Endoplazmik Retikulum Stresinin Tümör Sürecindeki Rolü ve Antikanser Uygulamaları

Abstract

Katlanmamış ya da yanlış katlanmış proteinlerin birikimi sonucu ortaya çıkan Endoplazmik retikulum stresi, kanser hücre çoğalması ve sağkalımı üzerinde büyük bir etkiye sahiptir. Tümör hücreleri büyümek için etraflarında hipoksik bir çevreye ihtiyaç duyarlar ve katlanmamış protein yanıtı 'nın uyarılması bu yanıtta kilit bir rol oynar. Kanserin stresli bir mikroçevrede oluşması ve ilerlemesi sonucunda ortaya çıkan onkogenik transformasyon süresince hücrelerin sağkalım stratejisi olarak katlanmamış protein yanıtını aktive edebildiği çeşitli çalışmalarla gösterilmiştir. Son zamanlarda katlanmamış protein yanıtı sinyal moleküllerinin kanser gelişimi boyunca fonksiyonlarının belirlenmesi için çalışmalar yürütülmektedir. Elde edilen verilerle, çeşitli onkogen ve tümör baskılayıcı genlerin katlanmamış protein yanıtı ile ilişkisi ortaya çıkmaya devam etmektedir. Bu sinyal yolaklarının birbirlerini etkileyip etkilemediklerini anlamamıza fayda sağlayacak detaylı çalışmalar, katlanmamış protein yanıtı ve kanser mekanizmasının açığa çıkmasında oldukça önemlidir. Bu derlemede katlanmamış protein yanıtı aktivasyonunun hem tümörü destekleyen hem de tümörü baskılayan rollerini anlamamıza ışık tutacak bilgilerin yanında kanser tedavisi için katlanmamış protein yanıtını hedefleyen yeni stratejilerin neler olduğu tartışılacaktır. 

Keywords

• Endoplazmik Retikulum stresi,katlanmamış protein yanıtı,kanser,terapötik hedef

The Role in Tumor Process of Endoplasmic Reticulum Stress and Anticancer Treatments

Abstract

Endoplasmic reticulum stress resulted from accumulation of unfolded or misfolded proteins have a large impact on proliferation and survival of cancer cell. In order to grow, tumor cells need a hypoxic environment and stimulation of the unfolded protein response plays a key role in this response. The emergence and progression of the cancer under stressful microenvironment lead to oncogenic transformation. Several studies have shown that during this process, cells could activate unfolded protein response as a survival strategy. Recent studies have focused on relationship between unfolded protein response signal molecules and cancer development; and association between various oncogenes and tumor suppressor genes with unfolded protein response have been emerging. Detailed studies that will help us to understand the effect of signalling pathways on each other's, are very important to figure out the unfolded protein response and cancer mechanism. In this review, knowledge shed light on our understanding about roles of UPR on both tumor sustaining and suppression and also new strategies targeting unfolded protein response for the treatment of cancer will be discussed.

Keywords

• Endoplasmic Reticulum stress,Unfolded protein response,cancer,therapeutic target

References

1. 1. Ackerman D, Simon MC. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol. 2014; 24(8):472-8.
2. 2. Sutherland RM, Ausserer WA, Murphy BJ, Laderoute KR. Tumor hypoxia and heterogeneity: challenges and opportunities for the future. Semin Radiat Oncol. 1996; 6:59–70.
3. 3. Höckel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001; 93(4):266-76.
4. 4. Schröder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem. 2005; 74: 739–89.
5. 5. Ratcliffe PJ, O'Rourke JF, Maxwell PH, Pugh CW. Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. J. Exp. Biol. 1998; 201, 1153-1162.
6. 6. Semenza GL. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer. 2003; 3, 721–732.
7. 7. Hill RP, De Jaeger K, Jang A, Cairns R. pH, hypoxia and metastasis. Novartis Found. Symp. 2001; 240, 154- 165.
8. 8. Cairns RA, Hill RP. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res. 2004; 64, 2054-2061.

9. 9. Koumenis C. ER Stress, Hypoxia Tolerance and Tumor Progression. Current Molecular Medicine. 2006; 6, 55-69.
10. 10. Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. 2008; 8(11):851–64.
11. 11. Kelly CJ, Hussien K, Fokas E, Kannan P, Shipley RJ, Ashton TM, Stratford M, Pearson N, Muschel RJ. Regulation of O2 consumption by the PI3K and mTOR pathways contributes to tumor hypoxia. Radiother Oncol. 2014;111(1):72-80.
12. 12. Edinger AL, Linardic CM, Chiang GG, Thompson CB, Abraham RT. Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res. 2003; 63, 8451–8460.
13. 13. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004; 18, 2893–2904.
14. 14. Inoki K, Zhu T, Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003; 115, 577–590.
15. 15. Walter P, Ron D. The unfolded protein response: from stres pathway to homeostatic regulation. Science. 2011; 334, 1081–1086.
16. 16. Li XC, Raghavan M. Structure and function of major histo compatibility complex class I antigens. Curr Opin Organ Transplant. 2010; 15(4):499–504.
17. 17. Gutiérrez T, Simmen T. Endoplasmic reticulum chaperones and oxidoreductases: critical regulators of tumor cell survival and immuno recognition. Front Oncol. 2014; Oct 27;4:291.
18. 18. Rauschert N, Brändlein S, Holzinger E, Hensel F, Müller-Hermelink HK, Vollmers HP. A new tumorspecific variant of GRP78 as target for antibody-based therapy. Lab Invest. 2008; 88(4):375–86.
19. 19. Uckun FM, Qazi S, Ozer Z, Garner AL, Pitt J, Ma H, et al. Inducing apoptosis in chemotherapy-resistant Blineage acute lymphoblastic leukaemia cells by targeting HSPA 5, a master regulator of the anti-apoptotic unfolded protein response signalling network. Br J Haematol. 2011; 153(6):741–52.
20. 20. Luo B, Lee AS. The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene. 2013; 32:805–18.
21. 21. Li Z. Glucose regulated protein 78: a critical link between tumor microenvironment and cancer hallmarks. Biochim Biophys Acta. 2012; 1826(1):13–22.
22. 22. Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer. 2014;14(9):581-97.
23. 23. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol. 2011;54:795–809.
24. 24. Schönthal AH. Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. Biochem Pharmacol. 2013;85(5):653-66.
25. 25. Ma Y, Brewer JW, Diehl JA, Hendershot LM. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol. 2002; 318:1351–65.
26. 26. 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.
27. 27. McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 2001;21:1249–59.
28. 28. Rutkowski DT, Arnold SM, Miller CN, Wu J, Li J, Gunnison KM, et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and proapoptotic mRNAs and proteins. PLoS Biol. 2006;4:e374.
29. 29. Kaufman RJ, Scheuner D, Schroder M, Shen X, Lee K, Liu CY, Arnold SM. The unfolded protein response in nutrient sensing and differentiation. Nat. Rev. Mol. Cell. Biol. 2002; 3: 411–421. 30. Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005; 24, 3470-3481.
30. 31. Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, Cavener D, and Diehl JA. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene. 2010; 29, 3881–3895.
31. 32. Huber AL, Lebeau J, Guillaumot P, Pétrilli V, Malek M, Chilloux J, et al. p58(IPK)-mediated attenuation of the proapoptotic PERK-CHOP pathway allows malignant progression upon low glucose. Mol. Cell. 2013; 49, 1049–1059.
32. 33. Brewer JW, Diehl JA. PERK mediates cell-cycle exit during the mammalianunfolded protein response. Proc Natl Acad Sci. 2000; 97:12625–30.
33. 34. Hamanaka RB, Bennett BS, Cullinan SB, Diehl JA. PERK and GCN2 contribute to eIF2 alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell. 2005; 16:5493–501.
34. 35.Avivar-Valderas A, Salas E, Bobrovnikova-Marjon E, Diehl JA, Nagi C, Deb-nath J, et al. PERK integrates autophagy and oxidative stress responsesto promote survival during extracellular matrix detachment. Mol Cell Biol. 2011;31:3616–29.
35. 36. Köditz J, Nesper J, Wottawa M, Stiehl DP, Camenisch G, Franke C, Myllyharju J, Wenger RH, Katschinski DM.Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood. 2007; 110, 3610–3617.
36. 37. Scortegagna M1, Kim H1, Li JL2, Yao H3, Brill LM2, Han J4, et al. Fine tuning of the UPR by the ubiquitin ligases Siah1/2. PLoS Genet. 2014; 10, e1004348.
37. 38. Pereira ER, Frudd K, Awad W, Hendershot LM. Endoplasmic reticulum (ER) stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 (HIF-1) transcriptional activity on targets like vascular endothelial growth factor (VEGF). J. Biol. Chem. 2014; 289, 3352–3364.
38. 39. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J. Clin. Invest. 2010; 120, 127–141.
39. 40. Blais JD, Filipenko V, Bi MX, Harding HP, Ron D, Koumenis C, et al. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol. 2004; 24:7469–82.
40. 41. Rouschop KM, Dubois LJ, Keulers TG, van den Beucken T, Lambin P, Bussink J, van der Kogel, et al. PERK/eIF2a signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Proc. Natl. Acad. Sci. USA. 2013; 110, 4622–4627.
41. 42. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008; 8:425–37.
42. 43. Fujimoto T, Onda M, Nagai H, Nagahata T, Ogawa K, Emi M. Upregulation and overexpression of human X-box binding protein 1 (hXBP-1) gene in primary breast cancers. Breast Cancer. 2003; 10:301-6.
43. 44. Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori K, et al. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: A possible i n v o l v eme n t o f t h e ER str e ss p a t hwa y i n hepatocarcinogenesis. Journal of Hepatology. 2003; 38:605-14.
44. 45. Koong AC, Chauhan V, Romero-Ramirez L. Targeting XBP-1 as a novel anti-cancer strategy. Cancer Biol Ther. 2006;5(7):756-9.
45. 46. Xu G, Liu K, Anderson J, Patrene K, Lentzsch S, Roodman GD, et al. Expression of XBP1s in bone marrow stromal cells is critical for myeloma cell growth and osteoclast formation. Blood. 2012; 119:4205–14.
46. 47. Iwakoshi NN, Lee AH, Glimcher LH. The X-box binding protein-1 transcription factor is required for plasma cell differentiation and the unfolded protein response. Immunol Rev. 2003; 194:29-38.
47. 48. Brewer JW, Hendershot LM. Building an antibody factory: A job for the unfolded protein response. Nat Immunol. 2005; 6:23-9.
48. 49. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity. 2004; 21:81-93.
49. 50. Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA. 2003; 100:9946-51.
50. 51. Clarke HJ, Chambers JE, Liniker E, Marciniak SJ. Endoplasmic reticulum stress in malignancy. Cancer Cell. 2014;25(5):563-73.
51. 52. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response inimmunity and autoimmunity. Nat Rev Immunol. 2008; 8:663–74.
52. 53. Nagelkerke A, Bussink J, Sweep F, Paul N. Span The unfolded protein response as a target for cancer therapy. Biochim Biophys Acta. 2014;1846(2):277-84.
53. 54. Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, et al. Discovery of 7-methyl-5-(1-{[3- (trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J. Med. Chem. 2012; 55:7193–7207.
54. 55. Nagelkerke A, Sweep F.C, Stegeman H, Grenman R, Kaanders J.H, Bussink J, Span P.N. Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma. Head Neck. 2015;37(6):896-905.
55. 56. Lin JH, Li H, Zhang Y, Ron D, Walter P. Divergent effects of PERK and IRE1 signaling on cell viability. PLoS One. 2009; 4, e4170.
56. 57. Cojocari D, Vellanki RN, Sit B, Uehling D, Koritzinsky M, Wouters BG. New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1alpha signaling is essential for promoting adaptation and survival to hypoxia. Radiother. Oncol. 2013; 108: 541–547.
57. 58. Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P. Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim Biophys Acta. 2010;1805:53-71.
58. 59. Mujtaba T, Dou QP. Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov Med. 2011;12: 471-80.
59. 60. Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV. Bortezomib enhances dendritic cell (DC)- mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood. 2007;109:4839-45.
60. 61. Gupta SV, Hertlein E, Lu Y, Sass EJ, Lapalombella R, Chen TL, Davis ME, et al. The proteasome inhibitor carfilzomib functions independently of p53 to induce cytotoxicity and an atypical NF-κB response in chronic lymphocytic leukemia cells. Clin Cancer Res. 2013;19(9):2406-19.
61. 62. Koltai T. Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity. Version 2. F1000Res. 2015 Jan 12 [revised 2015 Mar 5];4:9.
62. 63. Miller CP, Manton CA, Hale R, Debose L, Macherla VR, Potts BC, Palladino MA, Chandra J. Specific and prolonged proteasome inhibition dictates apoptosis induction by marizomib and its analogs. Chem Biol Interact. 2011;194(1):58-68.
63. 64. Matsuo J, Tsukumo Y, Sakurai J, Tsukahara S, Park HR, Shin-Ya K, Watanabe T,et al. Preventing the unfolded protein response via aberrant activation of 4E-binding protein 1 by versipelostatin, Cancer Sci. 2008; 100, 327–333.
64. 65. Hu CC, Dougan SK, Winter SV, Paton AW, Paton JC, Ploegh HL. Subtilase cytotoxin cleaves newly synthesized BiP and blocks antibody secretion in B lymphocytes, J. Exp. Med. 2009; 206,2429–2440.
65. 66. Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013; 73, 1993–2002.
66. 67. Martin S, Lamb HK, Brady C, Lefkove B, Bonner MY, Thompson P, et al. Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78. Br J Cancer. 2013;109:433-43.
67. 68. Li X, Zhang K, Li Z. Unfolded protein response in cancer: the physician's perspective. J Hematol Oncol. 2011;23; 4:8.
68. 69. Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L, et al. Blockade of XBP1 splicing by inhibition of IRE1 alpha is a promising therapeutic option in multiple myeloma. Blood. 2012; 119, 5772–5781.
69. 70. Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, et al. Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood. 2011; 117, 1311–1314.
70. 71. Healy SJ, Gorman AM, Mousavi-Shafaei P, Gupta S, Samali A. Targeting the endoplasmic reticulum-stress response as an anticancer strategy, Eur. J. Pharmacol. 625 (2009) 234–246.
71. 72. Saito S, Furuno A, Sakurai J, Sakamoto A, Park HR, Shin-Ya K, Tsuruo T, Tomida A. Chemical genomics identifies the unfolded protein response as a target for selective cancer cell killing during glucose deprivation. Cancer Res. 2009 May 15;69(10):4225-34.
72. 73. Montalbano R, Waldegger P, Quint K, Jabari S, Neureiter D, Illig R, Ocker M, Di Fazio P. Endoplasmic reticulum stress plays a pivotal role in cell death mediated by the pan-deacetylase inhibitor panobinostat in human hepatocellular cancer cells. Transl Oncol. 2013 Apr;6(2):143-57. Epub 2013 Apr 1.
73. 74. Rao R, Nalluri S, Kolhe R, Yang Y, Fiskus W, Chen J, Ha K, et al. Treatment with panobinostat induces glucoseregulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells. Mol Cancer Ther. 2010 Apr;9(4):942-52.