Gambogic acid down-regulates MDM2 oncogene and induces p21(Waf1/CIP1) expression independent of p53.
Gambogic acid (GA), the natural compound extracted from gamboges, has recently been established as a potent anti-tumor agent. Although it was proved that GA enhances p53 protein level through inhibition of MDM2 in p53 wild-type cancer cells, the mechanisms of MDM2 inhibition especially with the absence of p53 are not fully understood. Herein we further studied the MDM2 regulation by GA and propose novel explanations of its unrecognized mechanism. Regardless of p53 status, GA reduced MDM2 expression in a concentration- and time-dependent manner. Moreover, the inhibitory effects were exhibited at both transcriptional and posttranslational levels. We found that P1 and P2 promoter of MDM2 were both responsive to GA, resulting in decreased Mdm2 RNA level. At the posttranslational level, GA promoted the autoubiquitination of MDM2, followed by proteasome-mediated degradation. Additionally, GA increased p21(Waf1/CIP1) expression in p53 null cancer cells, which was associated with GA-mediated impairing of the interaction between MDM2 and p21(Waf1/CIP1). Furthermore, the apoptosis, cytotoxicity and G2/M cell cycle arrest induced by GA were detected in both p53 wild-type and p53 null cancer cells. In vivo anti-tumor activity of GA was also confirmed in H1299 xenografts. It is concluded that GA down-regulates the MDM2 oncogene and exerts the anti-tumor activity independent of p53, and therefore provide more evidences for its therapeutic application.
Rong
Jing-Jing
JJ
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China.
Hu
Rong
R
Qi
Qi
Q
Gu
Hong-Yan
HY
Zhao
Qing
Q
Wang
Jia
J
Mu
Rong
R
You
Qi-Dong
QD
Guo
Qing-Long
QL
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D044004:Xanthones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D044004:Xanthones; C052659:gambogic acid; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2