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FGF1 induces resistance to chemotherapy in ovarian granulosa tumor cells through regulation of p53 mitochondrial localization

Abstract : Ovarian cancer remains associated with a high mortality rate and relapse is too frequently seen after chemotherapeutic treatment of granulosa cell tumors (GCTs) or epithelial ovarian cancers (EOCs). It is thus of major importance to progress in the knowledge of the molecular mechanisms underlying chemoresistance of ovarian tumors. Overexpression of Fibroblast Growth Factor 1 (FGF1) is observed in various cancers, correlates with poor survival and could be responsible for resistance to platinum-based chemotherapy of serous ovarian cancers. How FGF1 promotes escape to chemotherapy remains unknown. In previous studies, we showed that FGF1 inhibits p53 transcriptional activities, leading to increased cell survival of neuronal or fibroblast cell lines. In this study, we show that FGF1 favors survival of COV434 cells upon treatment with etoposide and cisplatin, two common chemotherapeutic molecules used for ovarian cancer. Etoposide and cisplatin induced mitochondrial depolarization, cytochrome c release and caspase activation in COV434 cells. Overexpression of FGF1 counteracts these events and thus allows increased survival of ovarian cells. In this study, FGF1 had little effect on p53 stability and transcriptional activities. Etoposide induced p21 expression as expected, but p21 protein levels were even increased in the presence of FGF1. Using RNA interference, we showed that p21 exerts an anti-apoptotic activity in COV434 cells. However abrogating this activity was not sufficient to restore cell death of FGF1-overexpressing cells. We also show for the first time that p53 mitochondrial pathway is involved in the cell death of COV434 cells. Indeed, p53 accumulates at mitochondria upon etoposide treatment and inhibition of p53 mitochondrial localization using pifithrin-µ inhibits apoptosis of COV434 cells. FGF1 also decreases mitochondrial accumulation of p53 induced by etoposide. This constitutes a novel mechanism of action for FGF1 to promote cell survival in response to chemotherapy.
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Submitted on : Thursday, October 22, 2020 - 5:07:49 PM
Last modification on : Thursday, July 8, 2021 - 3:48:54 AM
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Sevasti Manousakidi, Arnaud Guillaume, Caroline Pirou, Sylvina Bouleau, Bernard Mignotte, et al.. FGF1 induces resistance to chemotherapy in ovarian granulosa tumor cells through regulation of p53 mitochondrial localization. Oncogenesis, Nature Publishing Group: Open Access Journals - Option C, 2018, ⟨10.1038/s41389-018-0033-y⟩. ⟨hal-02975491⟩

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