Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Compound K induced apoptosis via endoplasmic reticulum Ca2+ release through ryanodine receptor in human lung cancer cells

  • Shin, Dong-Hyun (Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University) ;
  • Leem, Dong-Gyu (Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University) ;
  • Shin, Ji-Sun (Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University) ;
  • Kim, Joo-Il (Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University) ;
  • Kim, Kyung-Tack (Traditional Food Research Center, Korea Food Research Institute) ;
  • Choi, Sang Yoon (Traditional Food Research Center, Korea Food Research Institute) ;
  • Lee, Myung-Hee (Traditional Food Research Center, Korea Food Research Institute) ;
  • Choi, Jung-Hye (Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University) ;
  • Lee, Kyung-Tae (Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University)
  • Received : 2016.10.29
  • Accepted : 2017.01.31
  • Published : 2018.04.15
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Abstract

Background: Extended endoplasmic reticulum (ER) stress may initiate apoptotic pathways in cancer cells, and ER stress has been reported to possibly increase tumor death in cancer therapy. We previously reported that caspase-8 played an important role in compound K-induced apoptosis via activation of caspase-3 directly or indirectly through Bid cleavage, cytochrome c release, and caspase-9 activation in HL-60 human leukemia cells. The mechanisms leading to apoptosis in A549 and SK-MES-1 human lung cancer cells and the role of ER stress have not yet been understood. Methods: The apoptotic effects of compound K were analyzed using flow cytometry, and the changes in protein levels were determined using Western blot analysis. The intracellular calcium levels were monitored by staining with Fura-2/AM and Fluo-3/AM. Results: Compound K-induced ER stress was confirmed through increased phosphorylation of $eIF2{\alpha}$ and protein levels of GRP78/BiP, XBP-1S, and $IRE1{\alpha}$ in human lung cancer cells. Moreover, compound-K led to the accumulation of intracellular calcium and an increase in m-calpain activities that were both significantly inhibited by pretreatment either with BAPTA-AM (an intracellular $Ca^{2+}$ chelator) or dantrolene (an RyR channel antagonist). These results were correlated with the outcome that compound K induced ER stress-related apoptosis through caspase-12, as z-ATAD-fmk (a specific inhibitor of caspase-12) partially ameliorated this effect. Interestingly, 4-PBA (ER stress inhibitor) dramatically improved the compound K-induced apoptosis. Conclusion: Cell survival and intracellular $Ca^{2+}$ homeostasis during ER stress in human lung cancer cells are important factors in the induction of the compound K-induced apoptotic pathway.

Keywords

References

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