Apoptosis induced by vitamin D compounds in breast cancer cells is inhibited by Bcl-2 but does not involve known caspases or p53.

摘要: The hormonally active form of vitamin D3, 1,25-dihydroxyvitamin and its two analogues, EB 1089 CB 1093, are novel putative anticancer agents with an interesting profile induction growth inhibition, differentiation, apoptosis in tumor cells. To study the signaling pathways mediating these events, we used human breast cancer cell lines: MCF-7 cells, expressing a wild-type p53 suppressor protein, T47D lacking functional p53. Vitamin D compounds induced arrest followed by both lines at concentrations ranging from 1 to 100 nM, indicating that is not necessary for growth-inhibitory effects compounds. Surprisingly, occurred also independently known caspases. Inhibition caspase activation overexpression cowpox-derived inhibitor CrmA or addition inhibitory peptides acetyl-Asp-Glu-Val-Asp-aldehyde (200 microM), acetyl-Ile-Glu-Thr-Asp-aldehyde (50 Z-Val-Ala-D,L-Asp-fluoromethylketone (1 microM) showed no effect on under assay conditions which TNF staurosporine was effectively inhibited. Moreover, caspase-3 cells had sensitizing compounds, neither caspase-3-like protease activity nor cleavage substrate poly(ADP)ribose polymerase detected lysates apoptotic following treatment Contrary CrmA, antiapoptotic protein Bcl-2 conferred nearly complete protection Taken together, data indicate induce via caspase- p53-independent pathway can be inhibited Bcl-2. This may prove useful tumors resistant therapeutic dependent and/or