Endoplazmik Retikulum Stresinin Tümör Sürecindeki Rolü ve Antikanser Uygulamaları
Yıl 2016,
Cilt: 13 Sayı: 1, 124 - 133, 28.04.2016
Sümeyra Çetinkaya
,
İlknur Çınar
,
Hatice Gül Dursun
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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surviving the harsh tumor microenvironment. Trends
Cell Biol. 2014; 24(8):472-8.
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KR. Tumor hypoxia and heterogeneity: challenges and
opportunities for the future. Semin Radiat Oncol. 1996;
6:59–70.
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current clinical, biologic, and molecular aspects. J Natl
Cancer Inst. 2001; 93(4):266-76.
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protein response. Annu Rev Biochem. 2005; 74: 739–89.
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Oxygen sensing, hypoxia-inducible factor-1 and the
regulation of mammalian gene expression. J. Exp. Biol.
1998; 201, 1153-1162.
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Nature Rev. Cancer. 2003; 3, 721–732.
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and metastasis. Novartis Found. Symp. 2001; 240, 154-
165.
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spontaneous lymph node metastasis in an orthotopic
murine model of human cervical carcinoma. Cancer
Res. 2004; 64, 2054-2061.
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Tumor Progression. Current Molecular Medicine. 2006;
6, 55-69.
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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.
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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.
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energy response to control cell growth and survival.
Cell. 2003; 115, 577–590.
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from stres pathway to homeostatic regulation. Science.
2011; 334, 1081–1086.
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histo compatibility complex class I antigens. Curr Opin
Organ Transplant. 2010; 15(4):499–504.
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chaperones and oxidoreductases: critical regulators of
tumor cell survival and immuno recognition. Front
Oncol. 2014; Oct 27;4:291.
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Müller-Hermelink HK, Vollmers HP. A new tumorspecific
variant of GRP78 as target for antibody-based
therapy. Lab Invest. 2008; 88(4):375–86.
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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.
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reticulum chaperones and unfolded protein response in
tumorigenesis and anticancer therapies. Oncogene.
2013; 32:805–18.
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between tumor microenvironment and cancer hallmarks.
Biochim Biophys Acta. 2012; 1826(1):13–22.
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reticulum protein-folding environment on cancer
development. Nat Rev Cancer. 2014;14(9):581-97.
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in liver disease. J Hepatol. 2011;54:795–809.
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endoplasmic reticulum stress signaling in cancer.
Biochem Pharmacol. 2013;85(5):653-66.
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distinct stress signaling pathways converge upon the
CHOP promoter during the mammalian unfolded protein
response. J Mol Biol. 2002; 318:1351–65.
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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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Holbrook NJ. Gadd153 sensitizes cells to endoplasmic
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Gunnison KM, et al. Adaptation to ER stress is mediated
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tolerance to extreme hypoxia and promotes tumor
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Zhang F, Ye J, Koumenis C, Cavener D, and Diehl JA.
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growth by limiting oxidative DNA damage. Oncogene.
2010; 29, 3881–3895.
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M, Chilloux J, et al. p58(IPK)-mediated attenuation of the
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during the mammalianunfolded protein response. Proc
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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
Sümeyra Çetinkaya
,
İlknur Çınar
,
Hatice Gül Dursun
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
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