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Expression Profiling in Squamous Carcinoma Cells Reveals Pleiotropic Effects of Vitamin D₃ Analog EB1089 Signaling on Cell Proliferation, Differentiation, and Immune System Regulation

Departments of Physiology (R.L., Y.N., Y.B., J.H., K.P., J.H.W.), and Medicine (R.S., T.J.H., J.H.W.), McGill University, Montréal, Québec H3G 1Y6, Canada; Montréal Genome Centre (Y.N., R.S., T.J.H.), Montréal General Hospital, McGill University, Montréal, Québec H3G 1A6, Canada; Centre for Nonlinear Dynamics (Y.N.), McGill University, Montréal, Québec H3G 1Y6, Canada; Department of Pharmacology (G.S.), School of Health Science, University of Patras, 26500 Patras, Greece; and Department of Pathology and Laboratory Medicine (E.P.D.), Mount Sinai Hospital and Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, Ontario M5G 1X5, Canada

Address all correspondence and requests for reprints to: Dr. John H. White, Department of Physiology, McGill University, 3655 Drummond Street, Montréal, Québec H3G 1Y6, Canada. E-mail: john.white{at}mcgill.ca.

The active form of vitamin D₃, 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] is key mediator of calcium homeostasis and is a component of the complex homeostatic system of the skin. 1,25-(OH)₂D₃ regulates cellular differentiation and proliferation and has broad potential as an anticancer agent. Oligonucleotide microarrays were used to assess profiles of target gene regulation at several points over a 48 h period by the low calcemic 1,25-(OH)₂D₃ analog EB1089 in human SCC25 head and neck squamous carcinoma cells. One hundred fifty-two targets were identified, composed of 89 up- and 63 down-regulated genes distributed in multiple profiles of regulation. Results are consistent with EB1089 driving SCC25 cells toward a less malignant phenotype, similar to that of basal keratinocytes. Targets identified control inter- and intra-cellular signaling, G protein-coupled receptor function, intracellular redox balance, cell adhesion, and extracellular matrix composition, cell cycle progression, steroid metabolism, and more than 20 genes modulating immune system function. The data indicate that EB1089 performs three key functions of a cancer chemoprevention agent; it is antiproliferative, it induces cellular differentiation, and has potential genoprotective effects. While no evidence was found for gene-specific differences in efficacy of 1,25-(OH)₂D₃ and EB1089, gene regulation by 1,25-(OH)₂D₃ was generally more transient. Treatment of cells with 1,25-(OH)₂D₃ and the cytochrome P450 inhibitor ketoconazole produced profiles of regulation essentially identical to those observed with EB1089 alone, indicating that the more sustained regulation by EB1089 was due to its resistance to inactivation by induced 24-hydroxylase activity. This suggests that differences in action of the two compounds arise more from their relative sensitivities to metabolism than from differing effects on VDR function.

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