Cordycepol C induces caspase-independent apoptosis in human hepatocellular carcinoma HepG2 cells.
Cordycepol C, a novel sesquiterpene isolated from the cultured mycelia of Cordyceps ophioglossoides, contains a hydroperoxy group and is cytotoxic to HepG2 cells. So far, no sesquiterpenes have been found in the genus Cordyceps and it would be interesting to investigate the antitumor efficacy as well as the mechanism of action of this unusual sesquiterpene. In this study, we showed that cordycepol C induced apoptosis of the HepG2 cells without affecting the normal liver cell line L-02. Cordycepol C caused poly(ADP-ribose)polymerase-1 (PARP-1) cleavage and triggered the loss of mitochondrial membrane potential (Δψm) in HepG2 cells in a time- and dose-dependent manner, resulting in the nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (Endo G). We also found that cordycepol C induced the expression of Bax protein, followed by its translocation from the cytosol to mitochondria in both wild type and p53 knockdown HepG2 cells. However, cordycepol C could not cause cleavages of procaspase-3, -8, and -9. Caspase activities were not increased and Z-VAD-fmk, a caspase inhibitor, could not prevent the apoptosis induced by cordycepol C. These findings indicate that cordycepol C induces caspase-independent apoptosis in HepG2 cells through a p53-independent and Bax-mediated mitochondrial pathway, leading to the nuclear translocation of AIF and Endo G. Our study provides the molecular mechanism by which cordycepol C induces apoptosis in hepatocellular carcinoma cells and indicates the potential use of cordycepol C as an antitumor agent.
College of Life Sciences, Zhejiang University.
Yi-Sheng
YS
Sun
Long-Xian
LX
Lv
Zhao
Z
Zhao
Xian
X
He
Lu
L
You
Ji-Kai
JK
Liu
Yong-Quan
YQ
Li
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D004706:Endodeoxyribonucleases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D061945:Caspase Inhibitors; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C000598343:cordycepol C; D011065:Poly(ADP-ribose) Polymerases; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases