Doan, H; Parsons, A; Devkumar, S; Selvarajah, J; Miralles, F; Carroll, VA
(2019)
HIF-mediated suppression of DEPTOR confers resistance to mTOR kinase inhibition in renal cancer.
iScience, 21.
pp. 509-520.
ISSN 2589-0042
https://doi.org/10.1016/j.isci.2019.10.047
SGUL Authors: Carroll, Veronica
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Abstract
Mechanistic target of rapamycin (mTOR) is a fundamental regulator of cell growth, proliferation, and metabolism. mTOR is activated in renal cancer and accelerates tumor progression. Here, we report that the mTOR inhibitor, DEP domain-containing mTOR-interacting protein (DEPTOR), is strikingly suppressed in clear cell renal cell carcinoma (ccRCC) tumors and cell lines. We demonstrate that DEPTOR is repressed by both hypoxia-inducible factors, HIF-1 and HIF-2, which occurs through activation of the HIF-target gene and transcriptional repressor, BHLHe40/DEC1/Stra13. Restoration of DEPTOR- and CRISPR/Cas9-mediated knockout experiments demonstrate that DEPTOR is growth inhibitory in ccRCC. Furthermore, loss of DEPTOR confers resistance to second-generation mTOR kinase inhibitors through deregulated mTORC1 feedback to IRS-2/PI3K/Akt. This work reveals a hitherto unknown mechanism of resistance to mTOR kinase targeted therapy that is mediated by HIF-dependent reprograming of mTOR/DEPTOR networks and suggests that restoration of DEPTOR in ccRCC will confer sensitivity to mTOR kinase therapeutics.
Item Type: | Article | ||||||||
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Additional Information: | © 2019 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). | ||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Institute of Medical & Biomedical Education (IMBE) Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE) |
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Journal or Publication Title: | iScience | ||||||||
ISSN: | 2589-0042 | ||||||||
Dates: |
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Publisher License: | Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0 | ||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/111319 | ||||||||
Publisher's version: | https://doi.org/10.1016/j.isci.2019.10.047 |
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