Hypoxia-inducible factor 1 alpha is required for the tumourigenic and aggressive phenotype associated with Rab25 expression in ovarian cancer
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Natividad Gomez-Roman1, Neha Mohan Sahasrabudhe2, Fiona McGregor1, Anthony J. Chalmers1, Jim Cassidy1,3, Jane Plumb1
1Wolfson Wohl Translational Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
2The University Medical Center in Groningen, Groningen, The Netherlands
3Current address: VP Oncology at Bristol Myers Squibb, Princeton, New Jersey, USA
Natividad Gomez-Roman, e-mail: [email protected]
Keywords: Rab25, HIF-1 alpha, tumourigenic, ovarian cancer, intraperitoneal
Received: July 24, 2015 Accepted: February 16, 2016 Published: March 9, 2016
The small GTPase Rab25 has been functionally linked to tumour progression and aggressiveness in ovarian cancer and promotes invasion in three-dimensional environments. This type of migration has been shown to require the expression of the hypoxia-inducible factor 1 alpha (HIF-1α). In this report we demonstrate that Rab25 regulates HIF-1α protein expression in an oxygen independent manner in a panel of cancer cell lines. Regulation of HIF-1α protein expression by Rab25 did not require transcriptional upregulation, but was dependent on de novo protein synthesis through the Erbb2/ERK1/2 and p70S6K/mTOR pathways. Rab25 expression induced HIF-1 transcriptional activity, increased cisplatin resistance, and conferred intraperitoneal growth to the A2780 cell line in immunocompromised mice. Targeting HIF1 activity by silencing HIF-1β re-sensitised cells to cisplatin in vitro and reduced tumour formation of A2780-Rab25 expressing cells in vivo in a mouse ovarian peritoneal carcinomatosis model. Similar effects on cisplatin resistance in vitro and intraperitoneal tumourigenesis in vivo were obtained after HIF1b knockdown in the ovarian cancer cell line SKOV3, which expresses endogenous Rab25 and HIF-1α at atmospheric oxygen concentrations. Our results suggest that Rab25 tumourigenic potential and chemoresistance relies on HIF1 activity in aggressive and metastatic ovarian cancer. Targeting HIF-1 activity may potentially be effective either alone or in combination with standard chemotherapy for aggressive metastatic ovarian cancer.
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