seocalcitol and Thyroid-Neoplasms

We have previously reported that the hormonal form of 1alpha,25-dihydroxyvitamin D3 (1,25-VD3), and its noncalciomimetic analog EB1089, arrest the growth of human thyroid cancer cells by increasing the cell cycle inhibitor p27. In the present study, we investigated whether the tumor-suppressive effects of vitamin D (VD) compounds may also be mediated by mechanisms that govern cell adhesiveness. Both 1,25-VD3 and EB1089 increased cell adhesiveness, an effect that was accompanied by consistent increases in fibronectin (FN) expression. Introduction of small interfering RNA against FN resulted in down-regulation of FN expression and diminished cell adhesiveness to a collagen-type I matrix. To determine whether this action of 1,25-VD3 was mediated through the PTEN/phosphoinositol 3-kinase pathway, we examined whether this tumor suppressor protein/dual phosphatase can influence FN expression and consequently cell adhesiveness Overexpression of wild-type PTEN induced FN expression as well as cell adhesiveness. In contrast, introduction of mutant forms of PTEN failed to induce FN and led to diminished cell adhesiveness. Conversely, small interfering RNA-mediated PTEN down-regulation attenuated FN expression as well as cell adhesiveness. The attenuated FN expression was also associated with relative insensitivity to 1,25-VD3 growth-suppressive action. Cells down-regulated for FN demonstrated a more aggressive growth pattern in xenografted mice and were also relatively insensitive to 1,25-VD3 treatment. Taken together, our findings highlight the significance of FN in modulating thyroid cancer cell adhesiveness and, at least in part, in mediating VD actions on neoplastic cell growth.

Topics: Animals; Antineoplastic Agents; Calcitriol; Cell Adhesion; Down-Regulation; Fibronectins; Humans; Mice; Mice, SCID; Mutation; RNA, Small Interfering; Thyroid Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

This study examined the action of 9-cis retinoic acid and 1,25-dihydroxyvitamin D3 analogues (KH 1060, EB 1089 and MC 903) on the release of calcitonin (CT) and calcitonin gene-related peptide (CGRP) in the rat C cell line CA-77. This cell line mainly secretes CGRP. Using radioimmunoassays (RIAs) for CT and CGRP, we measured the release of both peptides in the culture medium as well as the amount of these proteins contained in the CA-77 C cells. 9-cis retinoic acid decreased the release of both CGRP and CT dose-dependently in the range between 1 nM and 1 microM. The half-effective dose was 10 nM. The treatment of CA-77 C cells with 0.1 microM calcitriol alone only slightly decreased the release of both CT and CGRP. The increase in the amount of CT and CGRP released by the action of 1 microM dexamethasone was reduced by 1 microM 9-cis retinoic acid, and this effect was enhanced by the addition of 0.1 microM calcitriol or KH 1060, EB 1089 and MC 903. When the C cells were continuously stimulated by dexamethasone, after 6 days of exposure to the combined treatment with calcitriol analogues + 9-cis retinoic acid, there was a greater decrease in the amount of CGRP contained in the C cells than after treatment with 9-cis retinoic alone. Our data suggested that combined treatment with retinoic acid and calcitriol analogues exerted a stronger inhibition on the amounts of the two peptides either contained in the cells or released in the medium than each hormone alone.

Topics: Alitretinoin; Animals; Calcitonin; Calcitonin Gene-Related Peptide; Calcitriol; Carcinoma, Medullary; Dexamethasone; Dose-Response Relationship, Drug; Drug Interactions; Kinetics; Rats; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured