mTORC1 and mTORC2 regulate EMT, motility and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways
01 May 2011-Cancer Research (American Association for Cancer Research)-Vol. 71, Iss: 9, pp 3246-3256
TL;DR: It is found that increased expression of mTOR, Raptor, and Rictor mRNA was noted with advanced stages of CRC, suggesting that mTOR signaling may be associated with CRC progression and metastasis, and provides the rationale for including mTOR kinase inhibitors, which inhibit both mTORC1 and m TORC2, as part of the therapeutic regimen for CRC patients.
Abstract: Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling is associated with growth and progression of colorectal cancer (CRC). We have previously shown that the mammalian target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis of CRC. However, the contribution of mTOR and its interaction partners towards regulating CRC progression and metastasis remains poorly understood. We found that increased expression of mTOR, Raptor and Rictor mRNA was noted with advanced stages of CRC suggesting that mTOR signaling may be associated with CRC progression and metastasis. mTOR, Raptor and Rictor protein levels were also significantly elevated in primary CRCs (stage IV) and their matched distant metastasis compared to normal colon. Inhibition of mTOR signaling, using rapamycin or stable inhibition of mTORC1 (Raptor) and mTORC2 (Rictor), attenuated migration and invasion of CRCs. Furthermore, knockdown of mTORC1 and mTORC2 induced a mesenchymal-epithelial transition and enhanced chemosensitivity of CRCs to oxaliplatin. We observed increased cell-cell contact as well as decreased actin cytoskeletal remodeling concomitant with decreased activation of the small GTPases, RhoA and Rac1, upon inhibition of both mTORC1 and mTORC2. Finally, establishment of CRC metastasis in vivo was completely abolished with targeted inhibition of mTORC1 and mTORC2 irrespective of the site of colonization. Our findings support a role for elevated mTORC1 and mTORC2 activity in regulating EMT, motility and metastasis of CRCs via RhoA and Rac1 signaling. These findings provide the rationale for including mTOR kinase inhibitors, which inhibit both mTORC1 and mTORC2, as part of the therapeutic regimen for CRC patients.
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TL;DR: The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues, and the convergence of signalling pathways is essential for EMT.
Abstract: The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.
6,036 citations
TL;DR: This review focuses on recent developments on mammalian mTORC2 signaling mechanisms and its cellular and tissue-specific functions and examines the contribution of this less-studied mTOR complex in cancer, metabolic disorders and aging.
Abstract: The mechanistic target of rapamycin (mTOR) plays a central role in cellular growth and metabolism. mTOR forms two distinct protein complexes, mTORC1 and mTORC2. Much is known about the regulation and functions of mTORC1 due to availability of a natural compound, rapamycin, that inhibits this complex. Studies that define mTORC2 cellular functions and signaling have lagged behind. The development of pharmacological inhibitors that block mTOR kinase activity, and thereby inhibit both mTOR complexes, along with availability of mice with genetic knockouts in mTOR complex components have now provided new insights on mTORC2 function and regulation. Since prolonged effects of rapamycin can also disrupt mTORC2, it is worth re-evaluating the contribution of this less-studied mTOR complex in cancer, metabolic disorders and aging. In this review, we focus on recent developments on mammalian mTORC2 signaling mechanisms and its cellular and tissue-specific functions.
487 citations
TL;DR: The synergistic effect of hypoxia inducible factors (HIFs) and vascular endothelial growth factors (VEGFs) in the successful outgrowth of metastasis is focused on, integrating therefore many of the emerging models and theories in the field.
343 citations
Cites background from "mTORC1 and mTORC2 regulate EMT, mot..."
...[30] Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, et al....
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...Key regulators of this process are TGF(by the activation of Twist, SLUG and ZEB2), PI3K/Akt (increasing the mTOR kinase expression), Shh and Wnt [30,31]....
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TL;DR: This update summarizes the current knowledge of the coordination of TGF-β-induced Smad and non-Smad signaling pathways in EMT, and the remarkable ability of Smads to cooperate with other transcription-directed signaling pathway in the control of gene reprogramming during EMT.
302 citations
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TL;DR: Members of the Rho family of small guanosine triphosphatases have emerged as key regulators of the actin cytoskeleton, and through their interaction with multiple target proteins, they ensure coordinated control of other cellular activities such as gene transcription and adhesion.
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TL;DR: Recent progress in understanding mTOR signaling is discussed, paying particular attention to its relevance in cancer and the use of rapamycin in oncology.
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