKR)-like ER kinase (PERK). In the absence of ER stress, these sensors are maintained in an inactive state. However, under ER stress conditions, they became activated and induce the downstream targets. As a consequence of ER stress, the cell may stay alive or became dead. Several studies have shown that ER stress is associated with different types of diseases such as diabetes mellitus, Alzheimer’s disease, prion disease, and cancer. As a cancer type, it has been shown that pancreatic cancer is also associated with ER stress. Pancreatic cancer has a low cure potential with its late diagnosis. Its association with ER stress is seen as a new therapeutic approach. The aim of this is review is to provide an overview of the mechanisms of ER stress and its relationship with pancreatic cancer, one of the diseases in which ER stress affects pathogenesis.

Keywords

Endoplasmic reticulum, pancreatic cancer, stress

References

• 1. Engin F, Hotamisligil GS. Restoring endoplasmic reticulum function by chemical chaperones: an emerging therapeutic approach for metabolic diseases. Diabetes Obes Metab 2010; 12: 108-15. [CrossRef]
• 2. Qin L, Wang Z, Tao L, Wang Y. ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy 2010; 6: 239-47. [CrossRef]
• 3. Schroder M. Endoplasmic reticulum stress responses. Cel Mol Life Sci 2008; 65: 862-94. [CrossRef]
• 4. Hussain H, Maldonado-Agurto R, Dickson AJ. The endoplasmic reticulum and unfolded protein response in the control of mammalian recombinant protein production. Biotechnol Lett 2014, 36: 1581-93. [CrossRef]
• 5. Van der Kallen CJ, van Greevenbroek MM, Stehouwer CD, Schalkwijk CG. Endoplasmic reticulum stress-induced apoptosis in the development of diabetes: is there a role for adipose tissue and liver? Apoptosis 2009; 14: 1424-34. [CrossRef]
• 6. Araki E, Oyadomari s, Mori M. Endoplasmic Reticulum Stress and Diabetes Mellitus. Intern Med 2003; 42: 7-14. [CrossRef]
• 7. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8: 519-29. [CrossRef]
• 8. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2000; 2: 326-32. [CrossRef]
• 9. Chen Y and Brandizzi F. IRE1: ER stress sensor and cell fate executor. Trends Cell Biol 2013; 1-9. [CrossRef]
• 10. Oslowski CM, Urano F. Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol 2011; 490: 71-92. [CrossRef]
• 11. Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response. Mol Cell Biol 2003; 23: 7448-59. [CrossRef]
• 12. Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999; 397: 271-4. [CrossRef]
• 13. Harding HP, Calfon M, Urano F, Novoa I, and Ron D. Transcriptional and translational control in the mammalian unfolded protein response. Annu Rev Cell Dev Biol 2002; 18: 575-99. [CrossRef]
• 14. Harding HP, Novoa I, Zhang Y, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000; 6: 1099-108. [CrossRef]
• 15. Yoshida H, Haze K, Yanagi H, Yura T, Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem 1998; 273: 33741-9. [CrossRef]
• 16. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 1999; 10: 3787-99. [CrossRef]
• 17. Schönthal AH. Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy. Scientifica 2012; 2012: 857516. [CrossRef]
• 18. Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol 2001; 3: 255-63. [CrossRef]
• 19. Nakagawa T, Yuan J. Cross-talk between Two Cysteine Protease Families: Activation of Caspase-12 by Calpain in Apoptosis. J Cell Biol 2000; 150: 887-94. [CrossRef]
• 20. Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000; 403: 98-103. [CrossRef]
• 21. Ng FWH, Nguyen M, Kwan T, et al. p28 Bap31, a Bcl-2/Bcl-XL- and Procaspase-8-associated Protein in the Endoplasmic Reticulum. J Cell Biol 1997; 139: 327-38. [CrossRef]
• 22. Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 1999; 13: 1211-33. [CrossRef]
• 23. Mendlovic F, Conconi M. Calreticulin: a Multifaceted Protein. Nature Education 2010; 4: 1.
• 24. Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 2004; 11, 372-80. [CrossRef]
• 25. Brown MK, Naidoo N. The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol 2012, 16: 263. [CrossRef]
• 26. Wu J, Kaufman RJ. From acute ER stress to physiological roles of the Unfolded Protein Response. Cell Death Differ 2006; 13, 374-84. [CrossRef]
• 27. Harding HP, Zhang Y, Zeng H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 2003; 11: 619-33. [CrossRef]
• 28. Fribley A, Zhang K, Kaufman RJ. Regulation of Apoptosis by the Unfolded Protein Response. Methods Mol Biol 2009; 559: 191-204. [CrossRef]
• 29. Zinszner H, Kuroda M, Wang X, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 1998; 12: 982-95. [CrossRef]
• 30. Urano F, Wang X, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000; 287: 664-6. [CrossRef]
• 31. Zong WX, Li C, Hatzivassiliou G, Lindsten T, et al. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 2003; 162: 59-69. [CrossRef]
• 32. Nakagawa T, Yuan J. Crosstalk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 2000; 150: 887-94. [CrossRef]
• 33. Rao RV, Hermel E, Castro-Obregon S, et al. Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem 2001; 276: 33869-74. [CrossRef]
• 34. Jimbo A, Fujita E, Kouroku Y, er at. ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation. Exp Cell Res 2003; 15; 283: 156-66. [CrossRef]
• 35. Axel H. Schonthal. Targeting endoplasmic reticulum stress for cancer therapy. Front Biosci 2012, 412-31.
• 36. Wang Y, Qin ZH. Coordination of autophagy with other cellular activities. Acta Pharmacol Sin 2013; 34: 585-94. [CrossRef]
• 37. Randall-Demllo S, Chieppa M, Eri R. Intestinal epithelium and autophagy: partners in gut homeostasis. Front Immunol 2013; 4: 301. [CrossRef]
• 38. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Ann Rev Genet 2009 ; 43: 67-93. [CrossRef]
• 39. Kouroku Y, Fujita E, Tanida I, et al. ER stress (PERK/eIFα phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 2007; 14, 230-9. [CrossRef]
• 40. Verfaillie T, Salazar M, Velasco G, Agostinis P. Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy. Int J Cell Biol 2010; 2010: 930509. [CrossRef]
• 41. Pyo JO, Nah J, Jung YK. Molecules and their functions in autophagy. Experimental and Molecular Medicine 2012; 29; 44: 73-80. [CrossRef] Ergin and Gökmen. Endoplasmic reticulum and pancreas
• 42. Choe CU, Ehrlich BE. The inositol 1,4,5- trisphosphate receptor (IP3R) and its regulators: sometimes good and sometimes bad teamwork. Sci STKE 2006; 2006: 15.
• 43. Mattson MP, LaFerla FM, Chan SL, et al. Dysregula-tion of calcium in Alzheimer’s disease. Trends Neuroscience 2000; 23: 222-9. [CrossRef]
• 44. Sherman MY, Goldberg AL. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 2001; 29: 15-32. [CrossRef]
• 45. Song B, Scheuner D, Ron D, Pennathur S, Kaufman RJ. Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest 2008; 118: 3378. [CrossRef]
• 46. Boden G, Duan X, Homko C, et al. Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes 2008; 57: 2438-44. [CrossRef]
• 47. Oyadomari S, Koizumi A, Takeda K, et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stressmediated diabetes. J Clin Invest 2002; 109: 525-32. [CrossRef]
• 48. Li Y, Schwabe RF, DeVries-Seimon T, et al. Free cholesterolloaded macrophages are an abundant source of tumor necrosis factor-α and interleukin-6: model of NF- kappaB- and map kinasedependent infammation in advanced atherosclerosis. J Biol Chem 2005; 280: 21763-72. [CrossRef]
• 49. Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 2011; 53: 1752-63. [CrossRef]
• 50. Tardif KD, Mori K, Kaufman RJ, Siddiqui A. Hepatitis C virus suppresses the IRE1-XBP1 pathway of the unfolded protein response. J Biol Chem 2004; 279: 17158-64. [CrossRef]
• 51. Kouroku Y, Fujita E, Jimbo A, et al. Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation. Hum Mol Genet 2002; 11: 1505-15. [CrossRef]
• 52. Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J, Soto C. Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J 2003; 22: 5435-45. [CrossRef]
• 53. Kardosh A, Golden EB, Pyrko P, et al. Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl-celecoxib. Cancer Res 2008; 68: 843-51. [CrossRef]
• 54. Pyrko P, Schöntha AH, Hofman FM, Chen TC, Lee AS. The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res 2007; 67: 9809-16. [CrossRef]
• 55. Shuda M, Kondoh N, Imazeki N, et al. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 2003; 38: 605-14. [CrossRef]
• 56. Koumenis C, Naczki C, Koritzinsky M, et al. Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2α. Mol Cell Biol 2002; 22: 7405-16. [CrossRef]
• 57. Fernandez PM, Tabbara SO, Jacobs LK, et al. Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat 2000; 59: 15-26. [CrossRef]
• 58. Ozcan L, Tabas I. Role of Endoplasmic Reticulum Stress in Metabolic Disease and Other Disorders. Ann Rev Med 2012; 63: 317-28. [CrossRef]
• 59. Boyce M, Yuan J.Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death and Differentiation 2006; 13: 363–373. http://dx.doi.org/10.1038/sj.cdd.4401817 PMid:16397583 [CrossRef]
• 60. Suzuki T, Lu J, Zahed M, Kita K, Suzuki N. Reduction of GRP78 expression with siRNA activates unfolded protein response leading to apoptosis in HeLa cells. Arch Biochem Biophys 2007; 468: 1-14. [CrossRef]
• 61. Blais JD, Addison CL, Edge R, et al. Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stres. Mol Cell Biol 2006, 26: 9517. [CrossRef]
• 62. Verfaillie T, Garg AD, Agostinis P. Targeting ER stress induced apoptosis and inflammation in cancer. Cancer Lett2013; 332: 249-64. [CrossRef]
• 63. So AY, de la FE, Walter P, Shuman M, Bernales S. The unfolded protein response during prostate cancer development. Cancer Metastasis Rev 2009; 28: 219-23. [CrossRef]
• 64. National Cancer Institute. What You Need To Know About Cancer of the Pancreas.
• 65. Lin S, Zhang J, Chen H, et al. Involvement of Endoplasmic Reticulum Stress in Capsaicin-Induced Apoptosis of Human Pancreatic Cancer Cells. Evid Based Complement Alternat Med 2013; 2013: 629750. [CrossRef]
• 66. Oyadomari S, Araki E, Mori M. Endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cells. Apoptosis 2002; 7: 335-45. [CrossRef]
• 67. Nawrocki ST, Carew JS, Pino MS, et al. Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis. Cancer Res 2005; 65: 11658-66. [CrossRef]
• 68. Nawrocki ST, Sweeney-Gotsch B, Takamori R, McConkey DJ. The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 2004; 3: 59-70.
• 69. Lee JH, Lee HB, Jung GO, Oh JT, Park DE, Chae KM. Effect of quercetin on apoptosis of PANC-1 cells. J Korean Surg Soc 2013; 85: 249-60. [CrossRef]