Enhancement of Radiation Therapy in Prostate Cancer by DNA-PKcs Inhibitor
Abstract
Radiation therapy is both a common and effective strategy for the treatment of localized prostate cancer. However, a proportion of locally advanced cancers develop radiation resistance and recur after therapy, therefore the development of radiation sensitizing compounds is essential for treatment of these tumors. DAB2IP (DOC-2/DAB2 interactive protein) which is a novel member of the Ras GTPase-activating protein family and a regulator of PI3K/Akt activity, is often downregulated in aggressive prostate cancer (PCa). A novel DNA-PKcs inhibitor NU7441 can significantly enhance the effect of radiation in DAB2IP-deficient PCa cells. This enhanced radiation sensitivity after NU7441 treatment is primarily due to delayed DNA double-strand break (DSB) repair. More importantly, we reported that DAB2IPdeficient PCa cells show dramatic induction of autophagy after treatment with radiation and NU7441. Immunoblotting analysis showed that the autophagy-associated proteins such as LC3B and Beclin1 deregulated in DAB2IP proficient PCa cells. We observed decreased phosphorylation of S6K and mTOR in DAB2IP-overexpressed cells. Taken together, our study clearly shows that NU7441 is a potent radiosensitizer in aggressive PCa cells. More importantly, our study indicates that DAB2IP may act as an important factor in PCa cell death after combined treatment with NU7441 and radiation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2012
- Accession Number
- ADA626324
Entities
People
- Debabrata Saha
Organizations
- University of Texas at Dallas