Activation of bone morphogenetic protein signaling by a gemini vitamin D-3 analogue is mediated by Ras/protein kinase C alpha

作者：Lee Hong Jin; Ji Yan; Paul Shiby; Maehr Hubert; Uskokovic Nfilan; Suh Nanjoo^*

来源：Cancer Research, 2007, 67(24): 11840-11847.

DOI：10.1158/0008-5472.CAN-07-1549

Bone morphogenetic proteins (BMP) are members of the transforming growth factor-beta superfamily, and they play an important role for embryonic development, for bone and cartilage formation, and during carcinogenesis. We have previously shown that the novel Gemini vitamin D-3 analogue, Ro-438-3582 [Ro3582; 1 alpha,25-dihydroxy-20S,21(3-hydroxy-3-methylbutyl)-23-yne-26,27-hexafluorocholecalciferol], inhibited cell proliferation and activated the BMP/Smad signaling pathway in MCF10AT1 breast epithelial cells. In this report, we investigated the upstream signaling pathways responsible for the activation of BMP/Smad signaling by Ro3582. Among seven different serine/threonine kinase inhibitors that we tested, protein kinase C (PKC) inhibitors blocked the effects of Ro3582 on the phosphorylation of Smad1/5, mRNA synthesis for BMP-2 and BMP-6, and cell growth in MCF10AT1 cells. Overexpression of PKC alpha, but not PKC epsilon, PKC delta or PKC zeta isoforms, increased Ro3582-induced phosphorylation of Smad1/5, suggesting that PKC alpha mediates the activation of Smad signaling and inhibition of cell proliferation. Interestingly, the activation of Smad signaling by Ro3582 was shown in Ha-ras-transfected MCF10AT1 cells, but not in the parent cell line (MCF10A without Ras). Inhibiting Ras activity blocked the translocation of PKCa to the plasma membrane and the phosphorylation of Smad1/5 induced by Ro3582 , indicating that Ras is necessary for the activation of PKC alpha and Smad signaling. In conclusion, Ro3582 inhibits cell proliferation and activates BMP/Smad signaling via a Ras and PKC alpha pathway in breast epithelial cells.

• 出版日期2007-12-15
• 单位rutgers