Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:32730.

Mechanosensitive caveolin-1 activation-induced PI3K/Akt/mTOR signaling pathway promotes breast cancer motility, invadopodia formation and metastasis in vivo

Hong Yang, Liuyuan Guan, Shun Li, Ying Jiang, Niya Xiong, Li Li, Chunhui Wu, Hongjuan Zeng and Yiyao Liu _

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Oncotarget. 2016; 7:16227-16247. https://doi.org/10.18632/oncotarget.7583

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Hong Yang1,2,*, Liuyuan Guan1,*, Shun Li1,*, Ying Jiang1, Niya Xiong1, Li Li1, Chunhui Wu1,2, Hongjuan Zeng1,2, Yiyao Liu1,2

1Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P.R. China

2Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P.R. China

*These authors contributed equally to this work

Correspondence to:

Yiyao Liu, e-mail: liuyiyao@uestc.edu.cn, liuyiyao@hotmail.com

Keywords: low shear stress, caveolin-1, PI3K/Akt/mTOR, cell motility, invadopodia formation

Received: September 15, 2015     Accepted: February 05, 2016     Published: February 22, 2016


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.

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