PMID- 31710966
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2589-0042 (Electronic)
IS  - 2589-0042 (Linking)
VI  - 21
DP  - 2019 Nov 22
TI  - HIF-mediated Suppression of DEPTOR Confers Resistance to mTOR Kinase Inhibition 
      in Renal Cancer.
PG  - 509-520
LID - S2589-0042(19)30428-6 [pii]
LID - 10.1016/j.isci.2019.10.047 [doi]
AB  - 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.
CI  - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Doan, Hong
AU  - Doan H
AD  - Vascular Biology Research Centre, Molecular and Clinical Sciences Research 
      Institute, St George's, University of London, London SW17 0RE, UK.
FAU - Parsons, Alexander
AU  - Parsons A
AD  - Vascular Biology Research Centre, Molecular and Clinical Sciences Research 
      Institute, St George's, University of London, London SW17 0RE, UK.
FAU - Devkumar, Shruthi
AU  - Devkumar S
AD  - Vascular Biology Research Centre, Molecular and Clinical Sciences Research 
      Institute, St George's, University of London, London SW17 0RE, UK; Centre for 
      Biomedical Education, Institute of Medical and Biomedical Education, St George's, 
      University of London, London SW17 0RE, UK.
FAU - Selvarajah, Jogitha
AU  - Selvarajah J
AD  - Vascular Biology Research Centre, Molecular and Clinical Sciences Research 
      Institute, St George's, University of London, London SW17 0RE, UK; Centre for 
      Biomedical Education, Institute of Medical and Biomedical Education, St George's, 
      University of London, London SW17 0RE, UK.
FAU - Miralles, Francesc
AU  - Miralles F
AD  - Vascular Biology Research Centre, Molecular and Clinical Sciences Research 
      Institute, St George's, University of London, London SW17 0RE, UK; Centre for 
      Biomedical Education, Institute of Medical and Biomedical Education, St George's, 
      University of London, London SW17 0RE, UK.
FAU - Carroll, Veronica A
AU  - Carroll VA
AD  - Vascular Biology Research Centre, Molecular and Clinical Sciences Research 
      Institute, St George's, University of London, London SW17 0RE, UK; Centre for 
      Biomedical Education, Institute of Medical and Biomedical Education, St George's, 
      University of London, London SW17 0RE, UK. Electronic address: 
      vcarroll@sgul.ac.uk.
LA  - eng
PT  - Journal Article
DEP - 20191026
PL  - United States
TA  - iScience
JT  - iScience
JID - 101724038
PMC - PMC6849413
OTO - NOTNLM
OT  - Biological Sciences
OT  - Cancer
OT  - Cell Biology
EDAT- 2019/11/12 06:00
MHDA- 2019/11/12 06:01
PMCR- 2019/10/26
CRDT- 2019/11/12 06:00
PHST- 2018/08/08 00:00 [received]
PHST- 2019/07/26 00:00 [revised]
PHST- 2019/10/23 00:00 [accepted]
PHST- 2019/11/12 06:00 [pubmed]
PHST- 2019/11/12 06:01 [medline]
PHST- 2019/11/12 06:00 [entrez]
PHST- 2019/10/26 00:00 [pmc-release]
AID - S2589-0042(19)30428-6 [pii]
AID - 10.1016/j.isci.2019.10.047 [doi]
PST - ppublish
SO  - iScience. 2019 Nov 22;21:509-520. doi: 10.1016/j.isci.2019.10.047. Epub 2019 Oct 
      26.