Methionine-derived metabolites in apoptosis: therapeutic opportunities for inhibitors of their metabolism in chemoresistant cancer cells.
Methionine, in addition to its role in protein synthesis, participates in 3 important cellular functions: as AdoMet in transmethylation; as decarboxylated-AdoMet in aminopropylation; as homocysteine its demethylated form, in trans-sulphuration. Here we provide evidence from the literature and from our own work for a fourth role for its oxoacid: 4-methylthio-2-oxo-butanoate (MTOB) in apoptosis [28,29]. MTOB enters 2 pathways: (a) transamination by glutamine-transaminase K to methionine[13,14].(b)oxidative decarboxylation by the mitochondrial Branched-Chain-Oxo-Acid-Dehydrogenase-Complex to methional and finally to methylthiopropanoyl CoA (MTPCoA) [26,27]. Some of the methional formed after MTOB decarboxylation leaks into the cytoplasm as free methional [29]. Exogenous methional induces apoptosis in normal and cancer cells in culture [28, 29] but not in those overexpressing the antiapoptotic gene bcl2 [30]. In physiologically-induced apoptosis e.g; trophic factor (IL3) withdrawal, methional leakage is decreased [29] suggesting that MTPCoA is also involved in apoptosis. Both methional and MTPCoA give rise to metabolites that may act as cross-linking agents. In the case of methional, the CH3-S moiety is lost and malondialdehyde (MDA) is formed when methional is subjected to ( )OH attack [29]. MDA generated in situ from 1,3-propanediol, induces DNA-protein cross-linking [41].With regard to MTPCoA, it is metabolized to malonic semialdehyde CoA (MASACoA) with loss of the CH3-S moiety [48,49]. The capacity of MASACoA to form cross-links has not yet been established experimentally, but it could be a substrate for one of the histone acyl transferases [50, 51] and so form amides via the CoA at one end and imines by its CHO group at the other, with amino groups on proteins. Chromatin cross-linking/condensation is one of the hall-marks of apoptosis [40]. Methional, MDA and other apoptogenic aldehydes like 4-hydroxy-2-nonenal are oxidized by ALDHs to non-apoptogenic carboxylic acids [29,44, 45,68] but retain their apoptotic activity when the ALDHs are inhibited [98,110]. MASACoA would also lose its cross-linking capacity if its CoA moiety were putatively hydrolysed by ALDHs and/or acylCoA thioesterases [56,58,88,89]. ALDH inhibitors that control cellular MDA and possibly MASACoA homeostasis are cited as examples of targeted therapeutic approaches in chemoresistant cancers [62,84,97,98,110].
Quash
Gérard
G
Laboratoire d'Immunochimie, Faculté de Médecine Lyon-Sud, Chemin du Petit Revoyet BP.12, Oullins Cedex, France. gcquash@orange.fr
Fournet
Guy
G
D000447:Aldehydes / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008190:Lyases / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology; D010084:Oxidation-Reduction; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D015398:Signal Transduction; D000637:Transaminases / Q000378:metabolism
D000447:Aldehydes; D011448:Prostaglandin Antagonists; C008390:methional; C014632:2-keto-4-methylthiobutyric acid; D008715:Methionine; D000637:Transaminases; C427605:glutamine - phenylpyruvate transaminase; D008190:Lyases