Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells.
Gambogic acid (GA) is a natural product with potent apoptotic activity. Here, we showed that GA broadly inhibited the growth of cancer cells that expressed wild-type p53 as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol-iumbromide assay, (3)H-thymidine incorporation analysis, and an in vivo mouse xenograft model. GA induced massive cell apoptosis as judged by Annexin V and propidium iodide dual-staining experiments. Furthermore, we found that GA partially induced cancer cell growth inhibition in a p53-dependent manner because cell survival could be restored after endogenous p53 was attenuated by p53 transcriptional repressor pifithrin-alpha or p53 small interfering RNA. Interestingly, GA had no influence on p53 mRNA synthesis but dramatically enhanced its protein expression. This unique observation could be accounted for by the down-regulation of mdm2 at both mRNA and protein levels. It is concluded that GA enhances p53 protein level through inhibition of mdm2 expression and thereby hampers p53 harboring tumor growth.
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Jiangsu, China.
Hongyan
H
Gu
Xiaotang
X
Wang
Shuyun
S
Rao
Jia
J
Wang
Jie
J
Zhao
Fang Li
FL
Ren
Rong
R
Mu
Yong
Y
Yang
Qi
Q
Qi
Wei
W
Liu
Na
N
Lu
Hua
H
Ling
Qidong
Q
You
Qinglong
Q
Guo
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011419:Propidium / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D017304:Annexin A5; D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D044004:Xanthones; D011419:Propidium; C052659:gambogic acid; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2