title: 20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol, a metabolite of ginseng, inhibits colon cancer growth by targeting TRPC channel-mediated calcium influx.
abstract: Abnormal regulation of Ca(2+) mediates tumorigenesis and Ca(2+) channels are reportedly deregulated in cancers, indicating that regulating Ca(2+) signaling in cancer cells is considered as a promising strategy to treat cancer. However, little is known regarding the mechanism by which Ca(2+) affects cancer cell death. Here, we show that 20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol (20-GPPD), a metabolite of ginseng saponin, causes apoptosis of colon cancer cells through the induction of cytoplasmic Ca(2+). 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 Ca(2+) 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 Ca(2+) entry into CT-26 cells, whereas a transient receptor potential canonical (TRPC) blocker suppressed Ca(2+) 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 Ca(2+) influx, mainly through TRPC channels, and by targeting AMPK.
authors: WCU Biomodulation Program, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.
authors: Jeong Ah
authors: JA
authors: Hwang
authors: Mun Kyung
authors: MK
authors: Hwang
authors: Yongwoo
authors: Y
authors: Jang
authors: Eun Jung
authors: EJ
authors: Lee
authors: Jong-Eun
authors: JE
authors: Kim
authors: Mi Hyun
authors: MH
authors: Oh
authors: Dong Joo
authors: DJ
authors: Shin
authors: Semi
authors: S
authors: Lim
authors: Geun og
authors: Go
authors: Ji
authors: Uhtaek
authors: U
authors: Oh
authors: Ann M
authors: AM
authors: Bode
authors: Zigang
authors: Z
authors: Dong
authors: Ki Won
authors: KW
authors: Lee
authors: Hyong Joo
authors: HJ
authors: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D036145:Ginsenosides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D005894:Panax / Q000737:chemistry*; D010766:Phosphorylation; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D055372:AMP-Activated Protein Kinases; D000970:Antineoplastic Agents; D002118:Calcium; D036145:Ginsenosides; D050052:TRPC Cation Channels; C112772:ginsenoside compound K