Caspase-2 triggers Bax-Bak-dependent and -independent cell death in colon cancer cells treated with resveratrol.
Polyphenol phytoalexin (resveratrol), found in grapes and red wine is a strong chemopreventive agent with promising safety records with human consumption and unique forms of cell death induction in a variety of tumor cells. However, the mechanism of resveratrol-induced apoptosis upstream of mitochondria is still not defined. The results from this study suggest that caspase-2 activation occurs upstream of mitochondria in resveratrol-treated cells. The upstream activation of caspase-2 is not dependent on its antioxidant property or NF-kappaB inhibition. The activated caspase-2 triggers mitochondrial apoptotic events by inducing conformational changes in Bax/Bak with subsequent release of cytochrome c, apoptosis-inducing factor, and endonuclease G. Caspase-8 activation seems to be independent of these events and does not appear to be mediated by classical death receptor processing or downstream caspases. Both caspase-2 and caspase-8 contribute toward the mitochondrial translocation of Bid, since neither caspase-8 inhibition nor caspase-2 inhibition could prevent translocation of Bid DsRed into mitochondria. Caspase-2 inhibitors or antisense silencing of caspase-2 prevented cell death induced by resveratrol and partially prevented processing of downstream caspases, including caspase-9, caspase-3, and caspase-8. Studies using mouse embryonic fibroblasts deficient for both Bax and Bak indicate the contribution of both Bax and Bak in mediating cell death induced by resveratrol and the existence of Bax/Bak-independent cell death possibly through caspase-8- or caspase-2-mediated mitochondria-independent downstream caspase processing.
Mohan
John
J
Department of Cancer Biology, Rajiv Gandhi Centre for Biotechnology, Poojappura, Trivandrum-695 014, Kerala, India.
Gandhi
Alankaram Arul
AA
Bhavya
Balan Chandrika
BC
Rashmi
Ramachandran
R
Karunagaran
Devarajan
D
Indu
Ramachandran
R
Santhoshkumar
Thankayyan Ratnabhai
TR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C494829:AIFM1 protein, human; D000972:Antineoplastic Agents, Phytogenic; D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D013267:Stilbenes; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D004706:Endodeoxyribonucleases; C052391:endonuclease G; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D000077185:Resveratrol