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Bisphosphorylated PEA-15 sensitizes ovarian cancer cells to paclitaxel by impairing the microtubule-destabilizing effect of SCLIP.

ABSTRACT: Paclitaxel is a standard chemotherapeutic agent for ovarian cancer. PEA-15 (phosphoprotein enriched in astrocytes-15 kDa) regulates cell proliferation, autophagy, apoptosis, and glucose metabolism and also mediates AKT-dependent chemoresistance in breast cancer. The functions of PEA-15 are tightly regulated by its phosphorylation status at Ser104 and Ser116. However, the effect of PEA-15 phosphorylation status on chemosensitivity of cancer cells remains unknown. Here, we tested the hypothesis that PEA-15 phosphorylated at both Ser104 and Ser116 (pPEA-15) sensitizes ovarian cancer cells to paclitaxel. We first found that knockdown of PEA-15 in PEA-15-high expressing HEY and OVTOKO ovarian cancer cells resulted in paclitaxel resistance, whereas re-expression of PEA-15 in these cells led to paclitaxel sensitization. We next found that SKOV3.ip1-DD cells (expressing phosphomimetic PEA-15) were more sensitive to paclitaxel than SKOV3.ip1-AA cells (expressing nonphosphorylatable PEA-15). Compared with SKOV3.ip1-vector and SKOV3.ip1-AA cells, SKOV3.ip1-DD cells displayed reduced cell viability, inhibited anchorage-independent growth, and augmented apoptosis when treated with paclitaxel. Furthermore, HEY and OVTOKO cells displayed enhanced paclitaxel sensitivity when transiently overexpressing phosphomimetic PEA-15 and reduced paclitaxel sensitivity when transiently overexpressing nonphosphorylatable PEA-15. These results indicate that pPEA-15 sensitizes ovarian cancer cells to paclitaxel. cDNA microarray analysis suggested that SCLIP (SCG10-like protein), a microtubule-destabilizing protein, is involved in pPEA-15-mediated chemosensitization. We found that reduced expression and possibly posttranslational modification of SCLIP following paclitaxel treatment impaired the microtubule-destabilizing effect of SCLIP, thereby promoting induction of mitotic arrest and apoptosis by paclitaxel. Our findings highlight the importance of pPEA-15 as a promising target for improving the efficacy of paclitaxel-based therapy in ovarian cancer.

SUBMITTER: Xie X

PROVIDER: S-EPMC3681833 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Bisphosphorylated PEA-15 sensitizes ovarian cancer cells to paclitaxel by impairing the microtubule-destabilizing effect of SCLIP.

Xie Xuemei X Bartholomeusz Chandra C Ahmed Ahmed A AA Kazansky Anna A Diao Lixia L Baggerly Keith A KA Hortobagyi Gabriel N GN Ueno Naoto T NT

Molecular cancer therapeutics 20130329 6

Paclitaxel is a standard chemotherapeutic agent for ovarian cancer. PEA-15 (phosphoprotein enriched in astrocytes-15 kDa) regulates cell proliferation, autophagy, apoptosis, and glucose metabolism and also mediates AKT-dependent chemoresistance in breast cancer. The functions of PEA-15 are tightly regulated by its phosphorylation status at Ser104 and Ser116. However, the effect of PEA-15 phosphorylation status on chemosensitivity of cancer cells remains unknown. Here, we tested the hypothesis th ...[more]

PMID: 23543364

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Project description:Background:The aim of the study was to evaluate whether the use of chemotherapy in combination with naringin, a dietary plant polyphenolic flavonoid, could enhance the therapeutic efficacy of paclitaxel treatment in human prostate cancer (PCa) cells. Materials and methods:DU145, PC3, and LNCaP cells were treated with various concentrations of paclitaxel, naringin, and their combinations. Methylthiazolyldiphenyl-tetrazolium bromide (MTT), image-based cytometer, quantitative reverse transcription PCR (RT-qPCR), Western blot, and transwell assay were used to evaluate cell viability, apoptosis and cell cycle, the mRNA expression, protein expression, and cell migration, respectively. Results:Naringin treatment inhibited cell survival in a dose- and time-dependent manner by inducing apoptosis and cell cycle arrest in G1 phase. Among the pathways evaluated, naringin (150 ?M) significantly induced the mRNA expressions of BAX, BID, caspase 3, cytochrome c, p53, p21 Cip1 , and p27 Kip1 and downregulated the expressions of survivin and livin in DU145 cells. The combination of naringin and paclitaxel treatments synergistically increased the cytotoxic effects of paclitaxel in androgen-independent DU145 and PC3 cells, as well as in androgen-sensitive LNCaP cells. The combination of naringin with docetaxel has almost the same inhibitory effect on cell proliferation as the paclitaxel combination in androgen-independent cells, whereas there is no similar effect in LNCaP cells. Naringin exhibits significant inhibitory effects on the cell migration ability. The flavonoid either alone or in combination with paclitaxel therapy resulted in an increase in tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) protein expression and decrease in nuclear factor-?B p50 protein level in DU145 cells. Conclusion:In conclusion, naringin acts as a chemosensitizer which synergistically strengths the cytotoxic effect of paclitaxel in PCa cells. Therefore, naringin therapy alone or in combination with paclitaxel may be useful in the treatment of PCa. However, there is a need for more detailed in vivo studies of the mechanism of action.

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Bisphosphorylated PEA-15 sensitizes ovarian cancer cells to paclitaxel by impairing the microtubule-destabilizing effect of SCLIP.

Publications

Bisphosphorylated PEA-15 sensitizes ovarian cancer cells to paclitaxel by impairing the microtubule-destabilizing effect of SCLIP.

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