title: Panaxydol, a component of Panax ginseng, induces apoptosis in cancer cells through EGFR activation and ER stress and inhibits tumor growth in mouse models.
abstract: We reported previously that panaxydol, a component of Panax ginseng roots, induced mitochondria-mediated apoptosis preferentially in transformed cells. This study demonstrates that EGFR activation and the resulting ER stress mediate panaxydol-induced apoptosis, and that panaxydol suppresses in vivo tumor growth in syngeneic and xenogeneic mouse tumor models. In addition, we elucidated that CaMKII and TGF-β-activated kinase (TAK1) participate in p38/JNK activation by elevated cytoplasmic Ca(2+) concentration ([Ca(2+)]c). In MCF-7 cells, EGFR was activated immediately after exposure to panaxydol, and this activation was necessary for induction of apoptosis, suggesting that panaxydol might be a promising anticancer candidate, especially for EGFR-addicted cancer. Activation of PLCγ followed EGFR activation, resulting in Ca(2+) release from the endoplasmic reticulum (ER) via inositol triphosphate and ryanodine receptors. ER Ca(2+) release triggered mitochondrial Ca(2+) uptake indirectly through oxidative stress and ensuing ER stress. Elevated [Ca(2+)]c triggered sequential activation of calmodulin/CaMKII, TAK1 and p38/JNK. As shown previously, p38 and JNK activate NADPH oxidase. Here, it was shown that the resulting oxidative stress triggered ER stress. Among the three signaling branches of the unfolded protein response, protein kinase R-like ER kinase (PERK), but not inositol-requiring enzyme 1 or activating transcription factor 6, played a role in transmitting the apoptosis signal. PERK induced C/EBP homologous protein (CHOP), and CHOP elevated Bim expression, initiating mitochondrial Ca(2+) uptake and apoptosis. In summary, we identified roles of EGFR, the CAMKII-TAK1-p38/JNK pathway, and ER stress in panaxydol-induced apoptosis and demonstrated the in vivo anticancer effect of panaxydol.
authors.affiliation: Department of Biochemisty, Korea University College of Medicine, Seoul, Korea.|Korea Institute of Molecular Medicine and Nutrition, Seoul, Korea.
authors.forename: Hee Suk
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Biochemisty, Korea University College of Medicine, Seoul, Korea.|Korea Institute of Molecular Medicine and Nutrition, Seoul, Korea.
authors.forename: Jang Mi
authors.initials: JM
authors.lastname: Lim
authors.affiliation: Department of Biochemisty, Korea University College of Medicine, Seoul, Korea.|Korea Institute of Molecular Medicine and Nutrition, Seoul, Korea.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Biochemisty, Korea University College of Medicine, Seoul, Korea.|Korea Institute of Molecular Medicine and Nutrition, Seoul, Korea.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Biochemisty, Korea University College of Medicine, Seoul, Korea.|Korea Institute of Molecular Medicine and Nutrition, Seoul, Korea.
authors.forename: Serkin
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Biochemisty, Korea University College of Medicine, Seoul, Korea.|Korea Institute of Molecular Medicine and Nutrition, Seoul, Korea.
authors.forename: Jeongwon
authors.initials: J
authors.lastname: Sohn
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D053280:Diynes / Q000494:pharmacology*; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D066246:ErbB Receptors / Q000819:agonists*; D005233:Fatty Alcohols / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D005894:Panax / Q000737:chemistry; D051966:Phospholipase C gamma / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002945:Cisplatin; D053280:Diynes; D066246:ErbB Receptors; D005233:Fatty Alcohols; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D019255:NADPH Oxidases; D051966:Phospholipase C gamma; D010936:Plant Extracts; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C055778:panaxydol
keywords: CaMKII; EGFR; ER stress; NADPH oxidase; PERK; Panax ginseng; TAK1; calcium; panaxydol