1alpha,25-dihydroxyvitamin D3 induced growth inhibition of PC-3 prostate cancer cells requires an active transforming growth factor beta signaling pathway.
BACKGROUND
Prostate cancer growth inhibition by 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) is best characterized in the androgen dependent LNCaP cell line, where treatment with this hormone causes cell cycle arrest and apoptosis. 1,25(OH)2D3 also inhibits the growth of PC-3 prostate cancer cells, but not through the induction of G1 arrest or apoptosis. In this study, we have sought to elucidate the mechanism/s involved in PC-3 cell growth inhibition by 1,25(OH)2D3.


METHODS
We determined the effect of transforming growth factor beta (TGFbeta) blocking antibodies on 1,25(OH)2D3 mediated growth inhibition of PC-3 cells. In addition, we also studied the effects of 1,25(OH)2D3 on TGFbeta signaling and receptor expression. Finally, we assessed the role of TGFbeta signaling in the induction of the growth inhibitory protein, insulin like growth factor binding protein 3 (IGFBP-3), by 1,25(OH)2D3.


RESULTS
We find that 1,25(OH)2D3 action in PC-3 cells is mediated through at least two distinct pathways, the TGFbeta pathway and the IGFBP-3 pathway. We show that 1,25(OH)2D3 treatment elevates TGFbeta production and signaling, as well as receptor levels, in PC-3 cells. Further, using a blocking antibody against TGFbeta substantially reduces 1,25(OH)2D3 mediated growth inhibition without affecting IGFBP-3 induction, suggesting that IGFBP-3, alone, is insufficient to inhibit the growth of PC-3 cells.
Murthy
Shalini
S
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Weigel
Nancy L
NL
D000906:Antibodies; D002117:Calcitriol / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000906:Antibodies; D002120:Calcium Channel Agonists; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D002117:Calcitriol