Transforming growth factor-β1 signaling contributes to Caco-2 cell growth inhibition induced by 1,25(OH)2D3

Growth of Caco-2 and many cancer cells is inhibited by 1,25(OH)(2)D-3. Whereas TGF-beta1 inhibits normal colonic epithelial cell growth, most human colon cancer-derived cells, including Caco-2 and SW480 cells, are resistant to it. The mechanisms underlying these antiproliferative actions and resistance to TGF-beta growth inhibition are largely unknown. We observed that 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] sensitized Caco-2 and SW480 cells to TGF-beta1 growth inhibitory effects. Versus 1,25(OH)(2)D-3 alone, the combination of 1,25(OH)(2)D-3 and TGF-beta1 significantly reduced cell numbers. Also, the amount of active TGF-beta1 was increased (similar to4-fold) by this secosteroid in conditioned media from Caco-2 cells. The 1,25(OH)(2)D-3 increased the expression of IGF-II receptors (IGF-IIR), which facilitated activation of latent TGF-beta1, and was found to activate TGF-beta signaling in Caco-2 cells. By using neutralizing antibodies to human TGF-beta1, we showed that this cytokine contributes to secosteroid-induced inhibition of Caco-2 cell growth. Also, 1,25(OH)(2)D-3 was found to enhance the type I TGF-beta receptor mRNA and protein abundance in Caco-2 cells. Whereas the 1,25(OH)(2)D-3-induced sensitization of Caco-2 cells to TGF-beta1 was IGF-IIR independent, the type I TGF-beta1 receptor was required for this sensitization. Thus 1,25(OH)(2)D-3 treatment of Caco-2 cells results in activation of latent TGF-beta1, facilitated by the enhanced expression of IGF-IIR by this secosteroid. Also, 1,25(OH)(2)D-3 sensitized Caco-2 cells to growth inhibitory effects of TGF-beta1, contributing to the inhibition of Caco-2 cell growth by this secosteroid.