Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis

Nadege Gitego, Bogos Agianian, Oi Wei Mak, Vasantha Kumar Mv, Emily H. Cheng and Evripidis Gavathiotis ()
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Nadege Gitego: Albert Einstein College of Medicine
Bogos Agianian: Albert Einstein College of Medicine
Oi Wei Mak: Albert Einstein College of Medicine
Vasantha Kumar Mv: Albert Einstein College of Medicine
Emily H. Cheng: Memorial Sloan Kettering Cancer Center
Evripidis Gavathiotis: Albert Einstein College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44084-3

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