A Novel Approach to Increase Breast Cancer Chemosensitivity: Disruption of the Anti-Apoptotic Function of Translation Factor eIF4E
Abstract
In this report we present data in support of Aim 3 of our project We demonstrate that ectopic expression of wild type or phosphorylation site mutants of 4E-BPl in breast cancer cells increases apoptosis, reduces the ability of cells to form colonies in vitro, and markedly inhibits xenograft tumor growth in vivo in a manner dependent on the potency of 4E-BPl to inhibit cap-dependent translation During in vitro and in vivo progression, transfected breast cancer cells tend to lose expression of exogenous 4E-BPl. Silence of ectopic 4E-BPl is associated with restoration of cell malignant phenotype and chemoresistance We conclude that intensification of 4E-BPl phosphorylation and other event leading to inactivation of 4E- BPl are under strong selective pressure and contribute to tumor progression by providing cell survival advantages Together, these findings suggest that the sustained activation of the cap-dependent translation apparatus is an important mechanism by which cancer cells evade apoptosis and acquire chemoresistance Targeted disruption of aberrant cap-dependent translation provides the opportunity to utilize this cancer cell-selective death pathway for anticancer therapy which spares normal cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2002
- Accession Number
- ADA412912
Entities
People
- Vitaly A. Polunovsky
Organizations
- University of Minnesota