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

Oncotarget. 2016 Mar 29;7(13):16227-47. doi: 10.18632/oncotarget.7583.


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.

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

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Caveolin 1 / metabolism*
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Female
  • Heterografts
  • Humans
  • Mechanotransduction, Cellular / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Invasiveness / pathology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Podosomes / metabolism
  • Podosomes / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / physiology
  • Stress, Mechanical
  • TOR Serine-Threonine Kinases / metabolism


  • CAV1 protein, human
  • Caveolin 1
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases