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

FGF1 induces resistance to chemotherapy in ovarian granulosa tumor cells through regulation of... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oncogenesis Springer Journals

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

Loading next page...
 
/lp/springer_journal/fgf1-induces-resistance-to-chemotherapy-in-ovarian-granulosa-tumor-i0ROca06X7
Publisher
Nature Publishing Group UK
Copyright
Copyright © 2018 by The Author(s)
Subject
Medicine & Public Health; Medicine/Public Health, general; Internal Medicine; Cell Biology; Human Genetics; Oncology; Apoptosis
eISSN
2157-9024
D.O.I.
10.1038/s41389-018-0033-y
Publisher site
See Article on Publisher Site

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.

Journal

OncogenesisSpringer Journals

Published: Feb 21, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve Freelancer

DeepDyve Pro

Price
FREE
$49/month

$360/year
Save searches from
Google Scholar,
PubMed
Create lists to
organize your research
Export lists, citations
Read DeepDyve articles
Abstract access only
Unlimited access to over
18 million full-text articles
Print
20 pages/month
PDF Discount
20% off