title: Mechanosensitive caveolin-1 activation-induced PI3K/Akt/mTOR signaling pathway promotes breast cancer motility, invadopodia formation and metastasis in vivo.
abstract: Cancer cells are subjected to fluid shear stress during passage through the venous and lymphatic system. Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its mechanobiological roles under low shear stress (LSS) conditions remain largely unknown. Here, we identified Cav-1 is mechanosensitive to LSS exposure, and its activation-induced PI3K/Akt/mTOR signaling promotes motility, invadopodia formation and metastasis of breast carcinoma MDA-MB-231 cells. Application of LSS (1.8 and 4.0 dynes/cm2) to MDA-MB-231 cells significantly increased the cell motility, invadopodia formation, MT1-MMP expression, ECM degradation, and also induced a sustained activation of Cav-1 and PI3K/Akt/mTOR signaling cascades. Methyl-β-cyclodextrin-caused caveolae destruction markedly decreased LSS-induced activation of both Cav-1 and PI3K/Akt/mTOR, leading to suppress MT1-MMP expression, inhibit invadopodia formation and ECM degradation, suggesting that caveolae integrity also involved in metastasis. Immunocytochemical assay showed that LSS induces the Cav-1 clustering in lipid rafts and co-localization of Cav-1 and MT1-MMP on invadopodia. Immunofluorescence confocal analysis demonstrated that Cav-1 activation were required for the acquisition of a polarized phenotype in MDA-MB-231 cells. Finally, Cav-1 knockdown significantly suppressed tumor colonization in the lungs and distant metastases in animal models. Our findings highlight the importance of Cav-1 in hematogenous metastasis, and provide new insights into the underlying mechanisms of mechanotransduction induced by LSS.
authors.affiliation: Department of Biophysics, School of Life Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.|Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Biophysics, School of Life Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Liuyuan
authors.initials: L
authors.lastname: Guan
authors.affiliation: Department of Biophysics, School of Life Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Shun
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biophysics, School of Life Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Biophysics, School of Life Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Niya
authors.initials: N
authors.lastname: Xiong
authors.affiliation: Department of Biophysics, School of Life Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biophysics, School of Life Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.|Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Biophysics, School of Life Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.|Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Biophysics, School of Life Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.|Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Yiyao
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000069261:Podosomes / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C495540:CAV1 protein, human; C546842:MTOR protein, human
keywords: PI3K/Akt/mTOR; caveolin-1; cell motility; invadopodia formation; low shear stress