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Apoptosis Induced by a New Member of Saponin Family Is Mediated through Caspase-8-Dependent Cleavage of Bcl-2

Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (J.Z., L.X., J.W.); State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China (B.Y.); and Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science & Technology of China, Hefei, Anhui, China (J.W.)

OSW-1 is a new member of cholestane saponin family, which is cytotoxic against several types of malignant cells. We reported herein that OSW-1 induced apoptosis of mammalian cells in a concentration- and time-dependent manner. The drug-induced apoptosis was mediated through the mitochondrial pathway, involving the cleavage of Bcl-2. This drug-induced Bcl-2 cleavage in Chinese hamster ovary (CHO) cells could be suppressed either by dominant-negative caspase-8 or by a caspase-8 inhibitor, suggesting that the Bcl-2 cleavage is dependent on caspase-8. In contrast, the Bcl-2 cleavage was independent of caspase-3 activity. The inhibition of caspase-8 activity also resulted in the reduction of apoptotic cells, indicating that Bcl-2 cleavage induced by caspase-8 promotes the progression of apoptosis. The involvement of the caspase-8 activity in the processes of the OSW-1-induced apoptosis was further examined by using caspase-8-deficient Jurkat T cells. It was found that the caspase-8-deficient cells were resistant to OSW-1-induced Bcl-2 cleavage or apoptosis. Furthermore, the small subunit of caspase-8 was found to interact with Bcl-2 as determined by yeast two-hybrid and coimmunoprecipitation assays. Overexpression of caspase-8 small subunit reduced the cleavage of Bcl-2 and inhibited the apoptosis induced by OSW-1. Taken together, these results demonstrate that OSW-1 is capable of inducing apoptosis in mammalian cells, in which the caspase-8-dependent cleavage of Bcl-2 plays an important role.

Address correspondence to: Jiarui Wu, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, 320 Yue-Yang Road., Shanghai 200031, China. E-mail: wujr{at}sibs.ac.cn