22-Oxacalcitriol, a noncalcemic analogue of calcitriol, suppresses both cell 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 overproduce parathyroid hormone-related peptide (PTHRP) and cause hypercalcemia in patients with adult T cell leukemia. The present study was undertaken to test whether 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and its noncalcemic analogue, 22-oxa-1,25-(OH)2D3 (OCT), could suppress cell proliferation and PTHRP gene expression in an HTLV-I-infected T cell 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 analysis revealed that OCT, like the parent compound, caused a transition delay of cells through the G1 phase. OCT and 1,25-(OH)2D3 decreased the steady state levels of PTHRP mRNA, and nuclear runoff assays demonstrated that the effect of OCT occurred at a transcription level. As a result, OCT caused a reduction in PTHRP concentrations in the conditioned medium by approximately 50%. OCT inhibited not only the basal secretion 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 [3H]1,25-(OH)2D3 revealed unexpectedly that the vitamin D receptor was abundantly expressed in MT-2 cells. These results suggest that OCT, as well as 1,25-(OH)2D3, has the potential to suppress both cell proliferation and PTHRP gene expression through binding to the vitamin D receptor overexpressed in HTLV-I-infected T cells.
Inoue
D
D
Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Japan.
Matsumoto
T
T
Ogata
E
E
Ikeda
K
K
D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D010281:Parathyroid Hormone / Q000235:genetics*; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000235:genetics*; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000382:microbiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication
C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D002117:Calcitriol; C051883:maxacalcitol