title: The radiosensitization effect of parthenolide in prostate cancer cells is mediated by nuclear factor-kappaB inhibition and enhanced by the presence of PTEN.
abstract: Parthenolide has been shown to have anti-inflammatory and antitumor properties. However, whether and how parthenolide enhances tumor sensitivity to radiation therapy are unknown. In this study, we show that inhibition of the nuclear factor-kappaB (NF-kappaB) pathway is a common mechanism for the radiosensitization effect of parthenolide in prostate cancer cells LNCaP, DU 145, and PC3. Parthenolide inhibits radiation-induced NF-kappaB DNA-binding activity and the expression of its downstream target sod2, the gene coding for an important antiapoptotic and antioxidant enzyme (manganese superoxide dismutase) in the three prostate cancer cells. Different susceptibilities to parthenolide's effect are observed in two radioresistant cancer cells, DU 145 and PC3, with DU 145 cells showing higher sensitivity. This differential susceptibility to parthenolide is due, in part, to the fact that in addition to NF-kappaB inhibition, parthenolide activates the phosphatidylinositol-3-kinase/Akt prosurvival pathway in both cell lines. However, the activated Akt in DU 145 cells is kept at a relatively low level compared with that in PC3 cells due to the presence of functional PTEN. Transfection of wild-type PTEN into PTEN-null cells, PC3, confers the enhanced radiosensitization effect of parthenolide in PTEN-expressing cells. When PTEN expression is knocked down in DU 145 cells, the cells become more resistant to parthenolide's effect. Taken together, these results suggest that parthenolide inhibits the NF-kappaB pathway and activates the phosphatidylinositol-3-kinase/Akt pathway in prostate cancer cells. The radiosensitization effect of parthenolide is due, in part, to the inhibition of the NF-kappaB pathway. The presence of PTEN enhances the radiosensitization effect of parthenolide, in part, by suppressing the absolute amount of activated p-Akt.
authors: Graduate Center for Toxicology, University of Kentucky, 800 Rose Street, Lexington, KY 40536, USA.
authors: Yulan
authors: Y
authors: Sun
authors: Daret K
authors: DK
authors: St Clair
authors: Fang
authors: F
authors: Fang
authors: Graham W
authors: GW
authors: Warren
authors: Vivek M
authors: VM
authors: Rangnekar
authors: Peter A
authors: PA
authors: Crooks
authors: William H
authors: WH
authors: St Clair
mesh_terms: D015153:Blotting, Western; D024202:Electrophoretic Mobility Shift Assay; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D012717:Sesquiterpenes / Q000627:therapeutic use*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects
chemical_list: D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide; D013482:Superoxide Dismutase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human