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.

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

“…FGF1 expression in ovarian cancer is associated with chemotherapy resistance. FGF1 can reduce the transcriptional activity of p53 and increase expression of p21 and subsequent antiapoptotic activity in response to ovarian cancer therapies etoposide and cisplatin [ 98 ]. FGF1 expression and secretion are increased in ovarian cancer associated fibroblasts (CAFs), which, when cultured with the SKOV3 human ovarian cancer cell line, increases ERK1/2 activity through activation of FGFR4.…”

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

“…Inside the cell, FGF1 and FGF2 interact with many intracellular proteins, including p53, HSP90 (heat shock protein 90), CK2 (casein kinase 2), and others involved in the regulation of cell signaling, cell cycle, and apoptosis, which may contribute to the acquisition of drug resistance [ 128 ]. In PC12 cells, nuclear localization of FGF1 determines its anti-apoptotic effect, whereas in ovarian cancer cells FGF1 affects mitochondrial localization of p53 and reduces etoposide- and cisplatin-induced apoptosis ( Figure 3 ) [ 56 , 129 ]. Of note, the nuclear FGF2 was associated with doxorubicin resistance in triple negative breast cancers with high level of DNA-dependent protein kinase, which is responsible for repairing double-stranded breaks in DNA [ 130 ].…”

Network controllability solutions for computational drug repurposing using genetic algorithms

“…The genetic algorithm identified four specific top preferred inputs, out of which three are known to be of significance in ovarian cancer: DDR1 122 , SRC 124 , and ERBB2 125 . In contrast, only two were found by the greedy algorithms and not by the genetic algorithm, with one of significance in ovarian cancer: FGF1 144 . Both remaining inputs, one for each algorithm, are known to be important in other cancer types: PDPK1 123 and HCK 143 .…”