Inactivation of p38 MAPK contributes to stem cell-like properties of non-small cell lung cancer

Fang, Yan; Wang, Juan; Wang, Guanwen; Zhou, Chen; Wang, Peng; Zhao, Shuangtao; Zhao, Shaorong; Huang, Shan; Su, Weijun; Jiang, Pengling; Chang, Antao; Xiang, Rong; Sun, Peiqing

doi:10.18632/oncotarget.15804

Cited by 32 publications

(35 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[30][31][32] Consistent with the tumor-inhibiting effect of p38 on human cancer, we previously reported that the level of activated/ phosphorylated p38 (p-p38) was reduced in NSCLC tissue samples compared with normal/normal adjacent lung tissue samples (N/ NAT). 25 To explore the mechanism responsible for the downregulation of p38 activity in NSCLC, we investigated the relationship between WIP1, a p38 phosphatase overexpressed in cancer, and p-p38. We first performed immunohistochemistry to examine the expression of WIP1 in human lung cancer samples with a tissue array containing 116 NSCLC tumor tissue samples (60 squamous cell carcinoma and 56 adenocarcinoma specimens) and 16 normal lung tissues/normal adjacent lung tissue samples (N/NAT) (4N and 12 NAT specimens) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1b), as we reported previously. 25 Next, we divided the 116 NSCLC tumor tissue samples into two groups (high and low) based on their immunohistochemical staining scores for WIP1. The percentages of cases with high or low p-p38 levels were calculated by their staining scores in each group.…”

Section: Resultsmentioning

confidence: 99%

“…Increased expression of WIP1 correlates with increased levels of the CSC marker ALDH1 in NSCLC We previously demonstrated that reduced p-p38 levels correlated with increased SOX2 levels in NSCLC tissues, and that activated p38 suppressed CSC properties in NSCLC cell lines. 25 To investigate whether the WIP1-mediated suppression of p38 activity contributes to CSC properties, we determined the relationship between WIP1 expression and levels of ALDH1, which is a well-established CSC marker in NSCLC, 33 by analyzing data from The Cancer Genome Atlas (TCGA) database. We divided the cases for the two major NSCLC subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), in the TCGA into WIP1-high (the top 25%) and WIP1-low (the bottom 25%) groups, and compared the expression levels of the four ALDH1 isoforms (A1-A3 and B1) between the two groups.…”

Section: Resultsmentioning

confidence: 99%

“…We recently reported that p38, especially the γ and δ isoforms of p38, suppresses the expression and reduces the stability of the stemness-related proteins SOX2, OCT4, NANOG, KLF4, and c-Myc and CSC properties via MK2-mediated HSP27 phosphorylation in NSCLC cells. 25 Supporting a role of p38 in suppressing NSCLC development by inhibiting CSCs in vivo, we previously observed reduced levels of phosphorylated/activated p38 (p-p38), along with increased expression of SOX2, in NSCLC tissue samples compared with normal lung tissue samples. However, the mechanism underlying the reduced activation of p38 in NSCLC is unknown.…”

Section: Introductionmentioning

confidence: 83%

“…However, the mechanism underlying the reduced activation of p38 in NSCLC is unknown. 25 WIP1 (PPM1D) is a type 2C Ser/Thr phosphatase (PP2Cδ) with oncogenic activities that exhibits amplification and overexpression in human cancers. 26 WIP1 has multiple substrates, including p38, p53, MDM2, and DNA damage response mediators (ATM, Chk1, and Chk2).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Deng

Liu

Tan

et al. 2020

Sig Transduct Target Ther

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Deng

Liu

Tan

et al. 2020

Sig Transduct Target Ther

Self Cite

View full text Add to dashboard Cite

show abstract

Retracted: Effects of microRNA‐494 on proliferation, migration, invasion, and apoptosis of medulloblastoma cells by mediating c‐myc through the p38 MAPK signaling pathway

Zhang

et al. 2018

J of Cellular Biochemistry

View full text Add to dashboard Cite

Medulloblastoma (MB) is the most prevalent brain tumor that occurs during childhood and originates from cerebellar granule cell precursors. Based on recent studies, the differential expression of several microRNAs is involved in MB, while the role of microRNA‐494 (miR‐494) in MB remains unclear. Therefore, we conducted this study to investigate the regulative role of miR‐494 in MB cells via the p38 mitogen‐activated protein kinase (MAPK) signaling pathway by mediating c‐myc. In the current study, MB cells were collected and transfected with miR‐494 mimic, miR‐494 inhibitor, siRNA‐ c‐myc, and miR‐494 inhibitor + siRNA‐c‐myc. The expressions of miR‐494, c‐myc, p38 MAPK, B‐cell lymphoma‐2 (Bcl‐2), Bcl‐2‐associated X protein (Bax), interleukin‐6 (IL‐6), metadherin (MTDH), phosphatase and tensin homolog (PTEN) and survivin were determined. Cell proliferation, cell‐cycle distribution, apoptosis, migration, and invasion were evaluated. The results revealed that there was a poor expression of miR‐494 and high expression of c‐myc in MB tissues. C‐myc was determined as the target gene of miR‐494. In response to miR‐494 mimic, MB cells were found to have increased Bax and PTEN expressions, as well as cell number in G1 phase and cell apoptosis and decreased c‐myc, p38 MAPK, Bcl‐2, MTDH, IL‐6, and survivin expression and cell number count in the S phase, cell proliferation, migration, and invasion. In conclusion, the results demonstrated that the upregulation of miR‐494 results in the suppression of cell proliferation, migration, and invasion, while it promotes apoptosis of MB cells through the negative mediation of c‐myc, which in turn inactivates the p38 MAPK pathway.

show abstract