Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway.
The oncoprotein MDM2, a major ubiquitin E3 ligase of tumor suppressor p53, has been suggested as a novel target for human cancer therapy based on its p53-dependent and p53-independent activities. We have identified curcumin, which has previously been shown to have anticancer activity, as an inhibitor of MDM2 expression. Curcumin down-regulates MDM2, independent of p53. In a human prostate cancer cell lines PC3 (p53(null)), curcumin reduced MDM2 protein and mRNA in a dose- and time-dependent manner, and enhanced the expression of the tumor suppressor p21(Waf1/CIP1). The inhibitory effects occur at the transcriptional level and seem to involve the phosphatidylinositol 3-kinase/mammalian target of rapamycin/erythroblastosis virus transcription factor 2 pathway. Curcumin induced apoptosis and inhibited proliferation of PC3 cells in culture, but both MDM2 overexpression and knockdown reduced these effects. Curcumin also inhibited the growth of these cells and enhanced the cytotoxic effects of gemcitabine. When it was administered to tumor-bearing nude mice, curcumin inhibited growth of PC3 xenografts and enhanced the antitumor effects of gemcitabine and radiation. In these tumors, curcumin reduced the expression of MDM2. Down-regulation of the MDM2 oncogene by curcumin is a novel mechanism of action that may be essential for its chemopreventive and chemotherapeutic effects. Our observations help to elucidate the process by which mitogens up-regulate MDM2, independent of p53, and identify a mechanism by which curcumin functions as an anticancer agent.
Li
Mao
M
Department of Pharmacology and Toxicology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 32594, USA.
Zhang
Zhuo
Z
Hill
Donald L
DL
Wang
Hui
H
Zhang
Ruiwen
R
D000818:Animals; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology*; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D003474:Curcumin; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D050787:Proto-Oncogene Protein c-ets-2; D051736:Proto-Oncogene Proteins c-mdm2; D011838:Radiation-Sensitizing Agents; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C494069:ETS2 protein, human; C497206:MDM2 protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse