Transforming growth factor-beta 1 signaling contributes to Caco-2 cell growth inhibition induced by 1,25(OH)(2)D(3).
Growth of Caco-2 and many cancer cells is inhibited by 1,25(OH)(2)D(3). Whereas TGF-beta 1 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-beta 1 growth inhibitory effects. Versus 1,25(OH)(2)D(3) alone, the combination of 1,25(OH)(2)D(3) and TGF-beta 1 significantly reduced cell numbers. Also, the amount of active TGF-beta 1 was increased (~4-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-beta 1, and was found to activate TGF-beta signaling in Caco-2 cells. By using neutralizing antibodies to human TGF-beta 1, 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-beta 1 was IGF-IIR independent, the type I TGF-beta 1 receptor was required for this sensitization. Thus 1,25(OH)(2)D(3) treatment of Caco-2 cells results in activation of latent TGF-beta 1, 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-beta 1, contributing to the inhibition of Caco-2 cell growth by this secosteroid.
Chen
Anping
A
Gastroenterology Section, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
Davis
Bernard H
BH
Sitrin
Michael D
MD
Brasitus
Thomas A
TA
Bissonnette
Marc
M
D030201:Activin Receptors, Type I / Q000032:analysis / Q000502:physiology; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology*; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology; D017077:Culture Media, Conditioned; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000032:analysis; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D002117:Calcitriol