Panaxydol, a component of Panax ginseng, induces apoptosis in cancer cells through EGFR activation and ER stress and inhibits tumor growth in mouse models

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 Ca²⁺ concentration ([Ca²⁺]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 Ca²⁺ release from the endoplasmic reticulum (ER) via inositol triphosphate and ryanodine receptors. ER Ca²⁺ release triggered mitochondrial Ca²⁺ uptake indirectly through oxidative stress and ensuing ER stress. Elevated [Ca²⁺]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 Ca²⁺ 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. What's new? Panax ginseng contains active compounds that may have anticancer properties. In this study, the authors found that the ginseng compound panaxydol is able to suppress tumor growth in mice. They also identified the complex molecular pathways by which this occurs, including EGFR activation, oxidative and endoplasmic-reticulum stress, calcium release, and the induction of apoptosis mediated by the mitochondria. These results indicate that panaxydol may be a promising therapeutic candidate.