Induction of caspase-dependent and -independent apoptosis in response to methionine restriction.
Tumor cells are more sensitive to methionine restriction than normal tissues, a phenomenon known as methionine auxotrophy. Previous studies have demonstrated that methionine restriction causes tumor cell growth arrest and eventually apoptosis. The current studies were undertaken to elucidate the molecular pathways leading to apoptosis induced by methionine restriction. We found that methionine restriction induced formation of oligonucleosomal DNA fragment and cytochrome c release from mitochondria in methionine-dependent PC3 and Hela cells. Methionine restriction also led to cleavage and activation of initiator and effector caspases in Hela cells but not PC3 cells. Furthermore, methionine restriction resulted in cleavage of BID and reduction in Bcl-2 levels in both cell lines. These data suggest that apoptosis induced by methionine restriction is mitochondria-dependent. Methionine restriction induced caspase-independent cell death in PC3 cells, whereas it stimulated caspase-dependent cell death in Hela cells. Cleavage of BID and decreased expression of Bcl-2 upon methionine deprivation may be the underlying mechanism to stimulate release of cytochrome c from mitochondria.
Lu
Shan
S
Department of Medicine, Baylor College of Medicine and VA Medical Center, Houston, TX 77030, USA.
Hoestje
Sara M
SM
Choo
Eugene
E
Epner
Daniel E
DE
D000230:Adenocarcinoma / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000502:physiology*; D003574:Cytochrome c Group / Q000032:analysis; D053938:DNA Fragmentation / Q000187:drug effects; D004790:Enzyme Induction; D004792:Enzyme Precursors / Q000096:biosynthesis; D005260:Female; D006367:HeLa Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D008297:Male; D008715:Methionine / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects; D009363:Neoplasm Proteins / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology; D013312:Stress, Physiological / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D003574:Cytochrome c Group; D004792:Enzyme Precursors; D009363:Neoplasm Proteins; D006710:Homocysteine; D008715:Methionine; D003546:Cysteine Endopeptidases