Therapeutic potential of AIF-mediated caspase-independent programmed cell death.
Resistance to anticancer drugs is often related to deficient cell death execution pathways in cancer cells. Apoptosis, which denotes a form of cell death executed by caspases, was traditionally considered as the only physiological and programmed form of cell death. However, recent evidence indicates that programmed cell death (PCD) can occur in complete absence of caspase activation. Indeed, a large number of caspase-independent models are now defined and a key protein implicated in this type of PCD, apoptosis-inducing factor (AIF), has been identified. AIF is a mitochondrial protein with two faces looking in opposite life/death directions. Recently, the identification of five different isoforms allowed a better characterization of AIFs life/mitochondrial versus death/nuclear functions, as well as definition of its pro-apoptotic region and some of its nuclear partners. Importantly, much work on caspase-independent PCD has revealed that AIF participates in more PCD systems than initially thought. A wider molecular knowledge of AIF, and of the caspase-independent PCDs in which it is involved, are key to provide new insights into the role of PCD. There is no doubt that these insights will lead to the development of more selective and efficient drugs against cancer, degenerative diseases, and other pathological disorders implicating AIF.
Lorenzo
Hans K
HK
INSERM U542, Institut André Lwoff, Lavoisier Building, 94803 Villejuif, France. lorenzo@vjf.inserm.fr
Susin
Santos A
SA
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000737:chemistry / Q000378:metabolism*; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011487:Protein Conformation; D020033:Protein Isoforms / Q000378:metabolism
D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D002317:Cardiovascular Agents; D018696:Neuroprotective Agents; D020033:Protein Isoforms; D020169:Caspases