PPAR gamma negatively regulates the expression of TRPM8 in normal epidermal cells but mutually regulate their expressions with TRPM8 by feed-back loop regulation in squamous carcinoma cells

TRPM8, non-selective cation channel of the transient receptor potential (TRP) superfamily, required for the transduction of moderate cold temperatures, regulates proliferation of epidermal cells in cyclin-dependent kinase inhibitor p21/Cip1-dependent manner. Given that downregulation of TRPM8 decreases p21/Cip1 level, increasing risk for carcinogenesis, and other TRP family is regulated by nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, we examined whether TRPM8 expression was regulated by PPAR gamma. Knockdown assay and inhibition of PPAR gamma revealed that PPAR gamma negatively regulates the expression of TRPM8 in normal epidermal cells but positively regulates that in squamous carcinoma cells. Later restoration of decreased TRPM8 level in PPAR gamma antagonist-treated squamous carcinoma cells was attributed to feed-back loop regulation between TRPM8 and PPAR gamma using TRPM8 knockdown assay. Consisting with this finding, p21/Cip1 decrease by TRPM8 blocker, N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin- 2-yl) tetrahydropyrazine-1 (2H)-carbox-amide (BCTC), was restored by additional BCTC treatment in squamous carcinoma cells.