2. Academic Validation
  3. Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis

Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis

  • Nat Commun. 2023 Dec 16;14(1):8381. doi: 10.1038/s41467-023-44084-3.
Nadege Gitego 1 2 3,  Bogos Agianian 1 2 3,  Oi Wei Mak 1 2 3,  Vasantha Kumar Mv 1 2 3,  Emily H Cheng 4 5 6,  Evripidis Gavathiotis 7 8 9
Affiliations

Affiliations

  • 1 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 2 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 3 Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 4 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 5 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Weill Cornell Medicine, New York, NY, USA.
  • 7 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
  • 8 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
  • 9 Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
PMID: 38104127 DOI: 10.1038/s41467-023-44084-3
Abstract

The Bcl-2 Family protein Bax is a major regulator of physiological and pathological cell death. Bax predominantly resides in the cytosol in a quiescent state and upon stress, it undergoes conformational activation and mitochondrial translocation leading to mitochondrial outer membrane permeabilization, a critical event in Apoptosis execution. Previous studies reported two inactive conformations of cytosolic Bax, a monomer and a dimer, however, it remains unclear how they regulate Bax. Here we show that, surprisingly, Cancer cell lines express cytosolic inactive Bax dimers and/or monomers. Expression of inactive dimers, results in reduced Bax activation, translocation and Apoptosis upon pro-apoptotic drug treatments. Using the inactive Bax dimer structure and a pharmacophore-based drug screen, we identify a small-molecule modulator, BDM19 that binds and activates cytosolic Bax dimers and prompts cells to Apoptosis either alone or in combination with Bcl-2/Bcl-xL Inhibitor Navitoclax. Our findings underscore the role of the cytosolic inactive Bax dimer in resistance to Apoptosis and demonstrate a strategy to potentiate BAX-mediated Apoptosis.

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