mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3
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TLDR
It is proposed that mTORC1 drives HIF-1α synthesis in a multifaceted manner through 4E-BP1/eIF4E, S6K1 and STAT3, which has important implications for the treatment of vascularised tumours, where m TORC1 acts as a central mediator ofSTAT3, Hif-1 α, VEGF-A and angiogenesis via multiple signalling mechanisms.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.read more
Citations
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Journal ArticleDOI
A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations
Yiqun Zhang,Patrick Kwok Shing Ng,Melanie H. Kucherlapati,Fengju Chen,Yuexin Liu,Yiu Huen Tsang,Guillermo de Velasco,Guillermo de Velasco,Kang Jin Jeong,Rehan Akbani,Angela Hadjipanayis,Angeliki Pantazi,Christopher A. Bristow,Eunjung Lee,Harshad S. Mahadeshwar,Jiabin Tang,Jianhua Zhang,Lixing Yang,Sahil Seth,Semin Lee,Xiaojia Ren,Xingzhi Song,Huandong Sun,Jonathan G. Seidman,Lovelace J. Luquette,Ruibin Xi,Lynda Chin,Lynda Chin,Alexei Protopopov,Thomas F. Westbrook,Carl Simon Shelley,Toni K. Choueiri,Michael Ittmann,Carter Van Waes,John N. Weinstein,Han Liang,Elizabeth P. Henske,Andrew K. Godwin,Peter J. Park,Raju Kucherlapati,Kenneth L. Scott,Gordon B. Mills,David J. Kwiatkowski,Chad J. Creighton,Chad J. Creighton +44 more
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mTOR coordinates protein synthesis, mitochondrial activity and proliferation.
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Oncogenic Roles of the PI3K/AKT/mTOR Axis
Masahiro Aoki,Teruaki Fujishita +1 more
TL;DR: Possible mechanisms by which the PI3K/AKT/mTOR axis contributes to oncogenic transformation include stimulation of proliferation, survival, metabolic reprogramming, and invasion/metastasis, as well as suppression of autophagy and senescence.
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MicroRNA-100 shuttled by mesenchymal stem cell-derived exosomes suppresses in vitro angiogenesis through modulating the mTOR/HIF-1α/VEGF signaling axis in breast cancer cells.
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TL;DR: The findings suggest that exosomal transfer of miR-100 may be a novel mechanism underlying the paracrine effects of MSC-derived exosomes and may provide a means by which these vesicles can modulate vascular responses within the microenvironment of breast cancer cells.
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