24-hydroxyursolic acid from the leaves of the Diospyros kaki (Persimmon) induces apoptosis by activation of AMP-activated protein kinase.
There are multiple lines of evidence that persimmon extract and its constituents have potent antitumor activity against human cancer cells. However, the molecular mechanisms of 24-hydroxyursolic acid, a triterpenoid found in persimmon, on antitumor activities are not yet understood. Here, we demonstrate that 24-hydroxyursolic acid inhibited cell proliferation, strongly activated AMP-activated protein kinase (AMPK) and mediated critical anticancer effects by inhibition of cyclooxygenase (COX-2) expression in HT-29 cells. In addition, 24-hydroxyursolic acid induced cellular apoptosis by activation of poly(ADP-ribose) polymerase (PARP), caspase-3, and phosphorylation of p53 at Ser15. It also strongly induced DNA fragmentation in HT-29 cells and thereby significantly inhibited colony formation of HT-29 cells in soft agar. In addition, 24-hydroxyursolic acid blocked the EGF-induced ERKs phosphorylation and led to the inhibition of AP-1 activity and cell transformation in JB6 CL41 cells. Collectively, these findings are the first to reveal a molecular basis for the anticarcinogenic action of 24-hydroxyursolic acid and might account for the reported chemopreventive and chemotherapic effects of persimmon extracts.
Khanal
Prem
P
BK21 Project Team, College of Pharmacy, Chosun University, 501-759 Gwangju, Republic of Korea.
Oh
Won-Keun
WK
Thuong
Phuong Thien
PT
Cho
Sung Dae
SD
Choi
Hong Seok
HS
D055372:AMP-Activated Protein Kinases / Q000187:drug effects*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D029788:Diospyros / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D018515:Plant Leaves / Q000737:chemistry; D014315:Triterpenes / Q000494:pharmacology*
C553045:24-hydroxyursolic acid; D000972:Antineoplastic Agents, Phytogenic; D014315:Triterpenes; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D055372:AMP-Activated Protein Kinases