Vitamin D inhibits CEACAM1 to promote insulin/IGF-I receptor signaling without compromising anti-proliferative action.
Population studies suggest putative links between vitamin D (VD)-deficiency and risk of cancer and diabetes. The insulin/IGF-I receptor represents a signaling target of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) that is implicated in both diabetes and cancer, therefore we hypothesized that VD actions may be mediated through this adhesion molecule. In this study, we show that 1,25 vitamin D3 and its analogues EB1089 and KH1060 potently inhibit CEACAM1 expression in cancer cells. This effect was associated with significant reductions in mRNA and protein levels, resulting from transcriptional and posttranslational actions respectively. Insulin/IGF-I-mediated IRS-1 and Akt activation were enhanced by VD treatment. Similarly, CEACAM1 downregulation significantly upregulated the insulin and IGF-I receptors and mimicked the effect of VD-mediated enhanced insulin/IGF-I receptor signaling. Despite improved insulin/IGF-I signaling, the anti-proliferative actions of VD were preserved in the absence or presence of forced CEACAM1 expression. Forced CEACAM1, however, abrogated the anti-invasive actions of VD. Our findings highlight CEACAM1 as a target of VD action. The resulting inhibition of CEACAM1 has potentially beneficial effects on metabolic disorders without necessarily compromising the anticancer properties of this vitamin.
Liu
Wei
W
Department of Pathology, University of Toronto, Toronto, Ontario, Canada.
Guo
Miao
M
Ezzat
Shereen
S
Asa
Sylvia L
SL
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014815:Vitamins / Q000494:pharmacology
D015703:Antigens, CD; D000970:Antineoplastic Agents; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D014815:Vitamins; C074279:KH 1060; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D002117:Calcitriol; C078903:seocalcitol