期刊
ONCOGENE
卷 34, 期 17, 页码 2239-2250出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2014.164
关键词
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资金
- Association for International Cancer Research Career Development Fellowship [06-914/915]
- Tuberous Sclerosis Association [2013-F02]
- Cancer Research UK development fund
- Welsh Government's National Institute of Social Care and Health Research (NISCHR) through the Wales Gene Park
- Tuberous Sclerosis Association
- Worldwide Cancer Research [06-0914] Funding Source: researchfish
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.
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