Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

Xia, Zhen; Wu, Di; Wu, Zhong; Lu, Xi‐Ji; Yu, Tao; Chen, Qi‐Kui

doi:10.3892/ol.2017.6361

Cited by 7 publications

(3 citation statements)

References 27 publications

(28 reference statements)

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“…These findings suggest that Wip1 may be involved in chemoresistance in the advanced disease of OCCC, as TFI is well known to be an important surrogate marker for the chemosensitivity in ovarian cancer [ 24 – 26 ]. This hypothesis may be supported by the published findings that Wip1 is involved in chemoresistance in other types of cancer cells [ 27 , 28 ]. Chemoresistance is known to be related with low activity of cellular proliferation.…”

Section: Discussionsupporting

confidence: 60%

Differential roles of the Wip1–p38–p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas

Minaguchi

et al. 2022

World J Surg Onc

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Background Ovarian clear cell carcinoma (OCCC) is one of the most lethal types of ovarian cancer. Early-stage OCCC can be cured by surgery; however, advanced-stage disease shows poor prognosis due to chemoresistance unlike the more common high-grade serous carcinoma. Methods We explored the differential roles of the Wip1–p38–p53 DNA damage response pathway in respective early- or advanced-stage OCCC by immunohistochemistry of Wip1, phospho-p38, p53, and phospho-p53 from consecutive 143 patients. Results High Wip1 expression correlated with positive p53 (p=0.011), which in turn correlated with low nuclear phospho-p38 expression (p=0.0094). In the early stages, positive p53 showed trends toward worse overall survival (OS) (p=0.062), whereas in the advanced stages, high Wip1 correlated with worse OS (p=0.0012). The univariate and multivariate analyses of prognostic factors indicated that high Wip1 was significant and independent for worse OS (p=0.011) in the advanced stages, but not in the early stages. Additionally, high Wip1 showed trends toward shorter treatment-free interval (TFI) in the advanced stages, but not in the early stages (p=0.083 vs. 0.93). Furthermore, high Wip1 was significantly associated with positive p53 only in the patients with shorter TFI (<6 months), but not in those with longer TFI (≥6 months) (p=0.036 vs. 0.34). Conclusions Wip1 appears to play a crucial role for the prognosis of OCCC through chemoresistance specifically in the advanced stages, implicating that Wip1 possibly serves as a reasonable therapeutic target for improving chemoresistance and poor prognosis of advanced-stage OCCC.

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Section: Discussionsupporting

confidence: 60%

Differential roles of the Wip1–p38–p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas

Minaguchi

et al. 2022

World J Surg Onc

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“…cc is a common malignant gastrointestinal tumor; ~20% of patients suffer from liver metastasis after treatment, and the 3-year survival rate of these patients is 5% (23,24). Therefore, it is important to explore novel effective therapeutic options for cc treatment.…”

Section: Discussionmentioning

confidence: 99%

Rotenone restrains colon cancer cell viability, motility and epithelial‑mesenchymal transition and tumorigenesis in nude mice via the PI3K/AKT pathway

Xiao

Liu

Dai³

et al. 2020

Int J Mol Med

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Rotenone, a natural hydrophobic pesticide, has been reported to display anticancer activity in a variety of cancer cells. However, the mechanism of rotenone on colon cancer (cc) cell migration, invasion and metastasis is still unknown. In the present study, the cytotoxicity of rotenone on cc cells were detected by the cell counting Kit-8 assay and confirmed by clone formation assay. The effects of rotenone on cc cell invasion and migration activity were determined in vitro by Transwell invasion and wound healing assays, respectively. In addition, to reveal whether rotenone affected the epithelial-mesenchymal-transition (EMT) process, reverse transcription-quantitative PcR, western blotting and immunofluorescence assays were used to detect the expression of EMT markers. The expression levels of the key markers of the PI3K/AKT pathway after rotenone treatment alone or in combination with a PI3K/AKT signaling activator in cc were also detected by western blotting. Finally, the in vivo antitumor effects of rotenone were evaluated in a subcutaneous xenotransplant tumor model treated with an intraperitoneal injection of rotenone. The results of the present study demonstrated that rotenone treatment induced cc cell cytotoxicity and greater effects were observed with increasing concentrations and inhibited cell proliferation compared with untreated cells. In vitro cell function assays revealed that rotenone inhibited cc cell migration, invasion and EMT compared with untreated cells. Mechanically, the phosphorylation levels of AKT and mTOR were downregulated in rotenone-treated cc cells compared with untreated cells. Additionally, AKT and mTOR phosphorylation levels were increased by the PI3K/AKT signaling activator insulin-like growth factor 1 (IGF-1), which was reversed by rotenone treatment. The cell function assays confirmed that the IGF-1-activated cell proliferation, migration and invasion were decreased by rotenone treatment. These results indicated that rotenone affected cc cell proliferation and metastatic capabilities by inhibiting the PI3K/AKT/mTOR signaling pathway. In addition, rotenone inhibited tumor growth and metastatic capability of cc, which was confirmed in a xenograft mouse model. In conclusion, the present study revealed that rotenone inhibited cc cell viability, motility, EMT and metastasis in vitro and in vivo by inhibiting the PI3K/AKT/mTOR signaling pathway.

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“…Previous studies have demonstrated that targeting Wip1 enhances sensitivity to chemotherapy and promotes apoptosis in human cancers harboring wt p53. However, contradictory data have been reported for p53-deficient tumors (23,25). For example, the study conducted by Goloudina et al (23) demonstrated that the inhibition of Wip1 increased the sensitivity of wt p53 HCT116 colon cancer cells to cisplatin-induced apoptosis, but did not have such an effect on p53 -/-HCT116 or Saos-2 cells.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic WIP1 phosphatase attenuates the DNA damage response and sensitizes p53 mutant Jurkat cells to apoptosis

2021

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Wild-type (wt) p53-induced phosphatase 1 (Wip1), encoded by the protein phosphatase, Mg 2+ /Mn 2+ dependent 1D (PPM1D) gene, is a serine/threonine phosphatase induced upon genotoxic stress in a p53-dependent manner. Wip1/PPM1D is frequently overexpressed, amplified and mutated in human solid tumors harboring wt p53 and is thus currently recognized as an oncogene. Oncogenic Wip1 dampens cellular stress responses, such as cell cycle checkpoints, apoptosis and senescence, and consequently increases resistance to anticancer therapeutics. Targeting Wip1 has emerged as a therapeutic strategy for tumors harboring wt p53. However, little is known about the efficacy of Wip1-targeted therapies in tumors lacking p53. The present study aimed to investigate the potential role of oncogenic Wip1 in p53 mutant (mt) Jurkat cells. In the present study, it was demonstrated that p53 mt Jurkat cells exhibited PPM1D/Wip1 gene amplification and expressed relatively high levels of Wip1, as confirmed by gene copy number and RNA expression analysis. In addition, Jurkat cells underwent G2 cell cycle arrest, apoptotic cell death and senescence in response to etoposide and doxorubicin, although the phosphorylation levels of DNA damage response (DDR) elements, including ataxia-telangiectasia mutated, ataxia-telangiestasia and Rad3-related, checkpoint kinase (Chk)1 and Chk2 were significantly low. Accordingly, the targeting of Wip1 phosphatase by RNA interference increased the phosphorylation of DDR elements, but decreased the rate of apoptosis in response to etoposide or doxorubicin in Jurkat cells. The induction of senescence or cell cycle arrest was not affected by the knockdown of Wip1. The results suggest that increased Wip1 expression enhances the apoptotic sensitivity of Jurkat cells in response to chemotherapeutic agents by attenuating DDR signaling. The present study highlights the possible pro-apoptotic role of Wip1 in a p53 mt T-cell acute lymphoblastic leukemia cell line. The data suggest the careful consideration of future treatment strategies aiming to manipulate or target Wip1 in human cancers lacking p53.

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Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

Cited by 7 publications

References 27 publications

Differential roles of the Wip1–p38–p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas

Differential roles of the Wip1–p38–p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas

Rotenone restrains colon cancer cell viability, motility and epithelial‑mesenchymal transition and tumorigenesis in nude mice via the PI3K/AKT pathway

Oncogenic WIP1 phosphatase attenuates the DNA damage response and sensitizes p53 mutant Jurkat cells to apoptosis

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