Activation of PTEN by inhibition of TRPV4 suppresses colon cancer development

Transient receptor potential vanilloid type 4 (TRPV4) is a Ca(2+)-permeable cation channel that is known to be an osmosensor and thermosensor. Currently, limited evidence shows that TRPV4 plays opposite roles in either promoting or inhibiting cancer development in different cancer types. Furthermore, the precise biological functions and the underlying mechanisms of TRPV4 in carcinogenesis are still poorly understood. In this study, we demonstrated that TRPV4 is upregulated in colon cancer and associated with poor prognosis. Contrary to the reported cell death-promoting activity of TRPV4 in certain cancer cells, TRPV4 positively regulates cell survival in human colon cancer in vitro and in vivo. Inhibition of TRPV4 affects the cell cycle progression from the G1 to S phase through modulating the protein expression of D-type cyclins. Apoptosis and autophagy induced by TRPV4 silencing attenuate cell survival and potentiate the anticancer efficacy of chemotherapeutics against colon cancer cells. In addition, PTEN is activated by inhibition of TRPV4 as indicated by the dephosphorylation and increased nuclear localization. Knockdown of PTEN significantly abrogates TRPV4 silencing induced growth inhibition and recovers the capability of clonogenicity, as well as reduced apoptosis in colon cancer cells. Thus, PTEN regulates the antigrowth effects induced by TRPV4 inhibition through both phosphatase-dependent and independent mechanisms. In conclusion, inhibition of TRPV4 suppresses colon cancer development via activation of PTEN pathway. This finding suggests that downregulation of TPRV4 expression or activity would conceivably constitute a novel approach for the treatment of human colon cancer.