p62/SQSTM1 is involved in cisplatin resistance in human ovarian cancer cells via the Keap1-Nrf2-ARE system

• Published in: International journal of oncology Vol. 45; no. 6; pp. 2341 - 2348
• Main Authors: XIA, MEIHUI, YU, HUIMEI, GU, SHUANG, XU, YE, SU, JING, LI, HONGYAN, KANG, JINSONG, CUI, MANHUA
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.12.2014; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Antioxidants - metabolism; Apoptosis; Apoptosis - genetics; Autophagy; Cancer therapies; Cell Line, Tumor; Cisplatin; Cisplatin - therapeutic use; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Genetic aspects; Health aspects; Humans; Immunoglobulins; Intracellular Signaling Peptides and Proteins - biosynthesis; Keap1-Nrf2-ARE signaling pathway; Kelch-Like ECH-Associated Protein 1; Lasers; Microscopy; NF-E2-Related Factor 2 - biosynthesis; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Oxidative stress; Oxidative Stress - genetics; p62/SQSTM1; Proteins; Sequestosome-1 Protein; Signal Transduction - drug effects; Studies; Vesicular Transport Proteins - biosynthesis; China; United States > US
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2014.2669

The mechanisms underlying cisplatin resistance in tumors are not fully understood. Previous studies have reported that cellular resistance to oxidative stress is accompanied by resistance to cisplatin. However, the relationship between the resistance to oxidative stress and cisplatin drug resistance in human ovarian cancer cells (HOCCs) is not clear. Here, we reveal a critical role for the multifunctional protein p62/SQSTM1 in cisplatin resistance in human ovarian cancer cells (HOCCs). p62/SQSTM1 (sequestosome 1) plays important roles in cell differentiation, proliferation and as an antiapoptotic molecule. We found that cisplatin-resistant SKOV3/DDP cells express much higher levels of p62 than do cisplatin-sensitive SKOV3 cells. The protein p62 can activate the Keap1-Nrf2-ARE signaling pathway and induce the expression of antioxidant genes in SKOV3/DDP cells. Knockdown of p62 resensitizes SKOV3/DDP cells to cisplatin. Collectively, our data indicate that cisplatin resistance in HOCCs is partially attributable to their high expression of p62, which plays an important role in preventing ROS stress-induced apoptosis by regulating the Keap1-Nrf2-ARE signaling pathway.