Antiproliferative responses to two human colon cancer cell lines to vitamin D3 are differently modified by 9-cis-retinoic acid.
1 alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3] exerts antiproliferative actions in colorectal cancer, but their underlying molecular mechanisms have not been determined. 1,25(OH)2D3 regulates target gene transcription via a specific nuclear vitamin D receptor (VDR), which mediates hormone action preferentially as a heterodimer with 9-cis-retinoic acid receptors (RXRs). We investigated the actions of 1,25(OH)2D3 and 9-cis-retinoic acid (RA) in two human colon cancer cell lines, HT-29 and Caco-2. Both expressed mRNAs encoding VDR, RXR alpha, and RXR gamma, and VDR was regulated posttranscriptionally in Caco-2 cells. There was an antiproliferative response of both cell lines to 1,25(OH)2D3. 9-cis-RA exerted antiproliferative effects on Caco-2 cells but blocked 1,25(OH)2D3 actions in HT-29 cells. The 1,25(OH)2D3-responsive gene 25-hydroxyvitamin D3 24-hydroxylase was induced in both cell lines b 1,25(OH)2D3 but in only HT-29 cells by 9-cis-RA. 1,25(OH)2D3 and 9-cis-RA cotreatment enhanced 24-hydroxylase expression in HT-29 cells only. The 24-hydroxylase enzyme is known to result in catabolism of 1,25(OH)2D3 and attenuation of its actions. Increased 24-hydroxylase activity in HT-29 cells, but not in Caco-2 cells, in response to 9-cis-RA may account for some of the complex cell-specific responses demonstrated in these studies.
Kane
K F
KF
Department of Medicine, Queen Elizabeth Hospital, University of Birmingham, Edgbaston, United Kingdom.
Langman
M J
MJ
Williams
G R
GR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D018938:Caco-2 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions; D015971:Gene Expression Regulation, Enzymologic; D019073:HT29 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D065668:Vitamin D3 24-Hydroxylase
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol