Bcl-X(L) expression and its downregulation by a novel retinoid in breast carcinoma cells

We have recently found a novel retinoid, 6-[3-(1-adamantyl)-4-hydroxphenyl]-2-naphthalene carboxylic acid (CD437), which induces G1 cell cycle arrest and apoptosis in human breast carcinoma (HBC) cells (Oncogene 11, 493-504, 1995). CD437 downregulates the expression of a number of proteins which antagonize apoptosis. bcl-X(L), a homologue of bcl-2, antagonizes apoptosis, while bcl-X(S) enhances apoptosis. We have found that estrogen receptor (ER)-negative HBCs express higher levels of bcl-X(L) and significantly lower levels of bcl-2 than their ER-positive counterparts. Neither cell type expresses bcl-X(S). The addition of CD437 (1 microM) results in a fourfold downregulation of bcl-X(L) mRNA and protein levels followed by apoptosis in MDA-MB-231 and MDA-MB-468 cells. CD437 concentrations as low as 10 nM cause a significant reduction in both bcl-X mRNA and bcl-X(L) protein expression. CD437-dependent downregulation of bcl-X mRNA and bcl-X(L) protein expression occurs within 24 h of CD437 addition to the cells. Retinoic acid does not effect bcl-X mRNA or bcl-X(L) protein expression. CD437 is a potent inducer of apoptosis in a number of breast carcinoma cells lines and downregulates the expression of a number of proteins which antagonize apoptosis.