Accession Number:

ADA482236

Title:

The Role of Membrane-Derived Second Messengers and Bmx/Etk in Response to Radiation Treatment of Prostate Cancer

Descriptive Note:

Annual summary 1 Jan 2007-31 Dec 2007

Corporate Author:

VANDERBILT UNIV MEDICAL CENTER NASHVILLE TN

Personal Author(s):

Report Date:

2008-01-01

Pagination or Media Count:

13.0

Abstract:

Radiation-induced activation of the Pl3KAkt signal transduction pathway requires Akt binding to phosphatidyl-inositol phosphates PIPs on the cell membrane. The tyrosine kinase, bone marrow X-kinase Bmx, binds to PIPs in a manner similar to Akt. Since Bmx is known to be involved in cell growth and survival pathways, Bmx could contribute to the radiation response within the vascular endothelium and prostate cancer, which highly express this protein. We therefore are studying Bmx signaling within the vascular endothelium and prostate cancer. Our initial studies have focused on the vascular endothelium. Bmx was activated rapidly in response to clinically relevant doses of ionizing radiation. Bmx inhibition enhanced the efficacy of radiotherapy in endothelial cells within in vitro systems. Retroviral shRNA knockdown of Bmx protein enhanced HUVEC radiosensitization. Furthermore, pretreatment of HUVEC with a pharmacological inhibitor of Bmx, LFM-A13, produced significant radiosensitization of endothelial cells as measured by clonogenic survival analysis and apoptosis as well as functional assays including cell migration and tubule formation. In vivo, LFM-A13, when combined with radiation resulted in significant inhibition of blood flow within prostate tumors as measured by pixel weighted power doppler. Bmx, therefore, represents a molecular target for the development of novel radiosensitizing agents.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE