22-OXACALCITRIOL, A NONCALCEMIC ANALOG OF CALCITRIOL, SUPPRESSES BOTHCELL-PROLIFERATION AND PARATHYROID HORMONE-RELATED PEPTIDE GENE-EXPRESSION IN HUMAN T-CELL LYMPHOTROPHIC VIRUS, TYPE I-INFECTED T-CELLS

Human T cell lymphotrophic virus, type I (HTLV-I)-infected T cells ove rproduce parathyroid hormone-related peptide (PTHRP) and cause hyperca lcemia in patients with adult T cell leukemia. The present study was u ndertaken to test whether 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and its noncalcemic analogue, 22-oxa-1,25-(OH)2D3 (OCT), could suppress ce ll proliferation and PTHRP gene expression in an HTLV-I-infected T cel l line, MT-2. OCT as well as 1,25-(OH)2D3 inhibited the proliferation of MT-2 cells in a time- and dose-dependent manner. Cell cycle analysi s revealed that OCT, like the parent compound, caused a transition del ay of cells through the G1 phase. OCT and 1,25-(OH)2D3 decreased the s teady state levels of PTHRP mRNA, and nuclear runoff assays demonstrat ed that the effect of OCT occurred at a transcription level. As a resu lt, OCT caused a reduction in PTHRP concentrations in the conditioned medium by approximately 50%. OCT inhibited not only the basal secretio n but also the stimulation of PTHRP secretion by interleukin-2 or cAMP , which we had identified as two important stimulators. Northern blot analysis and the specific uptake of H-3!1,25-(OH)2D3 revealed unexpec tedly that the vitamin D receptor was abundantly expressed in MT-2 cel ls. These results suggest that OCT, as well as 1,25-(OH)2D3, has the p otential to suppress both cell proliferation and PTHRP gene expression through binding to the vitamin D receptor overexpressed in HTLV-I-inf ected T cells.