Sunday, May 11, 2025
5/11/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).