Open Accessp62/ SQSTM 1 as an oncotarget mediates cisplatin resistance through activating RIP 1‐ NF ‐κB pathway in human ovarian cancer cells
Author(s) -
Yan XiaoYu,
Zhang Yu,
Zhang JuanJuan,
Zhang LiChao,
Liu YaNan,
Wu Yao,
Xue YaNan,
Lu ShengYao,
Su Jing,
Sun LianKun
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13276
Subject(s) - cisplatin , apoptosis , ovarian cancer , cancer research , signal transduction , carcinogenesis , cell growth , cancer cell , nf κb , biology , cancer , microbiology and biotechnology , chemistry , chemotherapy , biochemistry , genetics
Platinum‐based therapeutic strategies have been widely used in ovarian cancer treatment. However, drug resistance has greatly limited therapeutic efficacy. Recently, tolerance to cisplatin has been attributed to other factors unrelated to DNA . p62 (also known as SQSTM 1) functions as a multifunctional hub participating in tumorigenesis and may be a therapeutic target. Our previous study showed that p62 was overexpressed in drug‐resistant ovarian epithelial carcinoma and its inhibition increased the sensitivity to cisplatin. In this study, we demonstrate that the activity of the NF ‐κB signaling pathway and K63‐linked ubiquitination of RIP 1 was higher in cisplatin‐resistant ovarian ( SKOV 3/ DDP ) cells compared with parental cells. In addition, cisplatin resistance could be reversed by inhibiting the expression of p62 using si RNA . Furthermore, deletion of the ZZ domain of p62 that interacts with RIP 1 in SKOV 3 cells markedly decreased K63‐linked ubiquitination of RIP 1 and inhibited the activation of the NF ‐κB signaling pathway. Moreover, loss of the ZZ domain from p62 led to poor proliferative capacity and high levels of apoptosis in SKOV 3 cells and made them more sensitive to cisplatin treatment. Collectively, we provide evidence that p62 is implicated in the activation of NF ‐κB signaling that is partly dependent on RIP 1. p62 promotes cell proliferation and inhibits apoptosis thus mediating drug resistance in ovarian cancer cells.