The radiosensitization effect of parthenolide in prostate cancer cells is mediated by nuclear factor-κB inhibition and enhanced by the presence of PTEN
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-κB (NF-κB) pathway is a common mechanism for the radiosensit...
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Published in | Molecular cancer therapeutics Vol. 6; no. 9; pp. 2477 - 2486 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Association for Cancer Research
01.09.2007
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Subjects | |
Online Access | Get full text |
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Summary: | 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-κB (NF-κB)
pathway is a common mechanism for the radiosensitization effect of parthenolide in prostate cancer cells LNCaP, DU145, and
PC3. Parthenolide inhibits radiation-induced NF-κB 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, DU145 and
PC3, with DU145 cells showing higher sensitivity. This differential susceptibility to parthenolide is due, in part, to the
fact that in addition to NF-κB inhibition, parthenolide activates the phosphatidylinositol-3-kinase/Akt prosurvival pathway
in both cell lines. However, the activated Akt in DU145 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 DU145 cells, the
cells become more resistant to parthenolide's effect. Taken together, these results suggest that parthenolide inhibits the
NF-κB 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-κB pathway. The presence of PTEN enhances the radiosensitization
effect of parthenolide, in part, by suppressing the absolute amount of activated p-Akt. [Mol Cancer Ther 2007;6(9):2477–86] |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-07-0186 |