Induction of anoikis and suppression of human ovarian tumor growth in vivoby down-regulation of Bcl-X-L

Normal or immortal epithelial cells are sensitive to a form of apoptosis, c ommonly referred to as anoikis, which is induced by detachment from the ext racellular matrix (ECM), In contrast, development of carcinomas is associat ed with acquisition of cellular resistance to anoikis, However, whether hum an cancer cells deprived of anoikis resistance necessarily display reduced tumorigenic properties in vivo is unknown, We decided to address this quest ion using human ovarian carcinoma cells as a model. Bd-X,, an apoptotic fac tor considered to play an important role in (resistance to) anoikis, is ove rexpressed in ovarian cancer, and represents an unfavorable prognostic indi cator for this type of human malignancy. We therefore evaluated whether Bcl -X-L, can be used as a tool to manipulate anoikis resistance and tumorigeni city of ovarian cancer cells. We show here that when nonmalignant ovarian e pithelial cells are detached From the ECM, down-regulation of Bcl-X-L and a poptotic cell death are observed, although these events do not occur in ova rian carcinoma cells. Moreover, enforced down-regulation of Bcl-X-L by tran sfection with antisense cDNA in the anoikis-resistant and highly tumorigeni c HEY ovarian carcinoma cell line had no impact on the viability of these c ells under adherent conditions but caused significant apoptosis in response to detachment from the ECM. This change was associated with a strong inhib ition of tumorigenicity of the Bcl-X-L-deficient HEY cells in nude mice, bo th s.c. and in the peritoneal cavity. These results suggest a critical role for Bcl-X-L in the maintenance of anoikis resistance in ovarian cancer cel ls. They also serve to establish a functional linkage between this property and the ability of human cancer cells to grow aggressively in vivo. Conseq uently, targeting molecular mechanisms responsible for anoikis resistance m ay serve as a potentially effective therapeutic strategy for the treatment of such human malignancies as ovarian cancer.