20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol, a metabolite of ginseng, inhibits colon cancer growth by targeting TRPC channel-mediated calcium influx.
- Authors
- Hwang, Jeong Ah; Hwang, Mun Kyung; Jang, Yong woo; Lee, Eun Jung; Kim, Jong-Eun; Oh, Mi Hyun; Shin, Dong Joo; Lim, Semi; Ji, Geun Og; Oh, Uhtaek; Bode, Ann M.; Dong, Zigang; Lee, Ki Won; Lee, Hyong Joo
- Issue Date
- Jun-2013
- Publisher
- ELSEVIER SCIENCE INC
- Keywords
- Calcium influx; Colon cancer; 20-GPPD; TRPC
- Citation
- JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v.24, no.6, pp.1096 - 1104
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF NUTRITIONAL BIOCHEMISTRY
- Volume
- 24
- Number
- 6
- Start Page
- 1096
- End Page
- 1104
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/162525
- DOI
- 10.1016/j.jnutbio.2012.08.008
- ISSN
- 0955-2863
- Abstract
- Abnormal regulation of Ca2+ mediates tumorigenesis and Ca2+ channels are reportedly deregulated in cancers, indicating that regulating Ca2+ signaling in cancer cells is considered as a promising strategy to treat cancer. However, little is known regarding the mechanism by which Ca2+ affects cancer cell death. Here, we show that 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (20-GPPD), a metabolite of ginseng saponin, causes apoptosis of colon cancer cells through the induction of cytoplasmic Ca2+center dot 20-GPPD decreased cell viability, increased annexin V-positive early apoptosis and induced sub-G1 accumulation and nuclear condensation of CT-26 murine colon cancer cells. Although 20-GPPD-induced activation of AMP-activated protein kinase (AMPK) played a key role in the apoptotic death of CT-26 cells, LKB1, a well-known upstream kinase of AMPK, was not involved in this activation. To identify the upstream target of 20-GPPD for activating AMPK, we examined the effect of Ca2+ on apoptosis of CT-26 cells. A calcium chelator recovered 20-GPPD-induced AMPK phosphorylation and CT-26 cell death. Confocal microscopy showed that 20-GPPD increased Ca2+ entry into CT-26 cells, whereas a transient receptor potential canonical (TRPC) blocker suppressed Ca2+ entry. When cells were treated with a TRPC blocker plus an endoplasmic reticulum (ER) calcium blocker, 20-GPPD-induced calcium influx was completely inhibited, suggesting that the ER calcium store, as well as TRPC, was involved. In vivo mouse CT-26 allografts showed that 20-GPPD significantly suppressed tumor growth, volume and weight in a dose-dependent manner. Collectively, 20-GPPD exerts potent anticarcinogenic effects on colon carcinogenesis by increasing Ca2+ influx, mainly through TRPC channels, and by targeting AMPK.
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