2',3'-dimethoxyflavanone induces apoptosis accompanied by caspase-8 activation mediated by ubiquitination in breast cancer stem-like cells (BCSCs)

Abstract

The cytotoxicities of 13 flavonoids were tested in the breast cancer stem-like cell MCF-7-SC. Among them, 2',3'-dimethoxyflavanone (DMF) showed the highest toxicity. DMF triggered apoptosis by activating caspase-9, -3, -8, and cleaved PARP. In addition, DMF induces a dramatic increase in the conversion of LC3, a well-known marker for autophagy. However, co-treatment with chloroquine, the lysosomal inhibitor that blocks autophagic degradation did not show any change in the degree of LC3 conversion, implying that LC3 could play a role in the non-autophagic cell death of MCF-7-SC. In the present study, we found that DMF induces the ubiquitination of caspase-8 accompanied by the interaction between caspase-8 and LC3, which leads to the aggregation and self-activation of caspase-8. Consistent with this, co-treatment of DMF with 3MA, an inhibitor of LC3 lipidation reduced the activation of caspase-8. Our findings provide new insights into the anti-cancer activity of DMF in breast cancer stem cell through apoptosis in company with LC3 conversion.