Identification of a Potent Apoptotic Peptide Produced by Fibroblasts; Studies Towards the Design of a Novel Agent for Breast Cancer Therapy
Abstract
We previously showed that constitutive activation of the PDGF beta receptor (PDGFR) in mortal human fibroblasts (HDFs) by certain viral oncoproteins results in partial transformation of these cells. However, two weeks after reaching their peak density, these partially transformed cells produce a small (<3 kDa) peptide that induces massive apoptosis in an autocrine manner. Specifically, this peptide induces apoptosis by promoting Bax activation and subsequent mitochondrial dysfunction. The primary goal of this project has been to identify the apoptotic peptide produced by these cells. Our recent evidence suggests that production of this peptide requires specific PDGFR signaling pathways and a matrix metalloprotease (MMP). Furthermore, we found that the peptide is negatively charged and can be competitively inhibited by a peptide derived from the N-terminus of MMP-2. Our evidence also implicated the proapoptotic protein p66Shc and increased levels of intracellular ROS in apoptosis of HDFs. We therefore speculate that the apoptotic peptide is a degradation product of an extracellular protein that binds to a cell surface receptor and enters the cell via endocytosis. We propose that the peptide, once inside the cell, affects the activity of p66Shc, which in turn promotes production of intracellular ROS followed by Bax activation and apoptosis. Although we have not yet identified the apoptotic peptide, we have discerned some of its unique characteristics and effects. We are optimistic that the information gained from these studies will allow us to identify this peptide in the future. Once identified, this peptide could be used to design a novel anti-cancer therapeutic.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 05, 2007
- Accession Number
- ADA480299
Entities
People
- Lisa M. Petti
Organizations
- Albany Medical College