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Oncogene. 2015 Apr 23;34(17):2239-50. doi: 10.1038/onc.2014.164. Epub 2014 Jun 16.

mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3.

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  • 1Institute of Cancer and Genetics, Cardiff University, Cardiff, UK.

Abstract

Recent clinical trials using rapalogues in tuberous sclerosis complex show regression in volume of typically vascularised tumours including angiomyolipomas and subependymal giant cell astrocytomas. By blocking mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signalling, rapalogue efficacy is likely to occur, in part, through suppression of hypoxia-inducible factors (HIFs) and vascular endothelial growth factors (VEGFs). We show that rapamycin reduces HIF-1α protein levels, and to a lesser extent VEGF-A levels, in renal cystadenoma cells in a Tsc2+/- mouse model. We established that mTORC1 drives HIF-1α protein accumulation through enhanced transcription of HIF-1α mRNA, a process that is blocked by either inhibition or knockdown of signal transducer and activation of transcription 3 (STAT3). Furthermore, we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription. mTORC1 also regulates HIF-1α synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whereas HIF-1α degradation remains unaffected. We therefore proposed that mTORC1 drives HIF-1α synthesis in a multifaceted manner through 4E-BP1/eIF4E, S6K1 and STAT3. Interestingly, we observed a disconnect between HIF-1α protein levels and VEGF-A expression. Although both S6K1 and 4E-BP1 regulate HIF-1α translation, VEGF-A is primarily under the control of 4E-BP1/eIF4E. S6K1 inhibition reduces HIF-1α but not VEGF-A expression, suggesting that mTORC1 mediates VEGF-A expression via both HIF-1α-dependent and -independent mechanisms. Our work has important implications for the treatment of vascularised tumours, where mTORC1 acts as a central mediator of STAT3, HIF-1α, VEGF-A and angiogenesis via multiple signalling mechanisms.

PMID:
24931163
[PubMed - indexed for MEDLINE]
PMCID:
PMC4172452
Free PMC Article

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