This paper deals with the inhibitory mechanisms of ginsenoside \{G Rh 2\} on the growth of tumor cells. \{G Rh 2\} significantly inhibited the proliferation of human cervical adenocarcinoma HeLa cells in a time ...This paper deals with the inhibitory mechanisms of ginsenoside \{G Rh 2\} on the growth of tumor cells. \{G Rh 2\} significantly inhibited the proliferation of human cervical adenocarcinoma HeLa cells in a time and dose dependent manner. G Rh 2 induced apoptotic manifestations in HeLa cells as evidenced by the changes in the cell morphology, the DNA fragmentation and the activation of caspases. Caspase inhibitors, caspase family inhibitor, z Val Ala Asp fmk(z VAD fmk); caspase 1 inhibitor, Ac Tyr Val Ala Asp chloromethyl ketone(Ac YVAD cmk); caspase 3 inhibitor, z Asp Glu Val Asp fmk(z DEVE fmk) and caspase 8 inhibitor, \{z Ile \}Glu Asp fmk(z IETD fmk) effectively attenuated G Rh 2 induced cell death. The activities of caspase 1 and caspase 3 were increased in the G Rh 2 induced apoptotic process. However, caspase inhibitors can not inhibit G Rh - 2 induced cell death completely. These results suggest that G Rh 2 induced cell death is mediated by the activation of caspase cascade, but there might be some other pathways for induction of this apoptosis.展开更多
We have recently reported that Ginsenoside Rh2 （G- Rh2） induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. How- ever, the molecular mechanism of its death-inducing funct...We have recently reported that Ginsenoside Rh2 （G- Rh2） induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. How- ever, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and cas- pase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process, Moreover, significant increases in Fas expression and caspase-8 activity temporally coin- cided with an increase in p53 expression in p53-non- mutated HeLa and SK-HEP-1 cells upon G-Rh2 treat- ment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation, These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immedi- ate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 ceils, p53-mediated Fas expression and sub- sequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti- tumor drug development.展开更多
文摘This paper deals with the inhibitory mechanisms of ginsenoside \{G Rh 2\} on the growth of tumor cells. \{G Rh 2\} significantly inhibited the proliferation of human cervical adenocarcinoma HeLa cells in a time and dose dependent manner. G Rh 2 induced apoptotic manifestations in HeLa cells as evidenced by the changes in the cell morphology, the DNA fragmentation and the activation of caspases. Caspase inhibitors, caspase family inhibitor, z Val Ala Asp fmk(z VAD fmk); caspase 1 inhibitor, Ac Tyr Val Ala Asp chloromethyl ketone(Ac YVAD cmk); caspase 3 inhibitor, z Asp Glu Val Asp fmk(z DEVE fmk) and caspase 8 inhibitor, \{z Ile \}Glu Asp fmk(z IETD fmk) effectively attenuated G Rh 2 induced cell death. The activities of caspase 1 and caspase 3 were increased in the G Rh 2 induced apoptotic process. However, caspase inhibitors can not inhibit G Rh - 2 induced cell death completely. These results suggest that G Rh 2 induced cell death is mediated by the activation of caspase cascade, but there might be some other pathways for induction of this apoptosis.
文摘We have recently reported that Ginsenoside Rh2 （G- Rh2） induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. How- ever, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and cas- pase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process, Moreover, significant increases in Fas expression and caspase-8 activity temporally coin- cided with an increase in p53 expression in p53-non- mutated HeLa and SK-HEP-1 cells upon G-Rh2 treat- ment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation, These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immedi- ate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 ceils, p53-mediated Fas expression and sub- sequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti- tumor drug development.
