Inhibition of the PI3K-Akt/PKB survival pathway enhanced an ethanol extract of Rhus verniciflua Stokes-induced apoptosis via a mitochondrial pathway in AGS gastric cancer cell lines.
Rhus verniciflua Stokes (RVS) has been used in traditional Eastern Asia medicine for the treatment of gastritis and stomach cancer, although the mechanism for its biological activity remains to be elucidated. We previously established that an ethanol extract of RVS-induced G(1)-cell cycle arrest via accumulation of p27(Kip1) controlled by Skp2 reduction and apoptosis in AGS human gastric cancer cells. Here, we showed that an ethanol extract of RVS-induced apoptosis via caspase-9 activation (mitochondrial death pathway) is mediated by the loss of mitochondrial membrane potential (MMP, Deltapsi(m)) and the release of cytochrome C from the mitochondrial intermembrane space. In addition, an ethanol extract of RVS inactivated PI3K-Akt/PKB kinase in a time-dependent manner. Moreover, combined treatment of an ethanol extract of RVS and LY294002 (a PI3K inhibitor) markedly increased apoptosis compared to treatment with an ethanol extract of RVS alone. The role of PI3K-Akt/PKB in this process was confirmed by constitutive expression of inactive mutants of this kinase in AGS cells. Finally, siRNA-mediated knockdown of Akt/PKB expression resulted in a significant reduction in AGS cell proliferation. Taken together, these results suggest that an ethanol extract of RVS induces apoptosis via a mitochondrial death pathway in human gastric cancer cells, but not in normal cells, and inhibition of the PI3K-Akt/PKB pathway enhanced the mitochondrial death pathway.
Kim
Ji Hye
JH
Department of Basic Science of Oriental Medicine, Lab of Clinical Biology and Pharmacogenomics, College of Oriental Medicine, Kyunghee University, Dongdaemun-gu, Seoul, Republic of Korea.
Go
Ho Yeon
HY
Jin
Dong Hoon
DH
Kim
Hwang-Phill
HP
Hong
Myung Hee
MH
Chung
Woo-Yeop
WY
Park
Jong-Hyeong
JH
Jang
Jun Bock
JB
Jung
Hee
H
Shin
Yong Cheol
YC
Kim
Sung-Hoon
SH
Ko
Seong-Gyu
SG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9; D045744:Cell Line, Tumor; D000431:Ethanol; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010936:Plant Extracts; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D029045:Rhus / Q000737:chemistry*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy*
D010936:Plant Extracts; D000431:Ethanol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053453:Caspase 9