Molecular mechanisms of ginsenoside Rp1-mediated growth arrest and apoptosis.
Ginsenoside Rp1, a semi-synthesized ginseng saponin, was shown to have chemopreventive action and anti-metastatic potential. However, the molecular mechanisms of Rp1 on cell growth and death are not fully understood. In this study, the antiproliferative effect of Rp1 on HeLa cells in vitro was investigated. Treatment with Rp1 at 40 microM inhibited the proliferation and partial accumulation of cells at the G1 phase. Rp1-mediated G1 arrest was accompanied by decreased expression of cyclin D1, E, and A and increased expression of p21 without any significant change in p53 or phospho-p53 (Ser15). On the other hand, prolonged incubation with Rp1 at 40 microM caused apoptosis and activation of caspase-3, -8, and -9. The participation of these three caspases in apoptosis was more clearly shown in experiments using inhibitors, which markedly prevented Rp1-induced apoptosis in the case of each caspase. Cleavage of the polyADP-ribose polymerase, often used as an apoptotic marker, was also found in Rp1-induced apoptosis. Among Bcl-2 family proteins (Bad, Bax, Bid, Bcl-2), Bax and Bid were activated by Rp1 treatment, which resulted in the release of cytochrome c from mitochondria, following activation of caspase-9. These observations indicate that multiple cell cycle regulatory proteins and apoptosis-inducing proteins are regulated by Rp1 and contribute to Rp1-induced growth arrest and apoptosis.
Kumar
Ashok
A
Radiation and Cancer Biology Lab, University of Rajasthan, Jaipur, India.
Kumar
Madhu
M
Park
Tae-Yoon
TY
Park
Myung-Hwan
MH
Takemoto
Tadashi
T
Terado
Tokio
T
Kitano
Masaru
M
Kimura
Hiroshi
H
D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D036145:Ginsenosides / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D036145:Ginsenosides; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C512675:ginsenoside Rp1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases