Accession Number:

ADA470295

Title:

Identification of a Potent Apoptotic Peptide Produced by Fibroblasts; Studies Towards the Design of a Novel Agent for Breast Cancer Therapy

Descriptive Note:

Annual rept. 6 Aug 2005-5 Aug 2006

Corporate Author:

ALBANY MEDICAL COLL NY

Personal Author(s):

Report Date:

2006-09-01

Pagination or Media Count:

11.0

Abstract:

We previously showed that constitutive activation of the platelet-derived growth factor beta receptor PDGFR in mortal human fibroblasts HDFs by the bovine papillomavirus E5 or the v-Sis oncoprotein induces partial transformation of these cells. However, two weeks after they reach their peak density E5- and v-Sis-expressing HDFs secrete a small, hydrophilic peptide that induces massive apoptosis in an autocrine manner. Specifically, this peptide induces a type of caspase-independent, Bcl-2-resistant apoptosis by promoting mitochondrial dysfunction, which results in the release of the apoptotic mitochondrial protein AIF into the cytosol and its subsequent translocation to the nucleus. We hypothesize that as a negative feedback response to sustained PDGFR signaling, HDFs release a small, hydrophilic peptide that induces apoptosis by activating or sensitizing pro-apoptotic Bcl-2-related proteins such as Bax, which in turn promote mitochondrial dysfunction. The primary goal of this project is to identify this apoptotic peptide produced by partially transformed HDFs. Since this peptide can induce apoptosis of a number of different tumor cell lines including MCF-7 and MDA human breast carcinoma cells, once identified it could serve as the forerunner of a novel anti-breast cancer agent. Our evidence suggests that this peptide is 3 kDa, negatively charged, and pH sensitive. We recently obtained evidence to suggest that the peptide is a degradation product of an extracellular matrix protein. Moreover, we identified a peptide competitive inhibitor of the apoptotic peptide.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE