Endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance in human ovarian cancer cells

• Published in: Oncotarget Vol. 8; no. 30; pp. 49380 - 49394
• Main Authors: Hu, Jin-Long, Hu, Xin-Long, Guo, Ai-Ye, Wang, Chao-Jie, Wen, Yi-Yang, Cang, Shun-Dong
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 25.07.2017
• Subjects: Adult; Aged; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy - drug effects; Autophagy - genetics; Autophagy-Related Proteins - genetics; Autophagy-Related Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; Female; Gene Expression; Humans; Middle Aged; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; Tunicamycin - pharmacology; Young Adult; apoptosis; PI3K/AKT/mTOR; autophagy; ovarian cancer; endoplasmic reticulum stress (ERS)
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.17673

Ovarian cancer presents the highest mortality rate among gynecological tumors. Here, we measured cell viability, proliferation, apoptosis, autophagy, and expression of endoplasmic reticulum stress (ERS)-related proteins, PI3K/AKT/mTOR pathway-related proteins, and apoptosis- and autophagy-related proteins in SKOV3 and SKOV3/CDDP cells treated with combinations of CDDP, tunicamycin, and BEZ235 (blank control, CDDP, CDDP + tunicamycin, CDDP + BEZ235, and CDDP + tunicamycin + BEZ235). Increasing concentrations of tunicamycin and CDDP activated ERS in SKOV3 cells, reduced cell viability and proliferation, increased apoptosis and autophagy, enhanced expression of ERS-related proteins, and inhibited expression of PI3K/AKT/mTOR pathway-related proteins. CDDP, tunicamycin, and BEZ235 acted synergistically to enhance these effects. We also detected lower expression of the ERS-related proteins caspase-3, LC3 II and Beclin 1 in ovarian cancer tissues than adjacent normal tissues. By contrast, expression of Bcl-2 and PI3K/AKT/mTOR pathway-related proteins was higher in ovarian cancer tissues than adjacent normal tissues. Lastly, expression of the ERS-related proteins Beclin 1, caspase-3 and LC3 II was higher in the sensitive group than the resistant group, while expression of Bcl-2, LC3 I, P62 and PI3K/AKT/mTOR pathway-related proteins was decreased. These results show that ERS promotes cell autophagy and apoptosis while reversing chemoresistance in ovarian cancer cells by inhibiting activation of the PI3K/AKT/mTOR signaling pathway.