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 i nvolvement of the bcl-2 family genes in the acquisition of neoplastic pheno type 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 apoptos is and the expression of the bcl-2 family genes, we see up a model system c onsisting of four human endometrial carcinoma cell lines. This system const itutes an array of two cell pairs presenting, respectively, endometrioid an d adenosquamous phenotypes. G2 and G3 gradings are represented within each pair; in addition, each set contains one cell line that is apoptosis-sensit ive and one that is resistant. Transfection of bcl-2 and bcl-XL into apopto sis-sensitive cells was used to monitor the biological function of protecti ve genes. Results. A differential pattern of expression of bcl-2 family genes was obs erved in apoptosis-sensitive versus resistant cells, independent from the h istological subtype. Resistant lines exhibited high amounts of Bcl-XL and l ow amounts of Bcl-2. Bax expression clearly correlates with cellular suscep tibility 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 proliferati ve 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 box retai ns its dominant proapototic role. (C) 2000 Academic Press.