title: mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways.
abstract: Activation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with growth and progression of colorectal cancer (CRC). We have previously shown that the mTOR kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis of CRC. However, the contribution of mTOR and its interaction partners toward 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 metastases compared with 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 (MET) and enhanced chemosensitivity of CRCs to oxaliplatin. We observed increased cell-cell contact and 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 epithelial-mesenchymal transition (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.
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, KT, USA.
authors.forename: Pat
authors.initials: P
authors.lastname: Gulhati
authors.forename: Kanika A
authors.initials: KA
authors.lastname: Bowen
authors.forename: Jianyu
authors.initials: J
authors.lastname: Liu
authors.forename: Payton D
authors.initials: PD
authors.lastname: Stevens
authors.forename: Piotr G
authors.initials: PG
authors.lastname: Rychahou
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Eun Y
authors.initials: EY
authors.lastname: Lee
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Weiss
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: O'Connor
authors.forename: Tianyan
authors.initials: T
authors.lastname: Gao
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
mesh_terms: D000199:Actins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D003599:Cytoskeleton / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D045325:HCT116 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009362:Neoplasm Metastasis; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; C493245:CRTC2 protein, human; D046912:Multiprotein Complexes; D011506:Proteins; C107953:RAC1 protein, human; D014157:Transcription Factors; C066737:RHOA protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein