p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Abstract

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 SQSTM1) 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 RIP1 was higher in cisplatin‐resistant ovarian (SKOV3/DDP) cells compared with parental cells. In addition, cisplatin resistance could be reversed by inhibiting the expression of p62 using siRNA. Furthermore, deletion of the ZZ domain of p62 that interacts with RIP1 in SKOV3 cells markedly decreased K63‐linked ubiquitination of RIP1 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 SKOV3 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 RIP1. p62 promotes cell proliferation and inhibits apoptosis thus mediating drug resistance in ovarian cancer cells.

p62/SQSTM1 – steering the cell through health and disease

“…Currently, the protein is a diagnostic and prognostic marker in multiple forms of cancer, i.e. osteosarcoma, oral squamous cell carcinoma, cutaneous malignant melanoma, esophageal adenocarcinoma, ovarian, colon, breast and non-small cell lung cancers, and solid tumors Daniels et al, 2013;Ellis et al, 2014;Giatromanolaki et al, 2014;Inoue et al, 2012;Iwadate et al, 2014;Liu et al, 2014a;Luo et al, 2013;Ma et al, 2018;Niklaus et al, 2017;Park et al, 2013;Ruan et al, 2018;Schläfli et al, 2016), and has attracted attention as a potential therapeutic target (Yan et al, 2017;Zhang et al, 2016). An antitumor SQSTM1 DNA vaccine has already been developed and trialed in humans (Gabai et al, 2014;Ponomarenko et al, 2017;Sabbieti et al, 2015;Venanzi et al, 2013); however, SQSTM1 can have both beneficial and deleterious effects depending on the pathological context, as is the case for autophagy itself (Dikic and Elazar, 2018).…”

Intranuclear inclusions in hepatocellular carcinoma contain autophagy‐associated proteins and correlate with prolonged survival

“…To clarify if autophagy-associated proteins [14] are detectable in these nuclear inclusions we looked for the presence of the proteins p62/sequestosome1, ubiquitin, LC3B, cathepsin B and cathepsin D by immunohistochemistry. Notably, p62 is also involved in several biological processes [15,16] including NFκB activity, cell proliferation [17,18], apoptosis [19], Keap1-Nrf2 system [20], DNA repair [21,22] and is associated with several cancer types [23][24][25][26][27][28][29][30][31]. In this study we investigated the occurrence of nuclear inclusions in hepatocytes of patients with HCC, characterised the inclusions by means of electron microscopy and immunohistochemistry, and explored if these inclusions have any impact on patient survival.…”

“…We detected p62 immunoreactivity in the intranuclear inclusions. p62 is a scaffold protein with multiple domains that allows interaction with various binding partners and the regulation of several physiological processes in addition to the autophagy pathway [15][16][17][18][19][20]31]. High p62 can induce activation of Nrf2 or NFκB signalling pathways promoting cancer progression; nuclear p62 is involved in delivering ubiquitinated proteins for degradation [29,31].…”

Opportunities and Challenges of the Human Microbiome in Ovarian Cancer

“…Nucleotidebinding oligomerization domain-containing protein 1 [(NOD1) and 2 (NOD2)] belong to the NLR family. NOD1 and NOD2 can induce an increase in IL-6 and NF-κB, which can enhance the metastasis and drug resistance of ovarian cancer (59,60).…”