Bcl-2 as a target in cancer

Project Summary Bcl-2, an anti-cell death protein, is overexpressed in about 40% of all human cancers and contributes to the development and progression of cancer. Overexpression of Bcl-2 correlates with poor survival and progression of the disease and correlates with resistance of breast cancer cells to chemotherapeutic drugs

and gamma irradiation. We have discovered a novel pathway to convert Bcl-2 from a cytoprotective to cytodestructive protein. This dramatic change in Bcl-2 function is brought about by orphan nuclear receptor Nur77 (which migrates from the nucleus to mitochondria upon stimulation by certain agents) binding, which

exposes a hidden "killer BH3 domain" of Bcl-2. During the course of identifying the minimal functional domain of Nur77, a nine amino acid peptide that mimics the mechanistic and functional activities of Nur77 was identified. This peptide is able to induce cancer cell death by selectively binding Bcl-2 and converting

Bcl-2 from a protector to a killer protein by inducing conformational changes. The apoptotic effects of Nur77 peptides are not inhibited, but rather potentiated, by Bcl-2 overexpression. Nur77-derived peptides thus represent a new class of anti-breast cancer agents. We have identified compounds that selectively induced

enhanced death in Bcl-2 overexpressing triple negative breast cancer cells. We now propose to evaluate the efficacy of the identified lead ‘Bcl-2 functional converters’ on breast cancer stem cells.