Affiliation:
1. Gastroenterology Section, Department of Medicine, The University of Chicago, Chicago, Illinois 60637
Abstract
Growth of Caco-2 and many cancer cells is inhibited by 1,25(OH)2D3. Whereas TGF-β1 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-β growth inhibition are largely unknown. We observed that 1,25-dihydroxyvitamin D3[1,25(OH)2D3] sensitized Caco-2 and SW480 cells to TGF-β1 growth inhibitory effects. Versus 1,25(OH)2D3 alone, the combination of 1,25(OH)2D3 and TGF-β1 significantly reduced cell numbers. Also, the amount of active TGF-β1 was increased (∼4-fold) by this secosteroid in conditioned media from Caco-2 cells. The 1,25(OH)2D3 increased the expression of IGF-II receptors (IGF-IIR), which facilitated activation of latent TGF-β1, and was found to activate TGF-β signaling in Caco-2 cells. By using neutralizing antibodies to human TGF-β1, we showed that this cytokine contributes to secosteroid-induced inhibition of Caco-2 cell growth. Also, 1,25(OH)2D3 was found to enhance the type I TGF-β receptor mRNA and protein abundance in Caco-2 cells. Whereas the 1,25(OH)2D3-induced sensitization of Caco-2 cells to TGF-β1 was IGF-IIR independent, the type I TGF-β1 receptor was required for this sensitization. Thus 1,25(OH)2D3 treatment of Caco-2 cells results in activation of latent TGF-β1, facilitated by the enhanced expression of IGF-IIR by this secosteroid. Also, 1,25(OH)2D3 sensitized Caco-2 cells to growth inhibitory effects of TGF-β1, contributing to the inhibition of Caco-2 cell growth by this secosteroid.
Publisher
American Physiological Society
Subject
Physiology (medical),Gastroenterology,Hepatology,Physiology
Cited by
64 articles.
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