Caspase-dependent and -independent cell death pathways after DNA damage (Review).
Apoptosis is known to be an important phenomenon in exerting antitumor response to cancer therapy, which is regulated by Bcl-2 family proteins through mitochondrial permeability transition (MPT). Insertion by the activated Bax/Bak in response to DNA damage induces mitochondrial membrane permeabilization (MMP) via an anion channel, VDAC in mitochondrial outer membrane that plays a crucial role in releasing small molecules such as cytochrome c, Smac/DIABLO, Omi/HtrA2, AIF, and endonuclease G leading to cell death. The released small molecules are involved in caspase-dependent and -independent cell death pathway that is inhibited by Bcl-2/xL. Despite the fact that the pancaspase inhibitor, zVAD-fmk inhibited the caspase cascade, cell death mediated by caspase-independent pathway was not blocked. Similarly, although etoposide induced-apoptosis was inhibited in Bax(-/-)/Bak(-/-)mouse embryonic fibroblasts, autophagy was not inhibited, which was regulated by Bcl-xL. It appears that the cross-talk between caspase-dependent and -independent apoptotic cell death including autophagic cell death that was mediated by MPT affects overall tumor response to anticancer treatment. In this review, to assist a comprehensive understanding of MPT-mediated cell death pathway for exploring appropriate targets in cancer therapy, role of the caspase-dependent and -independent cell death pathway in the interaction of these pathways is discussed.
Kim
Ryungsa
R
International Radiation Information Center, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan. rkim@hiroshima-u.ac.jp
Emi
Manabu
M
Tanabe
Kazuaki
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology*
D045304:Cytochromes c; D020169:Caspases