title: Mechanism of 2',3'-dimethoxyflavanone-induced apoptosis in breast cancer stem cells: role of ubiquitination of caspase-8 and LC3.
abstract: Accumulating evidence has displayed that targeting cancer stem cells (CSCs) is a very promising way for anti-cancer therapies. 2',3'-Dimethoxyflavanone (2',3'-DMF) showed the most potent toxicity of a group of 42 flavonoids tested in MCF-7-SC breast cancer stem cells. 2',3'-DMF triggered intrinsic and extrinsic apoptosis by stimulating the cleavage of PARP and the activation of caspase-9, -8, and -3. Interestingly, 2',3'-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',3'-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',3'-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',3'-DMF in breast cancer stem cells by revealing that it induced apoptosis in accompany with the activation of caspase-8 mediated by LC3 conversion.
authors.affiliation: Faculty of Biotechnology, College of Applied Life Sciences, SARI, Jeju National University, Jeju 690-756, Republic of Korea.
authors.forename: Thao Anh
authors.initials: TA
authors.lastname: Tran
authors.affiliation: Department of Oriental Pathology, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-Dong Dongdaemun-Gu, Seoul 130-701, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.affiliation: Faculty of Biotechnology, College of Applied Life Sciences, SARI, Jeju National University, Jeju 690-756, Republic of Korea.
authors.forename: Yeon Woo
authors.initials: YW
authors.lastname: Song
authors.affiliation: Faculty of Biotechnology, College of Applied Life Sciences, SARI, Jeju National University, Jeju 690-756, Republic of Korea; Subtropical Horticulture Research Institute, Jeju National University, Jeju 690-756, Republic of Korea.
authors.forename: Jeong Yong
authors.initials: JY
authors.lastname: Moon
authors.affiliation: Department of Medicine, Medical School, Jeju National University, Jeju 690-756, Republic of Korea.
authors.forename: Moonjae
authors.initials: M
authors.lastname: Cho
authors.affiliation: Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.affiliation: Faculty of Biotechnology, College of Applied Life Sciences, SARI, Jeju National University, Jeju 690-756, Republic of Korea; Subtropical Horticulture Research Institute, Jeju National University, Jeju 690-756, Republic of Korea. Electronic address: somikim@jejunu.ac.kr.
authors.forename: Somi Kim
authors.initials: SK
authors.lastname: Cho
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D001943:Breast Neoplasms / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D002448:Cell Adhesion; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D044950:Flavanones / Q000494:pharmacology*; D047309:Flavones / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D025801:Ubiquitin / Q000737:chemistry; D054875:Ubiquitination
chemical_list: C000595581:2',3'-dimethoxyflavanone; D000970:Antineoplastic Agents; D044950:Flavanones; D047309:Flavones; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D025801:Ubiquitin; D053181:Caspase 8
keywords: 2′,3′-Dimethoxyflavanone; Apoptosis; Breast cancer stem cells; Caspase-8; LC3; Ubiquitination