Novel Approach to Increase Breast Cancer Chemosensitivity: Disruption of the Anti-Apoptotic Function of Translation Factor eIF4E

摘要

The objective of the project was to experimentally test the idea that targeted disruption of the anti-apoptotic function of the translational complex eIF4F can sensitize breast carcinoma cells to therapeutic doses of a non- genotoxic cytostatic agents and/or to low concentrations of genotoxic agents. We demonstrated that enhanced integrity of the cap-dependent translational complex eIF4F cells breast carcinoma lines harboring diverse oncogenic alteration is associated with increased resistance of cancer cells to drug-induced apoptosis. Enforced activation of eIF4F in mammary epithelial cells increases their resistance to apoptosis and results in cells that are able to form transformed foci in vitro. Accordingly, targeted disruption of the cap-dependent translational complex by ectopic overexpression of the translational repressor 4E-BP1 stimulates apoptosis, abrogates chemoresistance and in vivo tumorigenicity in breast carcinoma cells in a manner dependent on a phosphorylation status of 4E-BP 1. These data show that both genesis and maintenance of a drug resistant neoplastic phenotype in mammary epithelial cells are strictly dependent upon the activation status of the eIF4F-mediated translational apparatus. They provide the conceptual basis for a new approach to anticancer therapy: correcting aberrant translation as a complement to strategies that target-malignant cells by activating apoptosis.