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

Abstract

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...

Mitochondrial dynamics regulating chemoresistance in gynecological cancers

“…Akt also inhibits p53 by phosphorylating MDM2 and facilitates its nuclear translocation to promote p53 degradation . We also found that Akt stabilizes the phosphatase PPM1D, which dephosphorylates p53 and Chk1, thereby destabilizing p53 and suppressing its functions …”

“…Mutation of these two sites significantly inhibited CDDP‐induced apoptosis, suggesting that p53 phosphorylation is needed for p53 function in gynecologic cancer cells. Our work also suggested that chemoresistant gynecologic cancer cells lose their response to CDDP partly due to deactivation of p53 via site‐specific dephosphorylation by protein phosphatase magnesium/manganese‐dependent 1D (PPM1D) …”

Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway

“…This could be a response of the cell to the stress induced by cisplatin. Furthermore, it was found that PPM1D played an important role in promoting cisplatin resistance, and as a novel downstream target of Akt, PPM1D mediates its action of conferring cisplatin resistance to gynecological cancer cells (41). PPM1D could also be induced by p53 to maintain the homeostasis in cells (42).…”

Role of wild-type p53-induced phosphatase 1 in cancer

“…However, cisplatin mediates tumor cell DNA damage and apoptotic function through these signaling pathways, suggesting that Wip1 may be responsible for the cisplatin resistance of ovarian clear cell carcinoma (41). In addition, a recent study demonstrated that Akt confers cisplatin resistance in part through the regulation of PPM1D protein stability, preventing its proteasomal degradation and consequently increasing its half-life (Table I) (42). Accumulating evidence has indicated that Wip1 is directly associated with tumor cell survival and chemoresistance (43).…”