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Endoplazmik Retikulum Stresinin Tümör Sürecindeki Rolü ve Antikanser Uygulamaları

Yıl 2016, Cilt: 13 Sayı: 1, 124 - 133, 28.04.2016

Öz

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. 

Kaynakça

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  • 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. Koumenis C. ER Stress, Hypoxia Tolerance and Tumor Progression. Current Molecular Medicine. 2006; 6, 55-69.
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  • 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.
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  • 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. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol. 2011;54:795–809.
  • 24. Schönthal AH. Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. Biochem Pharmacol. 2013;85(5):653-66.
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  • 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.
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  • 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.
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The Role in Tumor Process of Endoplasmic Reticulum Stress and Anticancer Treatments

Yıl 2016, Cilt: 13 Sayı: 1, 124 - 133, 28.04.2016

Öz

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.

Kaynakça

  • 1. Ackerman D, Simon MC. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol. 2014; 24(8):472-8.
  • 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. Höckel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001; 93(4):266-76.
  • 4. Schröder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem. 2005; 74: 739–89.
  • 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. Semenza GL. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer. 2003; 3, 721–732.
  • 7. Hill RP, De Jaeger K, Jang A, Cairns R. pH, hypoxia and metastasis. Novartis Found. Symp. 2001; 240, 154- 165.
  • 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. Koumenis C. ER Stress, Hypoxia Tolerance and Tumor Progression. Current Molecular Medicine. 2006; 6, 55-69.
  • 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. 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. 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. 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. Inoki K, Zhu T, Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003; 115, 577–590.
  • 15. Walter P, Ron D. The unfolded protein response: from stres pathway to homeostatic regulation. Science. 2011; 334, 1081–1086.
  • 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. 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. 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. 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. 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. Li Z. Glucose regulated protein 78: a critical link between tumor microenvironment and cancer hallmarks. Biochim Biophys Acta. 2012; 1826(1):13–22.
  • 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. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol. 2011;54:795–809.
  • 24. Schönthal AH. Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. Biochem Pharmacol. 2013;85(5):653-66.
  • 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. 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. 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. 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. 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.
  • 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.
  • 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.
  • 33. Brewer JW, Diehl JA. PERK mediates cell-cycle exit during the mammalianunfolded protein response. Proc Natl Acad Sci. 2000; 97:12625–30.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 42. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008; 8:425–37.
  • 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.
  • 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.
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Toplam 73 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Bölüm Derleme
Yazarlar

Sümeyra Çetinkaya

İlknur Çınar

Hatice Gül Dursun

Yayımlanma Tarihi 28 Nisan 2016
Gönderilme Tarihi 13 Ekim 2015
Kabul Tarihi 21 Kasım 2015
Yayımlandığı Sayı Yıl 2016 Cilt: 13 Sayı: 1

Kaynak Göster

Vancouver Çetinkaya S, Çınar İ, Dursun HG. Endoplazmik Retikulum Stresinin Tümör Sürecindeki Rolü ve Antikanser Uygulamaları. Harran Üniversitesi Tıp Fakültesi Dergisi. 2016;13(1):124-33.

Harran Üniversitesi Tıp Fakültesi Dergisi  / Journal of Harran University Medical Faculty