Accession Number:

ADA416696

Title:

The Paracrine Induction of TRAIL by Genotoxic Agents

Descriptive Note:

Annual summary 1 Jun 2001-31 May 2002

Corporate Author:

COLORADO UNIV HEALTH SCIENCES CENTER AURORA CO GRANTS AND CONTRACTS

Report Date:

2002-06-01

Pagination or Media Count:

23.0

Abstract:

TNF related apoptosis inducing ligand, TRAIL, is a recently cloned cytokine that has been shown to induce apoptosis in a synergistic fashion with chemotherapeutic agents on several cancer cell lines. Xenografts of several carcinoma cell lines demonstrate TRAIL and chemotherapy to cause complete regression of established tumors. Etoposide, a topoisomerase type II inhibitor, induces the upregulation of TRAIL in several breast and lung carcinoma lines, Analysis of human lung tumors demonstrates TRAIL mRNA expression is significantly decreased in tumor relative to autologous non-tumor lung tissue. Genotoxin-induced apoptosis of human cancer cells correlates with TRAIL surface expression. Expression of TRAIL and its death receptor, DR5, is regulated by NFkB. NFkB inhibition results in aggressive growth and chemotherapy resistance of H157 human lung squamous carcinoma. Gene profiling of 157 cells demonstrates that NFkB regulates the expression of both pro- and anti-apoptotic proteins including inhibitors of apoptosis IAPs in addition to DR5 and TRAIL. It is the predominance of the opposing NFkB-dependent signals that dictates the cells decision to survive or die. Loss of TRAIL expression in human lung cancer provides a means by which tumors can avert programmed cell death. DcRl, a GPI-linked TRAIL receptor, has been proposed to confer TRAIL resistance by serving as a membrane bound TRAIL trap. DcRl expression inhibits caspase 8 and BID cleavage as well as JNK phosphorylation induced by etoposide and TRAIL. DcRl, however, also induces potent survival signals. Restoration of DcRl in breast carcinoma cells to physiologic levels induces Akt activation in a src family kinase dependent manner. DcRl expression confers resistance to initochondria insult and apoptosis induced by currently utilized chemotherapeutic agents as well as to Antimycin A, a BH3 domain homdogue that targets mitochondria directly.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE