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

Dodd, K. M., Yang, J. ORCID: https://orcid.org/0000-0003-2631-4553, Shen, M. H. ORCID: https://orcid.org/0000-0002-3891-7231, Sampson, J. R. ORCID: https://orcid.org/0000-0002-2902-2348 and Tee, A. R. ORCID: https://orcid.org/0000-0002-5577-4631 2015. mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene 34 (17) , pp. 2239-2250. 10.1038/onc.2014.164

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Additional Information:	PDF uploaded in accordance with publisher's policies at http://www.sherpa.ac.uk/romeo/issn/0950-9232/ (accessed 31.3.16). Online publication 16 June 2014
Publisher:	Springer Nature
ISSN:	0950-9232
Date of First Compliant Deposit:	31 March 2016
Date of Acceptance:	1 May 2014
Last Modified:	07 Nov 2023 04:01
URI:	https://orca.cardiff.ac.uk/id/eprint/88409

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