20-O-(β-D-glucopyranosyl)-20(S)-protopanaxadiol induces apoptosis via induction of endoplasmic reticulum stress in human colon cancer cells

Zhang,Rui; Chung,Young; Kim,Hee  Sun; Kim,Dong   Hyun; Kim,Hye  Sun; Chang,Weon  Young; Hyun,Jin  Won

doi:10.3892/or.2013.2270

20-O-(β-D-glucopyranosyl)-20(S)-protopanaxadiol induces apoptosis via induction of endoplasmic reticulum stress in human colon cancer cells

Authors:
- Rui Zhang
- Young Chung
- Hee Sun Kim
- Dong Hyun Kim
- Hye Sun Kim
- Weon Young Chang
- Jin Won Hyun
View Affiliations

Affiliations: School of Medicine and Applied Radiological Science Research Institute, Jeju National University, Jeju 690-756, Republic of Korea, Pharmaceutical Chemistry, University of California, Davis, CA 95616, USA, Department of Neuroscience, College of Medicine, Ewha Womans University, Seoul 110-783, Republic of Korea, Department of Microbial Chemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
Published online on: February 4, 2013 https://doi.org/10.3892/or.2013.2270
Pages: 1365-1370

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Previously, we reported that 20-O-(β-D-glucopyranosyl)-20(S)-protopanaxadiol (Compound K, a metabolite of ginseng saponin) induces mitochondria-dependent and caspase-dependent apoptosis in HT-29 human colon cancer cells via the generation of reactive oxygen species. The aim of the present study was to elucidate the mechanism underlying apoptosis induced by Compound K with respect to endoplasmic reticulum (ER) stress in HT-29 cells. In the present study, Compound K induced apoptotic cell death as confirmed by DNA fragmentation and apoptotic sub-G1 cell population. Compound K also induced ER stress as indicated by staining with ER tracker, cytosolic and mitochondrial Ca2+ overloading, phosphorylation of protein-kinase-like endoplasmic reticulum kinase (PERK), phosphorylation of eukaryotic initiation factor-2α (eIF-2α), phosphorylation of IRE-1, splicing of ER stress-specific X-box transcription factor-1 (XBP-1), cleavage of activating transcription factor-6 (ATF-6), upregulation of glucose-regulated protein-78 (GRP-78/BiP) and CCAAT/enhancer-binding protein-homologous protein (CHOP), and cleavage of caspase-12. Furthermore, downregulation of CHOP expression using siCHOP RNA attenuated Compound K-induced apoptosis. Taken together, these results support the important role of ER stress response in mediating Compound K-induced apoptosis in human colon cancer cells.

View Figures

View References

1	Ilieva EV, Kichev A, Naudi A, Ferrer I, Pamplona R and Portero-Otin M: Mitochondrial dysfunction and oxidative and endoplasmic reticulum stress in argyrophilic grain disease. J Neuropathol Exp Neurol. 70:253–263. 2011. View Article : Google Scholar : PubMed/NCBI
2	Dolai S, Pal S, Yadav RK and Adak S: Endoplasmic reticulum stress-induced apoptosis in Leishmania through Ca²⁺-dependent and caspase-independent mechanism. J Biol Chem. 286:13638–13646. 2011. View Article : Google Scholar : PubMed/NCBI
3	Song HS, Kim HM, Jung SK and Lee DH: Characterization of tunicamycin as anti-obesity agent. Biomol Ther. 17:162–167. 2009. View Article : Google Scholar
4	Yoshida H: ER stress and diseases. FEBS J. 274:630–658. 2007. View Article : Google Scholar
5	Szegezdi E, Logue SE, Gorman AM and Samali A: Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7:880–885. 2006. View Article : Google Scholar : PubMed/NCBI
6	Vattem KM and Wek RC: Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci USA. 101:11269–11274. 2004. View Article : Google Scholar : PubMed/NCBI
7	Ma K, Vattem KM and Wek RC: Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. J Biol Chem. 277:18728–18735. 2002. View Article : Google Scholar
8	Calfon M, Zeng H, Urano F, et al: IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 415:92–96. 2002. View Article : Google Scholar : PubMed/NCBI
9	Kim R, Emi M, Tanabe K and Murakami S: Role of the unfolded protein response in cell death. Apoptosis. 11:5–13. 2006. View Article : Google Scholar : PubMed/NCBI
10	Okada T, Yoshida H, Akazawa R, Negishi M and Mori K: Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response. Biochem J. 366:585–594. 2002. View Article : Google Scholar
11	Wali VB, Bachawal SV and Sylvester PW: Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells. Apoptosis. 14:1366–1377. 2009. View Article : Google Scholar : PubMed/NCBI
12	Nakagawa T, Zhu H, Morishima N, et al: Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 403:98–103. 2000. View Article : Google Scholar : PubMed/NCBI
13	Cordero MD, Sanchez-Alcazar JA, Bautista-Ferrufino MR, et al: Acute oxidant damage promoted on cancer cells by amitriptyline in comparison with some common chemotherapeutic drugs. Anticancer Drugs. 21:932–944. 2010. View Article : Google Scholar : PubMed/NCBI
14	Cvorovic J, Tramer F, Granzotto M, Candussio L, Decorti G and Passamonti S: Oxidative stress-based cytotoxicity of delphinidin and cyanidin in colon cancer cells. Arch Biochem Biophys. 501:151–157. 2010. View Article : Google Scholar : PubMed/NCBI
15	Zhang R, Niu Y and Zhou Y: Increase the cisplatin cytotoxicity and cisplatin-induced DNA damage in HepG2 cells by XRCC1 abrogation related mechanisms. Toxicol Lett. 192:108–114. 2010. View Article : Google Scholar : PubMed/NCBI
16	Roos WP and Kaina B: DNA damage-induced cell death by apoptosis. Trends Mol Med. 12:440–450. 2006. View Article : Google Scholar : PubMed/NCBI
17	Akao T, Kida H, Kanaoka M, Hattori M and Kobashi K: Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of ginsenoside Rb1 from Panax ginseng. J Pharm Pharmacol. 50:1155–1160. 1998. View Article : Google Scholar : PubMed/NCBI
18	Hasegawa H, Sung JH and Huh JH: Ginseng intestinal bacterial metabolite IH901 as a new anti-metastatic agent. Arch Pharm Res. 20:539–544. 1997. View Article : Google Scholar : PubMed/NCBI
19	Hasegawa H, Sung JH and Benno Y: Role of human intestinal Prevotella oris in hydrolyzing ginseng saponins. Planta Med. 63:436–440. 1997. View Article : Google Scholar : PubMed/NCBI
20	Akao T, Kanaoka M and Kobashi K: Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration-measurement of compound K by enzyme immunoassay. Biol Pharm Bull. 21:245–249. 1998. View Article : Google Scholar : PubMed/NCBI
21	Kim HB, Kang CW, Kim BS, et al: Beneficial role of ginseng saponin on hemodynamic functions of porcine blood vessel. J Ginseng Res. 34:314–320. 2010. View Article : Google Scholar
22	Kim YS, Cho IH, Jeong MJ, et al: Therapeutic effect of total ginseng saponin on skin wound healing. J Ginseng Res. 35:360–367. 2011. View Article : Google Scholar : PubMed/NCBI
23	Chae S, Kang KA, Chang WY, et al: Effect of compound K, a metabolite of ginseng saponin, combined with gamma-ray radiation in human lung cancer cells in vitro and in vivo. J Agric Food Chem. 57:5777–5782. 2009. View Article : Google Scholar : PubMed/NCBI
24	Lee IK, Kang KA, Lim CM, et al: Compound K, a metabolite of ginseng saponin, induces mitochondria-dependent and caspase-dependent apoptosis via the generation of reactive oxygen species in human colon cancer cells. Int J Mol Sci. 11:4916–4931. 2010. View Article : Google Scholar
25	Kang KA, Lim HK, Kim SU, et al: Induction of apoptosis by ginseng saponin metabolite in U937 human monocytic leukemia cells. J Food Biochem. 29:27–40. 2005. View Article : Google Scholar
26	Kim AD, Kang KA, Zhang R, et al: Ginseng saponin metabolite induces apoptosis in MCF-7 breast cancer cells through the modulation of AMP-activated protein kinase. Environ Toxicol Pharmacol. 30:134–140. 2010. View Article : Google Scholar : PubMed/NCBI
27	Choo MK, Sakurai H, Kim DH and Saiki I: A ginseng saponin metabolite suppresses tumor necrosis factor-α-promoted metastasis by suppressing nuclear factor-κB signaling in murine colon cancer cells. Oncol Rep. 19:595–600. 2008.PubMed/NCBI
28	Kim do Y, Yuan HD, Chung IK and Chung SH: Compound K, intestinal metabolite of ginsenoside, attenuates hepatic lipid accumulation via AMPK activation in human hepatoma cells. J Agric Food Chem. 57:1532–1537. 2009.PubMed/NCBI
29	Kim do Y, Park MW, Yuan HD, Lee HJ, Kim SH and Chung SH: Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells. J Agric Food Chem. 57:10573–10578. 2009.PubMed/NCBI
30	Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C: A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 139:271–279. 1991. View Article : Google Scholar : PubMed/NCBI
31	Hajnóczky G, Robb-Gaspers LD, Seitz MB and Thomas AP: Decoding of cytosolic calcium oscillations in the mitochondria. Cell. 82:415–424. 1995.PubMed/NCBI
32	Cullinan SB and Diehl JA: PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem. 279:20108–20117. 2004. View Article : Google Scholar : PubMed/NCBI
33	Cullinan SB and Diehl JA: Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol. 38:317–332. 2006. View Article : Google Scholar : PubMed/NCBI
34	Abdelrahim M, Newman K, Vanderlaag K, Samudio I and Safe S: 3,3′-diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5. Carcinogenesis. 27:717–728. 2006.
35	Jiang HY and Wek RC: Phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition. J Biol Chem. 280:14189–14202. 2005. View Article : Google Scholar
36	Moenner M, Pluquet O, Bouchecareilh M and Chevet E: Integrated endoplasmic reticulum stress responses in cancer. Cancer Res. 67:10631–10634. 2007. View Article : Google Scholar : PubMed/NCBI
37	Sriburi R, Jackowski S, Mori K and Brewer JW: XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol. 167:35–41. 2004. View Article : Google Scholar : PubMed/NCBI
38	Oyadomari S and Mori M: Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11:381–389. 2004. View Article : Google Scholar : PubMed/NCBI
39	Rao R, Nalluri S, Kolhe R, et al: Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells. Mol Cancer Ther. 9:942–952. 2010. View Article : Google Scholar : PubMed/NCBI
40	Ariyama Y, Tanaka Y, Shimizu H, et al: The role of CHOP messenger RNA expression in the link between oxidative stress and apoptosis. Metabolism. 57:1625–1635. 2008. View Article : Google Scholar : PubMed/NCBI
41	Boyce M and Yuan J: Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ. 13:363–373. 2006. View Article : Google Scholar : PubMed/NCBI
42	Xu C, Bailly-Maitre B and Reed JC: Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 115:2656–2664. 2005. View Article : Google Scholar : PubMed/NCBI
43	Oyadomari S, Koizumi A, Takeda K, et al: Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest. 109:525–532. 2002. View Article : Google Scholar : PubMed/NCBI