Calpain-mediated Processing of p53-associated Parkin-like Cytoplasmic Protein (PARC) Affects Chemosensitivity of Human Ovarian Cancer Cells by Promoting p53 Subcellular Trafficking

Woo, Michael G.; Xue, Kai; Liu, Jiayin; McBride, Heidi M.; Tsang, Benjamin K.

doi:10.1074/jbc.m111.314765

Cited by 47 publications

(46 citation statements)

References 54 publications

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“…We have previously identified mechanisms responsible for a number of factors that regulate chemosensitivity in OVCA (8,11,34). The tumor suppressor p53 plays a central role in apoptosis, and its activation is critical for sensitivity to genotoxic agents like CDDP (27).…”

Section: Discussionmentioning

confidence: 99%

“…Piceatannol-induced Cisplatin Sensitivity Is Associated with p53 Activation and NOXA Up-regulation-Recent evidence has highlighted the key interplay between p53 and the mitochondria in CDDP-induced apoptosis (8,11). We investigated whether NOXA, a mitochondria-related apoptotic factor and a transcriptional target of p53, is involved in this regulation.…”

Section: Piceatannol Enhances the Effects Of Cddp In Chemosensitivementioning

confidence: 99%

“…Absorbance at 490 nm was determined by a Bio-Rad X-Mark microplate analyzer. Apoptosis was assessed based on stereotypic morphological changes, including chromatin condensation, nuclear fragmentation cytoplasmic shrinkage, and the formation of apoptotic bodies (with nuclear fragments) as assessed in previous studies (11,27,28). At least 400 cells/treatment group were counted, and the quantification process was blinded to avoid experiment bias.…”

Section: Mts Assay and Hoechst 33258mentioning

confidence: 99%

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Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission

Farrand

Byun

Kim

et al. 2013

Journal of Biological Chemistry

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Background: Chemotherapeutic sensitivity in ovarian cancer is dependent on effective apoptosis signaling. Results: Piceatannol enhances cisplatin sensitivity by modulating p53, XIAP (X-linked inhibitor of apoptosis protein), and mitochondrial fission in vitro and in vivo. Conclusion: Piceatannol is a potent enhancer of cisplatin-induced apoptosis. Significance: Piceatannol exhibits potential for clinical development for the treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Piceatannol Enhances the Effects Of Cddp In Chemosensitivementioning

confidence: 99%

Section: Mts Assay and Hoechst 33258mentioning

confidence: 99%

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Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission

Farrand

Byun

Kim

et al. 2013

Journal of Biological Chemistry

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“…These cell lines were gifts from Drs. Rakesh Goel and Barbara Vanderhyden (Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada) and were cultured as reported previously (17)(18)(19).…”

Section: Methodsmentioning

confidence: 99%

p53 Is Required for Cisplatin-induced Processing of the Mitochondrial Fusion Protein L-Opa1 That Is Mediated by the Mitochondrial Metallopeptidase Oma1 in Gynecologic Cancers

Kong

Wang

Fung

et al. 2014

Journal of Biological Chemistry

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110

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Background: Mitochondrial dynamics is involved in the regulation of apoptosis. Results: p53 regulates mitochondrial dynamics by interacting with Prohibitin 1 and subsequent releasing Opa1 for Oma1-mediated processing, thereby promoting apoptosis and chemoresponsiveness. Conclusion: CDDP resistance is in part due to dysregulation of p53-induced, Oma1-mediated L-Opa1 processing and mitochondrial fragmentation. Significance: Understanding the regulation of mitochondrial dynamics may offer new strategies for overcoming chemoresistance.

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“…PPM1D protein was immunoprecipitated with mouse anti-PPM1D (clone F-10, Santa Cruz Biotechnologies) using the Dynabeads protein G immunoprecipitation kit (Thermo Fisher Scientific) as previously described [62]. Normal mouse IgG (Santa Cruz Biotechnologies) served as a negative control.…”

Section: Immunoprecipitationmentioning

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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Calpain-mediated Processing of p53-associated Parkin-like Cytoplasmic Protein (PARC) Affects Chemosensitivity of Human Ovarian Cancer Cells by Promoting p53 Subcellular Trafficking

Cited by 47 publications

References 54 publications

Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission

Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission

p53 Is Required for Cisplatin-induced Processing of the Mitochondrial Fusion Protein L-Opa1 That Is Mediated by the Mitochondrial Metallopeptidase Oma1 in Gynecologic Cancers

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

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