Differential expression of antiapoptotic genes in human endometrial carcinoma: bcl-XL succeeds bcl-2 function in neoplastic cells.

OBJECTIVES: Previous histochemical observations have suggested a possible involvement of the bcl-2 family genes in the acquisition of neoplastic phenotype of the endometrium. Since knowledge of the type and function of genes controlling the transformed cell may result in new diagnostic, prognostic, and therapeutic approaches, we have investigated at the molecular level the biological role of bcl-2 family genes in endometrial neoplastic cells.

METHODS: To investigate the relationship between the sensitivity to apoptosis and the expression of the bcl-2 family genes, we set up a model system consisting of four human endometrial carcinoma cell lines. This system constitutes an array of two cell pairs presenting, respectively, endometrioid and adenosquamous phenotypes. G2 and G3 gradings are represented within each pair; in addition, each set contains one cell line that is apoptosis-sensitive and one that is resistant. Transfection of bcl-2 and bcl-XL into apoptosis-sensitive cells was used to monitor the biological function of protective genes.

RESULTS: A differential pattern of expression of bcl-2 family genes was observed in apoptosis-sensitive versus resistant cells, independent from the histological subtype. Resistant lines exhibited high amounts of Bcl-XL and low amounts of Bcl-2. Bax expression clearly correlates with cellular susceptibility to apoptosis. Transfection of bcl-XL resulted in a dose-dependent enhancement in resistance toward apoptosis. In contrast, the main effect of bcl-2 constitutive overexpression was to drastically abate the proliferative potential of transfected cells.

CONCLUSIONS: These data demonstrate, at the molecular level, that bcl-XL is selected as an apoptosis-protective gene in place of bcl-2 while bax retains its dominant proapototic role.