Curcumin, a Dietary Component, Has Anticancer, Chemosensitization, and Radiosensitization Effects by Down-regulating the MDM2 Oncogene through the PI3K/mTOR/ETS2 Pathway

Abstract

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. [Cancer Res 2007;67(5):1988-96]

Transcription Factor NFAT1 Activates the mdm2 Oncogene Independent of p53

“…The cells were collected at the indicated times post-transfection and lysed in Nonidet P-40 lysis buffer containing a protease inhibitor mixture from Sigma. Cell lysates were used for immunoblotting as described elsewhere (32).…”

Curcumin as “Curecumin”: From kitchen to clinic

“…We have found that (a) the combination of curcumin and gemcitabine inhibits pancreatic cancer growth in nude mice by inhibiting NF-kB regulated gene expression, cell proliferation, and angiogenesis [144]; (b) the combination of curcumin and docetaxel is effective against human ovarian cancer in nude mice [142]; (c) curcumin can suppress the growth of human glioblastoma in rodents [77]; and (d) curcumin sensitizes colon cancers in nude mice to oxaliplatin [137]. In addition, other recent studies have shown that curcumin sensitizes prostate cancers to chemotherapeutics and radiation by downregulating expression of the MDM2 oncogene [82]. Together, these in vivo animal studies clearly suggest curcumin's anticancer potential when administered either alone or in combination with currently employed chemotherapeutic agents or radiation.…”

“…By apparently inhibiting the induction of steady-state transcription levels of ICAM-1, VCAM-1 and E-selectin, curcumin may be interfering detrimentally with the TNF-a-induced signaling event at an early stage. Additionally, curcumin has been shown to mediate its anticancer, chemosensitive, and radiosensitive effects via activation of p53 and simultaneous downregulation of MDM2 oncogene expression via the PI3K/mTOR/ETS2 pathway in human prostate cancer (PC3) and colon cancer (HT-29) cell lines [82,83] and to induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma cells [84].…”

Curcumin promotes apoptosis in human lung adenocarcinoma cells through miR-186* signaling pathway

“…Curcumin has been shown to be anti-tumourigenic in different cancer cell types, including prostate cancer cells and human pituitary tumour cells (21,22). The effect of curcumin treatment on the proliferation and apoptosis of A549 cells was determined by MTT and apoptosis assays, respectively.…”