title: A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells.
abstract: Compound K (20-O-(β-D-glucopyranosyl)-20(S)-protopanaxadiol) is an active metabolite of ginsenosides and induces apoptosis in various types of cancer cells. This study investigated the role of autophagy in compound K-induced cell death of human HCT-116 colon cancer cells. Compound K activated an autophagy pathway characterized by the accumulation of vesicles, the increased positive acridine orange-stained cells, the accumulation of LC3-II, and the elevation of autophagic flux. Whereas blockade of compound K-induced autophagy by 3-methyladenein and bafilomycin A1 significantly increased cell viability. In addition, compound K augmented the time-dependent expression of the autophagy-related proteins Atg5, Atg6, and Atg7. However, knockdown of Atg5, Atg6, and Atg7 markedly inhibited the detrimental impact of compound K on LC3-II accumulation and cell vitality. Compound K-provoked autophagy was also linked to the generation of intracellular reactive oxygen species (ROS); both of these processes were mitigated by the pre-treatment of cells with the antioxidant N-acetylcysteine. Moreover, compound K activated the c-Jun NH2-terminal kinase (JNK) signaling pathway, whereas downregulation of JNK by its specific inhibitor SP600125 or by small interfering RNA against JNK attenuated autophagy-mediated cell death in response to compound K. Compound K also provoked apoptosis, as evidenced by an increased number of apoptotic bodies and sub-G1 hypodiploid cells, enhanced activation of caspase-3 and caspase-9, and modulation of Bcl-2 and Bcl-2-associated X protein expression. Notably, compound K-stimulated autophagy as well as apoptosis was induced by disrupting the interaction between Atg6 and Bcl-2. Taken together, these results indicate that the induction of autophagy and apoptosis by compound K is mediated through ROS generation and JNK activation in human colon cancer cells.
authors.affiliation: School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju, Korea.
authors.forename: A D
authors.initials: AD
authors.lastname: Kim
authors.forename: K A
authors.initials: KA
authors.lastname: Kang
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.forename: D H
authors.initials: DH
authors.lastname: Kim
authors.forename: Y H
authors.initials: YH
authors.lastname: Choi
authors.forename: S J
authors.initials: SJ
authors.lastname: Lee
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.forename: J W
authors.initials: JW
authors.lastname: Hyun
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D004789:Enzyme Activation; D036145:Ginsenosides / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000225:Adenine; D000970:Antineoplastic Agents; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D036145:Ginsenosides; D048031:JNK Mitogen-Activated Protein Kinases; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D044764:Ubiquitin-Activating Enzymes; C502778:ATG5 protein, human; C477012:MAP1LC3A protein, human; C025946:3-methyladenine; C112772:ginsenoside compound K; C509349:ATG7 protein, human
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