Inhibition of autophagy using 3‑methyladenine increases cisplatin‑induced apoptosis by increasing endoplasmic reticulum stress in U251 human glioma cells

Zhang,Ruijian; Wang,Ruijun; Chen,Qianxue; Chang,Hong

doi:10.3892/mmr.2015.3588

Inhibition of autophagy using 3‑methyladenine increases cisplatin‑induced apoptosis by increasing endoplasmic reticulum stress in U251 human glioma cells

Authors:
- Ruijian Zhang
- Ruijun Wang
- Qianxue Chen
- Hong Chang
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Affiliations: Department of Neurosurgery, People's Hospital of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia 010017, P.R. China, Department of Radiology, The First Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia 010050, P.R. China, Department of Neurosurgery, Renmin Hospital, Wuhan University, Wuhan, Hubei 430060, P.R. China, Department of Neurology, People's Hospital of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia 010017, P.R. China
Published online on: April 1, 2015 https://doi.org/10.3892/mmr.2015.3588
Pages: 1727-1732
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Cisplatin is one of the most widely used chemotherapeutic drugs; however, the side effects and drug resistance limit its usage. Previous findings have demonstrated that cisplatin kills tumor cells through endoplasmic reticulum (ER) stress, which provides a novel method to minimize cisplatin toxicity and circumvent cisplatin resistance. ER stress induces cell autophagy, cell apoptosis and the complicated regulatory network between them. The role of autophagy in cisplatin chemotherapy remains to be elucidated. 3‑Methyladenine (3‑MA) is normally used as an inhibitor of autophagy. The present study reveals a significant role of the inhibition of autophagy by treatment with 3‑MA and cisplatin in combination in U251 human glioma cells. It was demonstrated that cisplatin induced the ER stress associated with apoptosis and autophagy in U251 cells. Inhibition of autophagy by 3‑MA increased the expression levels of protein disulfide isomerase, ubiquitinated proteins, glucose regulated protein 78 and CCAAT‑enhancer‑binding protein homologous protein, and induced the activation of caspase‑4 and caspase‑3. Treatment with 3‑MA combined with cisplatin increased cisplatin‑induced apoptosis by increasing ER stress. Therefore, the inhibition of autophagy has the potential to improve cisplatin chemotherapy.

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1	Stathopoulos GP: Cisplatin: process and future. J BUON. 18:564–569. 2013.PubMed/NCBI
2	Köberle B, Tomicic MT, Usanova S and Kaina B: Cisplatin resistance: preclinical findings and clinical implications. Biochim Biophys Acta. 1806:172–182. 2010.PubMed/NCBI
3	Sleijfer DT, Meijer S and Mulder NH: Cisplatin: a review of clinical applications and renal toxicity. Pharm Weekbl Sci. 7:237–244. 1985. View Article : Google Scholar : PubMed/NCBI
4	Macciò A and Madeddu C: Cisplatin: an old drug with a newfound efficacy – from mechanisms of action to cytotoxicity. Expert Opin Pharmacother. 14:1839–1857. 2013. View Article : Google Scholar
5	Sancho-Martínez SM, Prieto-García L, Prieto M, López-Novoa JM and López-Hernández FJ: Subcellular targets of cisplatin cytotoxicity: an integrated view. Pharmacol Ther. 136:35–55. 2012. View Article : Google Scholar : PubMed/NCBI
6	Yu F, Megyesi J and Price PM: Cytoplasmic initiation of cisplatin cytotoxicity. Am J Physiol Renal Physiol. 295:F44–F52. 2008. View Article : Google Scholar : PubMed/NCBI
7	Peyrou M, Hanna PE and Cribb AE: Cisplatin, gentamicin and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys. Toxicol Sci. 99:346–353. 2007. View Article : Google Scholar : PubMed/NCBI
8	Mandic A, Hansson J, Linder S and Shoshan MC: Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem. 278:9100–9106. 2003. View Article : Google Scholar : PubMed/NCBI
9	Liu H and Baliga R: Endoplasmic reticulum stress-associated caspase 12 mediates cisplatin-induced LLC-PK1 cell apoptosis. J Am Soc Nephrol. 16:1985–1992. 2005. View Article : Google Scholar : PubMed/NCBI
10	Xu Y, Wang C and Li Z: A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress. Mol Clin Oncol. 2:3–7. 2014.PubMed/NCBI
11	Gardner BM, Pincus D, Gotthardt K, Gallagher CM and Walter P: Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol. 5:a0131692013. View Article : Google Scholar : PubMed/NCBI
12	Høyer-Hansen M and Jäättelä M: Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ. 14:1576–1582. 2007. View Article : Google Scholar : PubMed/NCBI
13	Benbrook DM and Long A: Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis. Exp Oncol. 34:286–297. 2012.PubMed/NCBI
14	Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F and Imaizumi K: Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 26:9220–9231. 2006. View Article : Google Scholar : PubMed/NCBI
15	Tian Z, Yang Z, Gao J, Zhu L, Jiang R and Jiang Y: Lower esophageal microbiota species are affected by the eradication of Helicobacter pylori infection using antibiotics. Exp Ther Med. 9:685–692. 2015.PubMed/NCBI
16	Xu Y, Yu H, Qin H, Kang J, Yu C, Zhong J, Su J, Li H and Sun L: Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells. Cancer Lett. 314:232–243. 2012. View Article : Google Scholar
17	Song L, Liu H, Ma L, Zhang X, Jiang Z and Jiang C: Inhibition of autophagy by 3-MA enhances endoplasmic reticulum stress-induced apoptosis in human nasopharyngeal carcinoma cells. Oncol Lett. 6:1031–1038. 2013.PubMed/NCBI
18	Stewart DJ: The role of chemotherapy in the treatment of gliomas in adults. Cancer Treat Rev. 16:129–160. 1989. View Article : Google Scholar : PubMed/NCBI
19	Lesser GJ and Grossman SA: The chemotherapy of adult primary brain tumors. Cancer Treat Rev. 19:261–281. 1993. View Article : Google Scholar : PubMed/NCBI
20	Basu A and Krishnamurthy S: Cellular responses to Cisplatin-induced DNA damage. J Nucleic Acids. 2010:2013672010. View Article : Google Scholar : PubMed/NCBI
21	Perlmutter DH: Misfolded proteins in the endoplasmic reticulum. Lab Invest. 79:623–638. 1999.PubMed/NCBI
22	Kopito RR and Ron D: Conformational disease. Nat Cell Biol. 2:E207–E209. 2000. View Article : Google Scholar : PubMed/NCBI
23	Ruiz A, Matute C and Alberdi E: Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes. Cell Death Dis. 1:e542010. View Article : Google Scholar
24	Brewer JW: Regulatory crosstalk within the mammalian unfolded protein response. Cell Mol Life Sci. 71:1067–1079. 2014. View Article : Google Scholar
25	Xu C, Bailly-Maitre B and Reed JC: Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 115:2656–2664. 2005. View Article : Google Scholar : PubMed/NCBI
26	Szegezdi E, Logue SE, Gorman AM and Samali A: Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7:880–885. 2006. View Article : Google Scholar : PubMed/NCBI
27	Wang XZ and Ron D: Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science. 272:1347–1349. 1996. View Article : Google Scholar : PubMed/NCBI
28	Klionsky DJ and Codogno P: The mechanism and physiological function of macroautophagy. J Innate Immun. 5:427–433. 2013. View Article : Google Scholar : PubMed/NCBI
29	Ryter SW, Cloonan SM and Choi AM: Autophagy: a critical regulator of cellular metabolism and homeostasis. Mol Cells. 36:7–16. 2013. View Article : Google Scholar : PubMed/NCBI
30	Parzych KR and Klionsky DJ: An overview of autophagy: morphology, mechanism and regulation. Antioxid Redox Signal. 20:460–473. 2014. View Article : Google Scholar :
31	Klionsky DJ, Cuervo AM and Seglen PO: Methods for monitoring autophagy from yeast to human. Autophagy. 3:181–206. 2007. View Article : Google Scholar : PubMed/NCBI