Enhancement of Radiation Therapy in Prostate Cancer by DNA-PKcs Inhibitor
Annual rept. 1 Jul 2011-30 Jun 2012
TEXAS UNIV AT DALLAS SOUTHWESTERN MEDICAL CENTER
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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-2DAB2 interactive protein which is a novel member of the Ras GTPase-activating protein family and a regulator of PI3KAkt 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.
- Anatomy and Physiology
- Medicine and Medical Research