Mechanism of 2 %26apos;,3 %26apos;-dimethoxyflavanone-induced apoptosis in breast cancer stem cells: Role of ubiquitination of caspase-8 and LC3

作者：Thao Anh Tran; Ahn Kwang Seok; Song Yeon Woo; Moon Jeong Yong; Cho Moonjae; Lim Yoongho; Cho Somi Kim^*

来源：Archives of Biochemistry and Biophysics, 2014, 562: 92-102.

DOI：10.1016/j.abb.2014.08.001

• Apoptosis
• Breast cancer stem cells
• Caspase-8
• 2 %26apos
• ,3 %26apos
• -Dimethoxyflavanone
• LC3
• Ubiquitination

Accumulating evidence has displayed that targeting cancer stem cells (CSCs) is a very promising way for anti-cancer therapies. 2%26apos;,3%26apos;-Dimethoxyflavanone (2%26apos;,3%26apos;-DMF) showed the most potent toxicity of a group of 42 flavonoids tested in MCF-7-SC breast cancer stem cells. 2%26apos;,3%26apos;-DMF triggered intrinsic and extrinsic apoptosis by stimulating the cleavage of PARP and the activation of caspase-9, -8, and -3. Interestingly, 2%26apos;,3%26apos;-DMF induces a dramatic increase in the conversion of LC3, a well-known marker for autophagy. However, acidic vesicular organelles (AVOs), one of the autophagic flux markers were not detected. 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. We found that 2%26apos;,3%26apos;-DMF induces the ubiquitination of caspase-8, this resulted in an interaction between caspase-8 and LC3, which led to the aggregation and activation of caspase-8. Co-treating cells with 2%26apos;,3%26apos;-DMF and 3-methyladenine, an inhibitor of LC3 lipidation, reduced the activation of caspase-8. These findings provide novel insights into the anti-cancer effects of 2%26apos;,3%26apos;-DMF in breast cancer stem cells by revealing that it induced apoptosis in accompany with the activation of caspase-8 mediated by LC3 conversion.

• 出版日期2014-11-15