Increased wild‐type p53‐induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma

Fuku, Takeichi; Semba, Shuho; Yutori, Hirokazu; Yokozaki, Hiroshi

doi:10.1111/j.1440-1827.2007.02140.x

Cited by 52 publications

(42 citation statements)

References 21 publications

(28 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, PPM1D amplification and/ or enhanced stabilization allow for sustained inhibition of DNA damage response proteins and numerous tumor suppressors, including ATM, Chk1 and 2, and p53. PPM1D over-expression has been implicated in a variety of human malignancies, including OVCA, and its level is directly related to poor prognosis and reduced therapeutic outcome [47][48][49][50][51][52][53][54][55][56][57].…”

Section: Discussionmentioning

confidence: 99%

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

Alayoud¹,

Kim²,

Pelletier

et al. 2014

Molecular Carcinogenesis

View full text Add to dashboard Cite

Ovarian cancer (OVCA) and cervical cancer (CECA) are lethal gynecological malignancies. Cisplatin (CDDP) and platinum derivatives are first line chemotherapeutics and their resistance impedes successful treatment. Understanding the molecular dysregulation underlying chemoresistance is important in developing rational therapeutic strategies. We have established that Protein Phosphatase Magnesium-dependent 1 D (PPM1D) confers CDDP resistance in gynecological cancer cells by deactivating p53. However, whether CDDP regulates intra-cellular PPM1D localization and whether this regulation is different between chemosensitive and chemoresistant cancer cells is unknown. Moreover, whether Akt regulates PPM1D in the context of CDDP resistance has not been studied. To illustrate the role of PPM1D in gynecological cancer cell chemoresistance and its regulation by Akt we have demonstrated that: (a) CDDP induced PPM1D downregulation through proteasomal degradation in sensitive CECA cells; (b) CDDP induced PPM1D nuclear localization in resistant CECA cells, and nuclear exclusion in sensitive CECA cells and OVCA xenografts; (c) Over-expression of active Akt in sensitive CECA cells stabilized PPM1D content through inhibition of CDDP-induced PPM1D down-regulation; (d) Inhibition of Akt activity in resistant OVCA cells leads to decreased PPM1D stability and CDDP-induced down-regulation in resistant CECA cells; and (e) PPM1D is highly expressed in human ovarian tumor subtypes and in a tissue microarray panel of human ovarian tumors. In conclusion, we have established that PPM1D plays an important role in promoting CDDP resistance and as a novel downstream target of Akt, PPM1D mediates its action in conferring CDDP resistance in gynecological cancer cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.Key words: cisplatin chemoresistance; ovarian cancer; PPM1D; Akt; apoptosis INTRODUCTIONOvarian cancer (OVCA) and cervical cancer (CECA) are the most lethal gynecological malignancies. Although OVCA ranks first in the number of deaths each year, due primarily to its late diagnosis and the development of chemoresistance [1], CECA is more frequent and less deadly due to early detection. Surgical de-bulking of the tumor mass followed by adjuvant chemotherapy is the conventional course of therapy for OVCA, whereas a combination of radiation and chemotherapy is the preferred treatment regimen for CECA. Platinum derivatives, including Cisplatin (CDDP; cis-diamminedichloroplatinum) in combination with paclitaxel, are first-line chemotherapeutic agents in the treatment of these gynecologic cancers. CDDP induces apoptosis by creating inter-and intra-strand DNA adducts through irreversible intercalation, thereby inducing both the DNA damage and the apoptotic responses [2]. The majority of patients respond to chemotherapy at first, however, recurrence of the disease is a common event and tumors are usually more aggressive, metastasize to secondary target tissues, and acquire resistance to conventional chemotherape...

show abstract

Section: Discussionmentioning

confidence: 99%

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

Alayoud¹,

Kim²,

Pelletier

et al. 2014

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…Given that 17q23.2 was one of the most commonly amplified regions in HER-2-positive cancers (20%) and also found in luminal tumors (8%) and the fact that PPM1D has been shown to have oncogenic properties (33,34) and to be a protein amenable to targeting with small-molecule inhibitors (24), we investigated whether PPM1D would be one of the drivers of the 17q23.2 amplicon. PPM1D encodes a serine/threonine phosphatase and has been described previously as an oncogene and potential therapeutic target (24).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, PPM1D also participates in the regulation of DNA repair via an interaction with UNG glycosylase (41), progesterone receptor function (42), and the regulation of CHK1, CHK2, and ATM kinases, which control DNA repair and cell cycle (43 -47). PPM1D overexpression has been shown to recapitulate the antiapoptotic effects of TP53 inactivating mutation in vitro and increases tumorigenicity in murine models in vivo (33,34). Recent studies have shown that inactivation of p38 due to PPM1D gene amplification and expression contributes to the development of human cancers by suppressing p53 activation (34).…”

Section: Discussionmentioning

confidence: 99%

Tiling Path Genomic Profiling of Grade 3 Invasive Ductal Breast Cancers

Natrajan

Lambros

Rodríguez‐Pinilla

et al. 2009

Clinical Cancer Research

155

202

View full text Add to dashboard Cite

Purpose: To characterize the molecular genetic profiles of grade 3 invasive ductal carcinomas of no special type using high-resolution microarray-based comparative genomic hybridization (aCGH) and to identify recurrent amplicons harboring putative therapeutic targets associated with luminal, HER-2, and basal-like tumor phenotypes. Experimental Design: Ninety-five grade 3 invasive ductal carcinomas of no special type were classified into luminal, HER-2, and basal-like subgroups using a previously validated immunohistochemical panel. Tumor samples were microdissected and subjected to aCGH using a tiling path 32K BAC array platform. Selected regions of recurrent amplification were validated by means of in situ hybridization. Expression of genes pertaining to selected amplicons was investigated using quantitative real-time PCR and gene silencing was done using previously validated short hairpin RNA constructs. Results: We show that basal-like and HER-2 tumors are characterized by ''sawtooth'' and ''firestorm'' genetic patterns, respectively, whereas luminal cancers were more heterogeneous. Apart from confirming known amplifications associated with basal-like (1q21, 10p, and 12p), luminal (8p12, 11q13, and 11q14), and HER-2 (17q12) cancers, we identified previously unreported recurrent amplifications associated with each molecular subgroup: 19q12 in basal-like, 1q32.1 in luminal, and 14q12 in HER-2 cancers. PPM1D gene amplification (17q23.2) was found in 20% and 8% of HER-2 and luminal cancers, respectively. Silencing of PPM1D by short hairpin RNA resulted in selective loss of viability in tumor cell lines harboring the 17q23.2 amplification. Conclusions: Our results show the power of aCGH analysis in unraveling the genetic profiles of specific subgroups of cancer and for the identification of novel therapeutic targets.

show abstract

“…Wip1 is closely associated with p53 (8). Wip1, which is overexpressed in numerous cancers, including breast cancer (19), medulloblastoma (20), pancreatic neuroendocrine tumor (21), liver cancer (22) and stomach cancer (23), is recognized as a novel oncogene inhibiting several p53-dependent tumor-suppressor signaling pathways, including the Ataxia telangiectasia mutated-checkpoint kinase 2-p53, p38 mitogen-activated protein kinase-p53 and nuclear factor-κB signaling pathways (19). Discher et al (14) reported that Wip1 was associated with the chemosensitivity of cancer, since downregulation of Wip1 gene expression could inhibit the self-proliferation of breast cancer stem cells and enhance the chemosensitivity of MCF-7 breast cancer cells to doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

Xia

et al. 2017

Oncology Letters

View full text Add to dashboard Cite

Abstract. Colon cancer is one of the most common cancers in the world. Multidrug resistance is one of the main reasons for failure of therapy in patients with advanced colon cancer. In previous studies, multiple methods were investigated to reverse the multidrug resistance of colon cancer cells. However, to date, no clinical method has been identified to be satisfactory. Therefore, successful reversal of drug resistance in colon cancer cells still requires new therapeutic strategies or pharmaceuticals. Wild-type p53-induced phosphatase (Wip1), a member of the 2C type serine/threonine protein phosphatase family, is closely associated with the p53 gene, which is the most important tumor-suppressor gene. Wip1 was reported to be associated with the chemosensitivity of breast cancer cells. However, the correlation between the expression of Wip1 gene and the chemosensitivity of colon cancer cells has not been reported yet. In the present study, Wip1-811 small interfering RNA (siRNA) targeting Wip1 was investigated to reverse the multidrug resistance of colon cancer cells. The siRNA duplexes were transfected into RKO colon cancer cells. The messenger RNA (mRNA) expression of Wip1 was measured by reverse transcription-quantitative polymerase chain reaction. The protein level of Wip1 was detected by western blotting. The cell viability was measured by MTS assay. The cell apoptosis and cell cycle were analyzed by flow cytometry. Intracellular adriamycin cumulative concentration was determined using flow cytometry. Wip1-811 siRNA efficiently inhibited the expression of Wip1 at the mRNA and protein levels, and enhanced the sensitivity of RKO colon cancer cells towards chemotherapy, which was accompanied by increased cell apoptosis, following the inhibition of Wip1 gene expression. These results indicate that Wip1 gene silencing could enhance the chemosensitivity of colon cancer cells, which may provide a new potential approach for the reversal of multidrug resistance in colon cancer cells.

show abstract

Increased wild‐type p53‐induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma

Cited by 52 publications

References 21 publications

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

Tiling Path Genomic Profiling of Grade 3 Invasive Ductal Breast Cancers

Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

Contact Info

Product

Resources

About