Targeting Autophagy and the Anticipatory Unfolded Protein Response Leads to Increased Breast Cancer Cell Death.

Activation of the anticipatory unfolded protein response (aUPR) by the small molecule 3,3-bis(4-hydroxyphenyl)-7-methyl-1,3,dihydro-2H-indol-2-one (BHPI) leads to necrotic cell death in a variety of cancer cells containing Estrogen Receptor alpha (ERα). A key feature of BHPI's mechanism of action is depletion of cellular ATP. Other pathways such as autophagy can regulate cellular energy levels and ATP production.

Computational approaches to identify a novel binding site of BHPI on estrogen receptor alpha.

3,3-bis(4-hydroxyphenyl)-7-methyl-1,3,dihydro-2H-indol-2-one (BHPI) is a biomodulator of Estrogen Receptor alpha (ERα) that targets ERα positive cancer cells by activating the unfolded protein response (UPR). BHPI induces strong and sustained activation of this pathway, eventually resulting in necrotic cell death. While much is known about how BHPI triggers the UPR leading to necrotic cell death, it is not known how BHPI binds to its putative molecular target, ERα.