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Sequential caspase-2 and caspase-8 activation is essential for saikosaponin a-induced apoptosis of human colon carcinoma cell lines

 Byeong Mo Kim  ;  Sung Hee Hong 
 APOPTOSIS, Vol.16(2) : 184-197, 2011 
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Apoptosis/drug effects* ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Blotting, Western ; Caspase 2/metabolism* ; Caspase 8/metabolism* ; Caspase 9/metabolism ; Cell Line, Tumor ; Colonic Neoplasms ; Cyclosporine/pharmacology ; Flow Cytometry ; Humans ; Inhibitor of Apoptosis Proteins/metabolism ; Mitochondria/metabolism ; Oleanolic Acid/analogs & derivatives* ; Oleanolic Acid/metabolism ; Oleanolic Acid/pharmacology ; Oligopeptides/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; RNA, Small Interfering/pharmacology ; Saponins/metabolism ; Saponins/pharmacology* ; Signal Transduction ; bcl-2-Associated X Protein/metabolism
In this study, we investigated the signaling pathways implicated in SSa-induced apoptosis of human colon carcinoma (HCC) cell lines. SSa-induced apoptosis of HCC cells was associated with proteolytic activation of caspase-9, caspase-3, and PARP cleavages and decreased levels of IAP family members, such as XIAP and c-IAP-2, but not of survivin. The fluorescence intensity of DiOC6 was significantly reduced after SSa treatment. CsA significantly inhibited SSa-induced loss of mitochondrial transmembrane potential and moderately inhibited SSa-induced cell death. SSa treatment also enhanced the activities of caspase-2 and caspase-8, Bid cleavage, and the conformational activation of Bax. Additionally, SSa-induced apoptosis was inhibited by both the selective caspase-2 inhibitor z-VDVAD-fmk and the selective caspase-8 inhibitor z-IETD-fmk and also by si-RNAs against caspase-2 and caspase-8. The selective caspase-9 inhibitor, z-LEHD-fmk, also inhibited SSa-induced apoptosis, albeit to a lesser extent compared to z-VDVAD-fmk and z-IETD-fmk, indicating that both mitochondria-dependent and mitochondria-independent pathways are associated with SSa-induced apoptosis. Both z-VDVAD-fmk and z-IETD-fmk significantly attenuated the colony-inhibiting effect of SSa. Moreover, inhibition of caspase-2 activation by the pharmacological inhibitor z-VDVAD-fmk, or by knockdown of protein levels using a si-RNA, suppressed SSa-induced caspase-8 activation, Bid cleavage, and the conformational activation of Bax. Although caspase-8 is an initiator caspase like caspase-2, the inhibition of caspase-8 activation by knockdown using a si-RNA did not suppress SSa-induced caspase-2 activation. Altogether, our results suggest that sequential activation of caspase-2 and caspase-8 is a critical step in SSa-induced apoptosis.
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5. Research Institutes (연구소) > Yonsei Integrative Research Institute for Cerebral & Cardiovascular Disease (뇌심혈관질환융합연구사업단) > 1. Journal Papers
Yonsei Authors
Kim, Byeong Mo(김병모) ORCID logo https://orcid.org/0000-0002-0582-3132
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