Inhibition of endoplasmic reticulum stress-induced autophagy sensitizes melanoma cells to temozolomide treatment

Ryabaya,Oxana; Prokofieva,Anastasia; Khochenkov,Dmitry; Abramov,Ivan; Zasedatelev,Alexander; Stepanova,Evgenia

doi:10.3892/or.2018.6430

Inhibition of endoplasmic reticulum stress-induced autophagy sensitizes melanoma cells to temozolomide treatment

Authors:
- Oxana Ryabaya
- Anastasia Prokofieva
- Dmitry Khochenkov
- Ivan Abramov
- Alexander Zasedatelev
- Evgenia Stepanova
View Affiliations

Affiliations: N.N. Blokhin National Medical Scientific Center of Oncology, 115478 Moscow, Russia, Engelhardt Institute of Molecular Biology, 119991 Moscow, Russia
Published online on: May 9, 2018 https://doi.org/10.3892/or.2018.6430
Pages: 385-394

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The incidence of malignant melanoma is increasing. The discovery of agents specifically targeting the mutated cascades has provided a good response for patients with oncogenic B-Raf proto-оncogene, serine/threonine kinase (BRAF). However, numerous studies continue to focus on novel methods of treatment to overcome acquired resistance to novel drugs. Recently, it has been revealed that inhibition of endoplasmic reticulum (ER) stress chaperon 78 kDa glucose-regulated protein 78 (GRP78) leads to downregulation of autophagy and increased sensitivity to temozolomide (TMZ) treatment. Melanoma cells have a different sensitivity to TMZ treatment, which corresponds to the basal autophagy level. In the present study, we demonstrated that downregulation of GRP78 mitigated chemoresistance to TMZ in three melanoma cell lines. We found that downregulation of GRP78 led to inhibition of autophagy, cell cycle arrest in the G0/G1 phase, and activation of caspase-7-induced apoptosis, and this was affected by the initial autophagy level. Moreover, inhibition of GRP78 mitigated the combined TMZ and chloroquine effect. Our data revealed that autophagy inhibition through downregulation of ER stress response could overcome resistance to TMZ treatment in melanoma cells with a high basal level of autophagy treatment, which makes this combination a potential potent antitumor treatment for metastatic melanoma.

View Figures

View References

1	Saito R de F, Tortelli TC Jr, Jacomassi MD, Otake AH and Chammas R: Emerging targets for combination therapy in melanomas. FEBS Lett. 589:3438–3448. 2015. View Article : Google Scholar : PubMed/NCBI
2	Luke JJ and Schwartz GK: Chemotherapy in the management of advanced cutaneous malignant melanoma. Clin Dermatol. 31:290–297. 2013. View Article : Google Scholar : PubMed/NCBI
3	Boussemart L, Malka-Mahieu H, Girault I, Allard D, Hemmingsson O, Tomasic G, Thomas M, Basmadjian C, Ribeiro N, Thuaud F, et al: eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature. 513:105–109. 2014. View Article : Google Scholar : PubMed/NCBI
4	Goding CR: The path of least resistance: Enhancing the effectiveness of BRAF inhibitors. Pigment Cell Melanoma Res. 26:296–297. 2013. View Article : Google Scholar
5	Iams WT, Sosman JA and Chandra S: Novel targeted therapies for metastatic melanoma. Cancer J. 23:54–58. 2017. View Article : Google Scholar : PubMed/NCBI
6	Codogno P and Meijer AJ: Autophagy and signaling: Their role in cell survival and cell death. Cell Death Differ. 12 Suppl 2:1509–1518. 2005. View Article : Google Scholar : PubMed/NCBI
7	Kondo Y, Kanzawa T, Sawaya R and Kondo S: The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 5:726–734. 2005. View Article : Google Scholar : PubMed/NCBI
8	Amaravadi RK, Lippincott-Schwartz J, Yin X-M, Weiss WA, Takebe N, Timmer W, DiPaola RS, Lotze MT and White E: Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 17:654–666. 2011. View Article : Google Scholar : PubMed/NCBI
9	Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y and Kondo S: Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 11:448–457. 2004. View Article : Google Scholar : PubMed/NCBI
10	Lazova R, Klump V and Pawelek J: Autophagy in cutaneous malignant melanoma. J Cutan Pathol. 37:256–268. 2010. View Article : Google Scholar : PubMed/NCBI
11	Rangwala R, Leone R, Chang YC, Fecher LA, Schuchter LM, Kramer A, Tan KS, Heitjan DF, Rodgers G, Gallagher M, et al: Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy. 10:1369–1379. 2014. View Article : Google Scholar : PubMed/NCBI
12	Ma X-H, Piao S, Wang D, McAfee QW, Nathanson KL, Lum JJ, Li LZ and Amaravadi RK: Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. Clin Cancer Res. 17:3478–3489. 2011. View Article : Google Scholar : PubMed/NCBI
13	Ma X-H, Piao S-F, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, et al: Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest. 124:1406–1417. 2014. View Article : Google Scholar : PubMed/NCBI
14	Levy JMM, Thompson JC, Griesinger AM, Amani V, Donson AM, Birks DK, Morgan MJ, Mirsky DM, Handler MH, Foreman NK, et al: Autophagy inhibition improves chemosensitivity in BRAF(V600E) brain tumors. Cancer Discov. 4:773–780. 2014. View Article : Google Scholar : PubMed/NCBI
15	Tsai YC and Weissman AM: The unfolded protein response, degradation from endoplasmic reticulum and cancer. Genes Cancer. 1:764–778. 2010. View Article : Google Scholar : PubMed/NCBI
16	Hersey P and Zhang XD: Adaptation to ER stress as a driver of malignancy and resistance to therapy in human melanoma. Pigment Cell Melanoma Res. 21:358–367. 2008. View Article : Google Scholar : PubMed/NCBI
17	Bernales S, McDonald KL and Walter P: Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4:e4232006. View Article : Google Scholar : PubMed/NCBI
18	Hetz C: The unfolded protein response: Controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 13:89–102. 2012. View Article : Google Scholar : PubMed/NCBI
19	Pyrko P, Schönthal AH, Hofman FM, Chen TC and Lee AS: The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res. 67:9809–9816. 2007. View Article : Google Scholar : PubMed/NCBI
20	Lee AS: The glucose-regulated proteins: Stress induction and clinical applications. Trends Biochem Sci. 26:504–510. 2001. View Article : Google Scholar : PubMed/NCBI
21	Li J, Ni M, Lee B, Barron E, Hinton DR and Lee AS: The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells. Cell Death Differ. 15:1460–1471. 2008. View Article : Google Scholar : PubMed/NCBI
22	Golden EB, Cho H-Y, Jahanian A, Hofman FM, Louie SG, Schönthal AH and Chen TC: Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy. Neurosurg Focus. 37:E122014. View Article : Google Scholar : PubMed/NCBI
23	Cook KL, Shajahan AN, Wärri A, Jin L, Hilakivi-Clarke LA and Clarke R: Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Res. 72:3337–3349. 2012. View Article : Google Scholar : PubMed/NCBI
24	Cerezo M, Lehraiki A, Millet A, Rouaud F, Plaisant M, Jaune E, Botton T, Ronco C, Abbe P, Amdouni H, et al: Compounds triggering ER stress exert anti-melanoma effects and overcome BRAF inhibitor resistance. Cancer Cell. 29:805–819. 2016. View Article : Google Scholar : PubMed/NCBI
25	Vandewynckel Y-P, Laukens D, Geerts A, Bogaerts E, Paridaens A, Verhelst X, Janssens S, Heindryckx F and Van Vlierberghe H: The paradox of the unfolded protein response in cancer. Anticancer Res. 33:4683–4694. 2013.PubMed/NCBI
26	Mikhaĭlova IN, Lukashina MI, Baryshnikov AIu, Morozova LF, Burova OS, Palkina TN, Kozlov AM, Golubeva VA, Cheremushkin EA, Doroshenko MB, et al: Melanoma cell lines as the basis for antitumor vaccine preparation. Vestn Ross Akad Med Nauk. 60:37–40. 2005.(In Russian).
27	Mikhaylova IN, Kovalevsky DA, Morozova LF, Golubeva VA, Cheremushkin EA, Lukashina MI, Voronina ES, Burova OS, Utyashev IA, Kiselev SL, et al: Cancer/testis genes expression in human melanoma cell lines. Melanoma Res. 18:303–313. 2008. View Article : Google Scholar : PubMed/NCBI
28	Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B, et al: RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 526:583–586. 2015. View Article : Google Scholar : PubMed/NCBI
29	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
30	Ryabaya OO, Inshakov AN, Egorova AV, Emelyanova MA, Nasedkina TV, Zasedatelev AS, Khochenkov DA and Stepanova EV: Autophagy inhibitors chloroquine and LY294002 enhance temozolomide cytotoxicity on cutaneous melanoma cell lines in vitro. Anticancer Drugs. 28:307–315. 2017. View Article : Google Scholar : PubMed/NCBI
31	Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A and Thompson CB: Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest. 117:326–336. 2007. View Article : Google Scholar : PubMed/NCBI
32	Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al: BRIM-3 Study Group: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 364:2507–2516. 2011. View Article : Google Scholar : PubMed/NCBI
33	Romano E, Pradervand S, Paillusson A, Weber J, Harshman K, Muehlethaler K, Speiser D, Peters S, Rimoldi D and Michielin O: Identification of multiple mechanisms of resistance to vemurafenib in a patient with BRAFV600E-mutated cutaneous melanoma successfully rechallenged after progression. Clin Cancer Res. 19:5749–5757. 2013. View Article : Google Scholar : PubMed/NCBI
34	Caporali S, Alvino E, Lacal PM, Levati L, Giurato G, Memoli D, Caprini E, Cappellini Antonini GC and D'Atri S: Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor. Int J Oncol. 49:1164–1174. 2016. View Article : Google Scholar : PubMed/NCBI
35	Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, et al: Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 468:973–977. 2010. View Article : Google Scholar : PubMed/NCBI
36	Armstrong JL, Corazzari M, Martin S, Pagliarini V, Falasca L, Hill DS, Ellis N, Al Sabah S, Redfern CP, Fimia GM, et al: Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition. Clin Cancer Res. 17:2216–2226. 2011. View Article : Google Scholar : PubMed/NCBI
37	White E: Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 12:401–410. 2012. View Article : Google Scholar : PubMed/NCBI
38	Corazzari M, Fimia GM, Lovat P and Piacentini M: Why is autophagy important for melanoma? Molecular mechanisms and therapeutic implications. Semin Cancer Biol. 23:337–343. 2013. View Article : Google Scholar : PubMed/NCBI
39	Martin S, Dudek-Perić AM, Maes H, Garg AD, Gabrysiak M, Demirsoy S, Swinnen JV and Agostinis P: Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells. Biochem Pharmacol. 93:290–304. 2015. View Article : Google Scholar : PubMed/NCBI
40	Oyadomari S and Mori M: Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11:381–389. 2004. View Article : Google Scholar : PubMed/NCBI
41	Lin C-J, Lee C-C, Shih Y-L, Lin C-H, Wang S-H, Chen T-H and Shih C-M: Inhibition of mitochondria- and endoplasmic reticulum stress-mediated autophagy augments temozolomide-induced apoptosis in glioma cells. PLoS One. 7:e387062012. View Article : Google Scholar : PubMed/NCBI
42	Yang P-M, Liu Y-L, Lin Y-C, Shun C-T, Wu M-S and Chen C-C: Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res. 70:7699–7709. 2010. View Article : Google Scholar : PubMed/NCBI
43	Xi H, Kurtoglu M, Liu H, Wangpaichitr M, You M, Liu X, Savaraj N and Lampidis TJ: 2-Deoxy-D-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. Cancer Chemother Pharmacol. 67:899–910. 2011. View Article : Google Scholar : PubMed/NCBI