Wip1 over‐expression correlated with TP53/p14<sup>ARF</sup> pathway disruption in human astrocytomas

Wang, Peng; Rao, Jingyi; Yang, Haifeng; Zhao, Hongyang; Yang, Lin

doi:10.1002/jso.22004

Cited by 12 publications

(10 citation statements)

References 21 publications

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“…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

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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...

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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

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“…However, PPM1D amplification and/or enhanced stabilization allow for sustained inhibition of DNA damage response proteins and numerous tumor suppressors. PPM1D overexpression has been implicated in a variety of human malignancies, including ovarian carcinoma, and its level is directly related to poor prognosis and reduced therapeutic outcome 38–48 . PPM1D has been identified as a potent oncogene, enhancing mammary transformation in a breast cancer‐susceptible animal model 49 .…”

Section: Regulation Of the Dna Damage Response And Apoptosis By Ppm1dmentioning

confidence: 99%

Molecular determinants of ovarian cancer chemoresistance: new insights into an old conundrum

Alayoud

Farrand

Kim

et al. 2012

Annals of the New York Academy of Sciences

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Ovarian cancer is the most lethal gynecological malignancy. Cisplatin and its derivatives are first-line chemotherapeutics, and their resistance is a major hurdle in successful ovarian cancer treatment. Understanding the molecular dysregulation underlying chemoresistance is important for enhancing therapeutic outcome. Here, we review two established pathways in cancer chemoresistance. p53 is a major tumor suppressor regulating proliferation and apoptosis, and its mutation is a frequent event in human malignancies. The PI3K/Akt axis is a key oncogenic pathway regulating survival and tumorigenesis by controlling several tumor suppressors, including p53. The interplay between these pathways is well established, although the oncogenic phosphatase PPM1D adds a new layer to this intricate relationship and provides new insights into the processes determining cell fate. Inhibition of the PI3K/Akt pathway by functional food compounds as an adjunct to chemotherapeutics may tip the balance in favor of apoptosis rather than survival, enhancing therapeutic efficacy, and reducing side effects.

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“…PPM1D has been reported to be upregulated in neuroblastoma, as well as pancreatic, lung, bladder, liver, ovarian and breast cancer (6,7,12,13). However, the role of PPM1D in CRC is yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

PPM1D is a prognostic marker and therapeutic target in colorectal cancer

Peng

Nie

et al. 2014

Experimental and Therapeutic Medicine

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Protein phosphatase, Mg2+/Mn2+ dependent, 1D (PPM1D) has been associated with carcinogenesis. The present study investigated PPM1D expression as a potential biomarker in colorectal cancer (CRC). PPM1D expression was assessed using immunohistochemistry in 368 patients with CRC. The correlation between PPM1D expression, clinicopathological features and prognosis was analyzed. PPM1D small interfering (si)RNA-induced PPM1D silencing was performed in CRC cell lines to assess the effect of PPM1D on tumor cell proliferation and invasion in vitro. A total of 68.48% (252/368) of the CRC samples displayed high PPM1D expression. By contrast, only 9.24% (34/368) of the matched non-cancerous tissue samples exhibited high PPM1D expression. High PPM1D expression was correlated with node metastasis (P=0.0024), distant metastasis (P<0.001) and TNM stage (P=0.0016). Kaplan-Meier survival analysis revealed that patients with low PPM1D expression had significantly longer survival than those with high PPM1D expression (P=0.012). Moreover, multivariate analyses demonstrated that high PPM1D expression was an independent prognostic factor for overall survival (hazard ratio = 0.24; 95% confidence interval, 0.13–0.86; P=0.004). Furthermore, PPM1D gene silencing was found to significantly reduce the proliferation and invasion of CRC cells in vitro. These findings suggest a role for PPM1D as a prognostic marker and potential therapeutic target in CRC.

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Wip1 over‐expression correlated with TP53/p14^ARF pathway disruption in human astrocytomas

Abstract: Wip1 is selectively over-expressed in astyrocytomas without alterations in TP53 or p14(ARF). Wip1 may inhibit the TP53/p14(ARF) pathway.

Cited by 12 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

Molecular determinants of ovarian cancer chemoresistance: new insights into an old conundrum

PPM1D is a prognostic marker and therapeutic target in colorectal cancer

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Wip1 over‐expression correlated with TP53/p14ARF pathway disruption in human astrocytomas

Abstract: Wip1 is selectively over-expressed in astyrocytomas without alterations in TP53 or p14(ARF). Wip1 may inhibit the TP53/p14(ARF) pathway.

Cited by 12 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

Molecular determinants of ovarian cancer chemoresistance: new insights into an old conundrum

PPM1D is a prognostic marker and therapeutic target in colorectal cancer

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Wip1 over‐expression correlated with TP53/p14^ARF pathway disruption in human astrocytomas