NF-kappaB inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation.

Abstract:

:Most cancer cells show resistance to ionizing radiation (IR)-induced cell death. Recently, Ki-Ras was reported to be responsible for the increased radioresistance. We report here that inhibition of IR-induced activaton of nuclear transcription factor kappa B (NF-kappaB) but not of either Akt or MAPK kinase (MEK), increased the radiosensitization of Ki-Ras transformed human prostate epithelial 267B1/K-ras cells. Proteosome inhibitor-1 (Pro1) reduced NF-kappaB activation, and this inhibition was accompanied by increased levels of cytoplasmic IkappaBalpha and p65/RelA. However, translocation of p50/NF-kappaB1 did not occur on exposure to IR, suggesting the cell-specific involvement of p50 in radiation signaling. Clonogenic cell survival and soft agar assays further confirmed the increased radiosensitivity of 267B1/K-ras cells by proteosome inhibition. In addition, proteosome inhibition enhanced the IR-induced degradation of apoptotic protein caspases 8 and 3, with the level of antiapoptotic protein Bcl-2 being unaffected, suggesting the involvement of an apoptotic process in IR-induced cell death of 267B1/K-ras cells. LY294002 and PD98059, specific inhibitors of phosphatidylinositol-3-kinase (PI3K) and MEK, respectively however, did not affect the radiosensitization. All these results suggest an application of blocking NF-kappaB activation pathway to the development of anticancer therapeutics in IR-induced radiotherapy of Ki-Ras-transformed cancer cells.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Kim BY,Kim KA,Kwon O,Kim SO,Kim MS,Kim BS,Oh WK,Kim GD,Jung M,Ahn JS

doi

10.1093/carcin/bgi081

keywords:

subject

Has Abstract

pub_date

2005-08-01 00:00:00

pages

1395-403

issue

8

eissn

0143-3334

issn

1460-2180

pii

bgi081

journal_volume

26

pub_type

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