Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak

The pro-apoptotic multidomain Bcl-2 proteins Bax and Bak are considered the gatekeepers of the intrinsic pathway of apoptosis by triggering the mitochondrial release of cytochrome c. The role of the third Bax/Bak-homologous multidomain protein Bok however is still rather unknown. As cells doubly deficient for Bax and Bak are largely resistant to various apoptotic stimuli, Bok was proposed to be either dispensable for apoptosis or dependent on Bax and Bak. Here, we demonstrate in several cell systems that Bok efficiently induces cytochrome c release and apoptosis even in the complete absence of both, Bak and Bax. Moreover, modulation of endogenous Bok levels affected the apoptosis response. By RNA interference and targeted deletion of the Bok gene we demonstrate that Bok can significantly influence the apoptotic response in ovarian carcinoma cells to chemotherapeutic drugs. Hence, our results not only establish Bok as a Bak/Bax-independent apoptosis inducer, but also suggest a potential impact of Bok expression for ovarian cancer therapy.