WIP1 promotes cancer stem cell properties by inhibiting p38 MAPK in NSCLC

Abstract

Cancer stem cells (CSCs) are a small population of stem cell-like cancer cells that can initiate tumors in vivo, and are the major source of cancer initiation, relapse, and drug resistance. We previously reported that the p38 MAPK, through its downstream effectors MK2 and HSP27, suppressed CSC properties by downregulating the expression of transcription factors that mediate stemness in non-small-cell lung cancer (NSCLC) cells, and that despite unaltered total expression of total p38 proteins, the levels of activated p38 were reduced in NSCLC tissues. However, the mechanism underlying the reduced levels of activated p38 in NSCLC is unknown. In this study, we identified WIP1, a p38 phosphatase frequently overexpressed in cancer, as a suppressor of p38 in a pathway that regulates CSC properties in NSCLC. Increased WIP1 expression correlated with reduced levels of activated p38, and with increased levels of a CSC marker in NSCLC tissues. Further investigation revealed that WIP1 promoted stemness-related protein expression and CSC properties by inhibiting p38 activity in NSCLC cells. WIP1 inhibitors are currently under development as anticancer drugs based on their ability to reactivate p53. We found that a WIP1 inhibitor suppressed stemness-related protein expression and CSC properties by activating p38 in NSCLC cells in vitro and in vivo. These studies have identified the WIP1-p38-MK2-HSP27 cascade as a novel signaling pathway that, when altered, promotes CSC properties in NSCLC development, and have defined novel mechanisms underlying the oncogenic activity of WIP1 and the anticancer efficacy of WIP1 inhibitors.Signal Transduction and Targeted Therapy (2020) 5:36; https://doi.

A novel assay for screening WIP1 phosphatase substrates in nuclear extracts

“…Similarly, inhibition or loss of WIP1 did not increase the level of p38 activation after UVC or other forms of stress. Most of the studies describing the effect of WIP1 on p38 pathway relied on shRNA‐mediated depletion of WIP1 in the stable cell lines or on prolonged treatment with WIP1 inhibitor [40]. For instance, Deng et al .…”

“…For instance, Deng et al . [40] reported that treatment of A549 cells with GSK2830371 for 24–48 h increased the level of active p38. In the short treatment with an efficient dose of GSK2830371, we did not observe any effect on the basal level of active p38.…”

Targeting Phosphatases and Kinases: How to Checkmate Cancer

“…The protein phosphatase WIP1 (PPM1D) inhibitors are currently under clinical evaluation for their capability to subtract p53 from proteolytic degradation or inactivation. Deng et al (2020a) described a novel function of the WIP1 inhibitor GSK283071, which suppresses stemness features in NSCLC through the activation of p38 MAPK. Specifically, the inhibition of WIP1 induced p38 MAPK phosphorylation and consequent activation of the downstream targets MK2 and HSP27 and reduction of the SOX2, OCT4, NANOG and ALDH1A1 stemness markers, sphere forming capability and tumor-initiating potential (Deng et al, 2020a).…”

Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy

“…Recently, numerous studies have confirmed that HspB1 phosphorylation/dephosphorylation is a critical regulator in the formation/maintenance of CSC properties. HspB1 undergoes phosphorylation as the terminal substrate in the p38/MAPK pathway, and there are increasing reports linking this p38 MAPK/MAPKAPK2/HSP27 pathway to chemoresistance in lung CSCs [128,131] and oral CSCs [138], maintenance of CSC properties in lung CSCs [131], and EMT in renal [143] and lung CSCs [139]. Similarly, in colorectal CSCs, protein phosphatase PP2A was reported to dephosphorylate HspB1 and attenuate HspB1 effects by promoting CSC properties [136,144], indicating that the status of phosphorylated HspB1, mediated by kinase and phosphatase, is essential for HspB1 effects on CSC properties.…”

“…Then, HspB1 was identified to be related to CSC stemness by proteomics [ 129 ]. Indeed, several studies have shown that HspB1 is essential for CSC stemness in salivary adenoid cystic carcinoma [ 130 ], non-small-cell lung cancer [ 131 ], and breast cancer [ 132 ]. There are also reports linking HspB1 to the maintenance of CSC phenotypes in breast cancer stem cells [ 133 ] and gynecologic cancer stem cells [ 134 ].…”