EGCG-induced selective death of cancer cells through autophagy-dependent regulation of the p62-mediated antioxidant survival pathway
- Authors
- Lee, Ho Woon; Choi, Jee-Hye; Seo, Dongbeom; Gavaachimed, Lkhagvasuren; Choi, Jaesung; Park, Sehwan; Min, Na Young; Lee, Dong Ho; Bang, Hyo-Weon; Ham, Seung Wook; Kim, Jung-Woong; Lee, Sung Chul; Rhee, Sangmyung; Seo, Sang-Beom; Lee, Kwang-Ho
- Issue Date
- Mar-2024
- Publisher
- Elsevier B.V.
- Keywords
- (−)-Epigallocatechin-3-gallate (EGCG); AKT; AMPK; Autophagy; p62; ROS
- Citation
- Biochimica et Biophysica Acta - Molecular Cell Research, v.1871, no.3
- Journal Title
- Biochimica et Biophysica Acta - Molecular Cell Research
- Volume
- 1871
- Number
- 3
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/72800
- DOI
- 10.1016/j.bbamcr.2024.119659
- ISSN
- 0167-4889
1879-2596
- Abstract
- The effects of EGCG on the selective death of cancer cells by modulating antioxidant pathways through autophagy were explored in various normal and cancer cells. EGCG positively regulated the p62-KEAP1-NRF2-HO-1 pathway in normal cells, while negatively regulating it in cancer cells, leading to selective apoptotic death of cancer cells. In EGCG-treated MRC5 cells (EGCG-MRC5), autophagic flux was blocked, which was accompanied by the formation of p62-positive aggregates. However, EGCG-treated HeLa cells (EGCG-HeLa) showed incomplete autophagic flux and no aggregate formation. The levels of P-ULK1 S556 and S758 increased in EGCG-MRC5 through AMPK-mTOR cooperative interaction. In contrast, EGCG treatment in HeLa cells led to AMPK-induced mTOR inactivation, resulting in abrogation of P-ULK1 S556 and S758 levels. AMPK knockout in EGCG-HeLa restored positive regulation of the p62-mediated pathway, which was accompanied by increased P-mTOR S2448 and P-ULK1 S758 levels. Knockdown of 67LR in EGCG-HeLa abolished AMPK activity but did not restore the p62-mediated pathway. Surprisingly, both AMPK knockout and 67LR knockdown in EGCG-HeLa markedly increased cell viability, despite differential regulation of the antioxidant enzyme HO-1. In conclusion, EGCG induces the selective death of cancer cells through the modulation of at least two autophagy-dependent and independent regulatory pathways: negative regulation involves the mTOR-ULK1 (S556 and S758)-p62-KEAP1-NRF2-HO-1 axis via AMPK activation, whereas positive regulation occurs through the 67LR-AMPK axis. © 2024 Elsevier B.V.
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