Basic & Clinical Cancer Research 2017. 9(2):38-48.

Endoplasmic Reticulum Stress as a Therapeutic Target in Cancer: A mini review
Marveh Rahmati, Saeid Amanpour, Amirhossein Kharman-Biz, Mohammad Amin Moosavi


Perturbation of endoplasmic reticulum (ER) homeostasis induces a stress condition described as “ER stress”, which in turn leads to a well-regulated program termed as unfolded protein response (UPR). The principal purpose of UPR is to reestablish the ER homeostasis. Some of the physiological and pathological situations that disrupt the homeostasis include hypoxia, glucose limitations, nutrient deprivation, low pH, genomic instability, and some cytotoxic compounds are frequently observed during the core formation and progression of tumors. These stressful microenvironments around the tumors affect the innate and adaptive immune responses. The ER stress is usually induced to activate the UPR and to handle the stress. Although the UPR mechanism is primarily a pro-survival process, preserved and/or prolonged stress may induce cell death. In tumors, ER stress may modify apoptotic and autophagic cell death and, thereby provokes drug resistance of cancerous cells to current therapies. In this mini-review, at first, we highlight the role of UPR and its mediators in cancerous cells fate and then discuss their potential opportunities in cancer therapy.


ER stress response; unfolded protein response; cancer therapy

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Bernales S, Schuck S, Walter P. ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy. 2007;3(3):285-7.

Tsai YC, Weissman AM. The unfolded protein response, degradation from the endoplasmic reticulum, and cancer. Genes & cancer. 2010;1(7):764-78.

Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nature Reviews Cancer. 2014;14(9):581-97.

Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nature reviews Molecular cell biology. 2012;13(2):89-102.

Clarke HJ, Chambers JE, Liniker E, Marciniak SJ. Endoplasmic reticulum stress in malignancy. Cancer cell. 2014;25(5):563-73.

Rutkowski DT, Kaufman RJ. A trip to the ER: coping with stress. Trends in cell biology. 2004;14(1):20-8.

Liu Z, Lv Y, Zhao N, Guan G, Wang J. Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress-decided cell fate. Cell death & disease. 2015;6(7):e1822.

Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death & Differentiation. 2004;11(4):381-9.

Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. The Journal of cell biology. 2001;153(5):1011-22.

Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129(7):1337-49.

Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress‐induced apoptosis. EMBO reports. 2006;7(9):880-5.

Yadav RK, Chae S-W, Kim H-R, Chae HJ. Endoplasmic reticulum stress and cancer. Journal of cancer prevention. 2014;19(2):75.

Cubillos-Ruiz JR, Mohamed E, Rodriguez PC. Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer. Journal for immunotherapy of cancer. 2017;5(1):5.

Dalton L, Clarke H, Knight J, Lawson M, Wason J, Lomas D, et al. The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma. British journal of cancer. 2013;108(6):1340.

Davies M, Barraclough DL, Stewart C, Joyce KA, Eccles RM, Barraclough R, et al. Expression and splicing of the unfolded protein response gene XBP‐1 are significantly associated with clinical outcome of endocrine‐treated breast cancer. International journal of cancer. 2008;123(1):85-8.

Lee B-R, Chang S-Y, Hong E-H, Kwon B-E, Kim HM, Kim Y-J, et al. Elevated endoplasmic reticulum stress reinforced immunosuppression in the tumor microenvironment via myeloidderived suppressor cells. Oncotarget. 2014;5(23):12331.

Maurel M, McGrath EP, Mnich K, Healy S, Chevet E, Samali A, editors. Controlling the unfolded protein response-mediated life and death decisions in cancer. Seminars in cancer biology; 2015: Elsevier.

Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic Reticulum Stress and the Hallmarks of Cancer. Trends in Cancer. 2016;2(5):252-62.

Cullinan SB, Diehl JA. PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. Journal of Biological Chemistry. 2004;279(19):20108-17.

Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nature Reviews Cancer. 2014;14(9):611-22.

Ranganathan AC, Zhang L, Adam AP, Aguirre-Ghiso JA. Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase–like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer research. 2006;66(3):1702-11.

Kurosawa S, Hashimoto E, Ukai W, Toki S, Saito S, Saito T. Olanzapine potentiates neuronal survival and neural stem cell differentiation: regulation of endoplasmic reticulum stress response proteins. Journal of neural transmission. 2007;114(9):1121-8.

Kaufman RJ, Scheuner D, Schröder M, Shen X, Lee K, Liu CY, et al. The unfolded protein response in nutrient sensing and differentiation. Nature Reviews Molecular Cell Biology.2002;3(6):411-21.

Wielenga MC, Colak S, Heijmans J, de Jeude JFvL, Rodermond HM, Paton JC, et al. ER-stress-induced differentiation sensitizes colon cancer stem cells to chemotherapy. Cell reports. 2015;13(3):489-94.

Ulianich L, Garbi C, Treglia AS, Punzi D, Miele C, Raciti GA, et al. ER stress is associated with dedifferentiation and an epithelial-to-mesenchymal transition-like phenotype in PC Cl3 thyroid cells. J Cell Sci. 2008;121(4):477-86.

Gorman AM, Healy SJ, Jäger R, Samali A. Stress management at the ER: regulators of ER stress-induced apoptosis. Pharmacology & therapeutics. 2012;134(3):306-16.

Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, et al. IRE1 signaling affects cell fate during the unfolded protein response. science. 2007;318(5852):944-9.

Rao RV, Ellerby H, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program. Cell Death & Differentiation. 2004;11(4):372-80.

Mokarram P, Albokashy M, Zarghooni M, Moosavi MA, Sepehri Z, Chen QM, et al. New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets. Autophagy. 2017;13(5):781-819.

Rashid H-O, Yadav RK, Kim H-R, Chae H-J. ER stress: Autophagy induction, inhibition and selection. Autophagy 2015;11(11):1956-77.

Salazar M, Carracedo A, Salanueva ÍJ, Hernández-Tiedra S, Lorente M, Egia A, et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. The Journal of clinical investigation. 2009;119(5):1359.

Moosavi MA, Sharifi M, Ghafary SM, Mohammadalipour Z, Khataee A, Rahmati M, et al. Photodynamic N-TiO2 nanoparticle treatment induces controlled Ros-mediated autophagy and terminal differentiation of leukemia cells. Scientific reports. 2016;6:34413.

Moosavi MA, Rahmati M, Ashtari N, Alizadeh J, Hashemi M, Bathaei SZ, et al. Apoptosis, Autophagy, and Unfolded Protein Response and Cerebellar Development. Development of the Cerebellum from Molecular Aspects to Diseases: Springer; 2017. p. 153-78.

Matus S, Nassif M, Glimcher LH, Hetz C. XBP-1 deficiency in the nervous system reveals a homeostatic switch to activate autophagy. Autophagy. 2009;5(8):1226-8.

Gabrilovich DI, Nagaraj S. Myeloid-derived-suppressor cells as regulators of the immune system. Nature reviews Immunology. 2009;9(3):162.

Zanetti M, Rodvold J, Mahadevan N. The evolving paradigm of cell-nonautonomous UPR-based regulation of immunity by cancer cells. Oncogene. 2016;35(3):269.

Pol J, Vacchelli E, Aranda F, Castoldi F, Eggermont A, Cremer I, et al. Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology. 2015;4(4):e1008866.

Schonthal AH. Targeting endoplasmic reticulum stress for cancer therapy. Frontiers in bioscience (Scholar edition). 2011;4:412-31.

Pyrko P, Schönthal 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 research. 2007;67(20):9809-16.

Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 2005;35(4):373-81.

Koong AC, Chauhan V, Romero-Ramirez L. Targeting XBP-1 as a novel anti-cancer strategy. Cancer biology & therapy. 2006;5(7):756-9.

Trivedi R, Mishra DP. Trailing TRAIL resistance: novel targets for TRAIL sensitization in cancer cells. Frontiers in oncology. 2015;5.

Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, et al. ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proceedings of the National Academy of Sciences 2009;106(7):2200-5.

Lawson B, Brewer JW, Hendershot LM. Geldanamycin, an hsp90/GRP94‐binding drug, induces increased transcription of endoplasmic reticulum (ER) chaperones via the ER stress pathway. Journal of cellular physiology. 1998;174(2):170-9.

Neckers L, Workman P. Hsp90 molecular chaperone inhibitors: are we there yet? Clinical cancer research. 2012;18(1):64-76.

Rao RV, Hermel E, Castro-Obregon S, del Rio G, Ellerby LM, Ellerby HM, et al. Coupling endoplasmic reticulum stress to the cell death program mechanism of caspase activation. Journal of Biological Chemistry. 2001;276(36):33869-74.

Moon JL, Kim SY, Shin SW, Park J-W. Regulation of brefeldin A-induced ER stress and apoptosis by mitochondrial NADP+-dependent isocitrate dehydrogenase. Biochemical and biophysical research communications. 2012;417(2):760-4.

Lee AS. The glucose-regulated proteins: stress induction and clinical applications. Trends in biochemical sciences. 2001;26(8):504-10.

Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer letters. 2008;269(1):7-17.

Liu Y-L, Yang P-M, Shun C-T, Wu M-S, Weng J-R, Chen C-C. Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Autophagy. 2010;6(8):1057-65.

Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. Journal of Clinical Oncology. 2009;27(32):5459-68.

Samson JM, Thorburn A. Autophagy as a Therapeutic Target in Cancer. Targeting Autophagy in Cancer Therapy: Springer; 2016. p. 1-16.

Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Molecular cancer therapeutics. 2011;10(9):1533-41.


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