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

作者：Dodd K M; Yang J; Shen M H; Sampson J R; Tee A R^*

来源：Oncogene, 2015, 34(17): 2239-2250.

DOI：10.1038/onc.2014.164

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-1 alpha 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-1 alpha protein accumulation through enhanced transcription of HIF-1 alpha 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-1 alpha mRNA transcription. mTORC1 also regulates HIF-1 alpha 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-1 alpha degradation remains unaffected. We therefore proposed that mTORC1 drives HIF-1 alpha synthesis in a multifaceted manner through 4E-BP1/eIF4E, S6K1 and STAT3. Interestingly, we observed a disconnect between HIF-1 alpha protein levels and VEGF-A expression. Although both S6K1 and 4E-BP1 regulate HIF-1 alpha translation, VEGF-A is primarily under the control of 4E-BP1/eIF4E. S6K1 inhibition reduces HIF-1 alpha but not VEGF-A expression, suggesting that mTORC1 mediates VEGF-A expression via both HIF-1 alpha-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-1 alpha, VEGF-A and angiogenesis via multiple signalling mechanisms.

• 出版日期2015-4-23