Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells.
Although compound K (CK), an intestinal metabolite of ginseng protopanaxadiol saponins, has been known to induce apoptosis in various cancer cells, association of AMP-activated protein kinase (AMPK) with apoptosis in HT-29 colon cancer cells remains unclear. We hypothesized that CK may exert an anticancer activity through modulating the AMPK pathway in HT-29 cells. CK-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic factors (cytochrome c and apoptosis-inducing factor) from mitochondria, and cleavage of caspase-9, caspase-3, caspase-8, Bid, and PARP proteins. This apoptotic effect of CK on colon cancer cells was found to be initiated by AMPK activation, and AMPK was activated through phosphorylation by Ca2+/calmodulin-activated protein kinase-IV (CAMK-IV). Treatment of HT-29 cells with compound C (AMPK inhibitor) or siRNA for AMPK completely abolished the CK-induced apoptosis. STO-609, CAMKs inhibitor, also attenuated CK-induced AMPK activation and apoptosis. In conclusion, the present study demonstrates that CK-mediated cell death of HT-29 colon cancer cells is regulated by CAMK-IV/AMPK pathways, and these findings provide a molecular basis for the anticancer effect of CK.
Kim
Do Yeon
DY
Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea.
Park
Min Woo
MW
Yuan
Hai Dan
HD
Lee
Hyo Jung
HJ
Kim
Sung Hoon
SH
Chung
Sung Hyun
SH
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D003110:Colonic Neoplasms / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D036145:Ginsenosides / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction
D055372:AMP-Activated Protein Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D004791:Enzyme Inhibitors; D036145:Ginsenosides; D034741:RNA, Small Interfering; C112772:ginsenoside compound K