BCL-X-L EXPRESSION AND ITS DOWN-REGULATION BY A NOVEL RETINOID IN BREAST-CARCINOMA CELLS

We have recently found a novel retinoid, 6-[3-(1-adamantyl) -4-hydroxp henyl]-2-naphthalene carboxylic acid (CD437), which induces G(1) cell cycle arrest and apoptosis in human breast carcinoma (HBC) cells (Onco gene 11, 493-504, 1995). CD437 downregulates the expression of a numbe r of proteins which antagonize apoptosis. bcl-X-L, a homologue of bcl- 2, antagonizes apoptosis, while bcl-X-S enhances apoptosis. We have fo und that estrogen receptor (ER)-negative HBCs express higher levels of bcl-X-L and significantly lower levels of bcl-2 than their ER-positiv e counterparts. Neither cell type expresses bcl-X-S. The addition of C D437 (1 mu M) results in a fourfold downregulation of bcl-X-L mRNA and protein levels followed by apoptosis in MDA-MB-231 and MDA-MB-468 cel ls. CD437 concentrations as low as 10 nM cause a significant reduction in both bcl-X mRNA and bcl-X-L protein expression. CD437-dependent do wnregulation of bcl-X mRNA and bcl-X-L protein expression occurs withi n 24 h of CD437 addition to the cells. Retinoic acid does not effect b cl-X mRNA or bcl-X-L protein expression. CD437 is a potent inducer of apoptosis in a number of breast carcinoma cells lines and downregulate s the expression of a number of proteins which antagonize apoptosis. ( C) 1997 Academic Press.