Targeting the apoptosome for cancer therapy.
Apoptosis is a programmed mechanism of cell death that ensures normal development and tissue homeostasis in metazoans. Avoidance of apoptosis is an important contributor to the survival of tumor cells, and the ability to specifically trigger tumor cell apoptosis is a major goal in cancer treatment. In vertebrates, numerous stress signals engage the intrinsic apoptosis pathway to induce the release of cytochrome c from mitochondria. Cytochrome c binds to apoptosis protease activating factor-1, triggering formation of the apoptosome, a multisubunit protein complex that serves as a platform for caspase activation. In this review we summarize the mechanisms of apoptosome assembly and activation, and our current understanding of the regulation of these processes. We detail the evidence that loss-of-function of the apoptosome pathway may contribute to the development of specific cancers. Finally we discuss recent results showing enhanced sensitivity of some tumor cells to cytochrome c-induced apoptosis, suggesting that agents able to directly or indirectly trigger apoptosome-catalyzed caspase activation in tumor cells could provide new approaches to cancer treatment.
Ledgerwood
Elizabeth C
EC
Department of Biochemistry, University of Otago, Dunedin, New Zealand. liz.ledgerwood@otago.ac.nz
Morison
Ian M
IM
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002474:Cell-Free System; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*
C506592:APAF1 protein, human; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D000244:Adenosine Diphosphate; D045304:Cytochromes c; D020169:Caspases