WIP1 promotes cancer stem cell properties by inhibiting p38 MAPK in NSCLC.
Animals
Apoptosis
/ genetics
Carcinoma, Non-Small-Cell Lung
/ genetics
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
/ genetics
Heterografts
Humans
MAP Kinase Signaling System
/ genetics
Mice
Neoplastic Stem Cells
/ metabolism
Phosphorylation
/ genetics
Protein Phosphatase 2C
/ genetics
Signal Transduction
p38 Mitogen-Activated Protein Kinases
/ genetics
Journal
Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423
Informations de publication
Date de publication:
15 04 2020
15 04 2020
Historique:
received:
19
10
2019
accepted:
04
02
2020
revised:
02
02
2020
entrez:
17
4
2020
pubmed:
17
4
2020
medline:
13
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32296033
doi: 10.1038/s41392-020-0126-x
pii: 10.1038/s41392-020-0126-x
pmc: PMC7156655
doi:
Substances chimiques
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
PPM1D protein, human
EC 3.1.3.16
Protein Phosphatase 2C
EC 3.1.3.16
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
36Subventions
Organisme : NCI NIH HHS
ID : R01 CA131231
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172115
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA012197
Pays : United States
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