Octyl Ester of Ginsenoside Rh2 Induces Apoptosis and G1 Cell Cycle Arrest in Human HepG2 Cells by Activating the Extrinsic Apoptotic Pathway and Modulating the Akt/p38 MAPK Signaling Pathway.
Ginsenoside Rh2 is a potential active metabolite of ginseng that has antitumor activity against a variety of tumor cells. Previously, we reported that Rh2-O, an octyl ester derivative of ginsenoside Rh2, had a higher anticancer activity than Rh2 through activating the intrinsic apoptotic pathway. In this study, we found that the extrinsic apoptotic pathway was also involved in Rh2-O-induced HepG2 cells apoptosis as evidenced by the up-regulation of Fas, FasL, TNFR1, and TNF-α as well as the cleavage of caspase 8. Moreover, flow cytometric analysis demonstrated that Rh2-O induced G1 cell cycle arrest in HepG2 cells. Rh2-O-induced G1 phase arrest was accompanied by the down-regulation of cyclin D3 and cyclin E and cyclin-dependent kinases (CDK) 4 and 6 and the up-regulation of p21WAF1/CIP1and p27KIP1. In addition, Rh2-O down-regulated the phosphorylation of Akt, and its inhibitor LY294002 promoted Rh2-O-induced G1 phase arrest. Rh2-O treatment also activated p38 MAPK, JNK, and ERK expression. Inhibitors of p38 MAPK (SB203580), but not those of JNK (SP600125) or ERK (PB98095), promoted Rh2-O-induced G1 phase arrest in HepG2 cells. These results indicated that the disruption of Akt and p38 MAPK cascades played a pivotal role in Rh2-O-induced G1 phase arrest.
State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang, Jiangxi 330047, China.|College of Food Science, Nanchang University , Nanchang, Jiangxi 330047, China.
Fang
F
Chen
State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang, Jiangxi 330047, China.|College of Food Science, Nanchang University , Nanchang, Jiangxi 330047, China.
Shi-Lian
SL
Zheng
State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang, Jiangxi 330047, China.|College of Food Science, Nanchang University , Nanchang, Jiangxi 330047, China.
Jiang-Ning
JN
Hu
State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang, Jiangxi 330047, China.|College of Food Science, Nanchang University , Nanchang, Jiangxi 330047, China.
Yong
Y
Sun
State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang, Jiangxi 330047, China.|College of Food Science, Nanchang University , Nanchang, Jiangxi 330047, China.
Yue-Ming
YM
He
State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang, Jiangxi 330047, China.|College of Food Science, Nanchang University , Nanchang, Jiangxi 330047, China.
Han
H
Peng
State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang, Jiangxi 330047, China.
Bing
B
Zhang
Department of Food Science, University of Massachusetts Amherst , Amherst, Massachusetts 01003, United States.
David Julian
DJ
McClements
State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang, Jiangxi 330047, China.|College of Food Science, Nanchang University , Nanchang, Jiangxi 330047, China.
Ze-Yuan
ZY
Deng
Akt; HepG2 cells; MAPKs; cell cycle; ginsenoside Rh2; octyl ester derivative