Accession Number:

ADA626324

Title:

Enhancement of Radiation Therapy in Prostate Cancer by DNA-PKcs Inhibitor

Descriptive Note:

Annual rept. 1 Jul 2011-30 Jun 2012

Corporate Author:

TEXAS UNIV AT DALLAS SOUTHWESTERN MEDICAL CENTER

Personal Author(s):

Report Date:

2012-07-01

Pagination or Media Count:

37.0

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-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.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research
  • Radiobiology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE