RESUMEN
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.
Asunto(s)
Antioxidantes , Neoplasias , Humanos , Antioxidantes/farmacología , Proteína 1 Asociada A ECH Tipo Kelch , Proteínas Quinasas Activadas por AMP/genética , Células HeLa , Factor 2 Relacionado con NF-E2/genética , Autofagia , Serina-Treonina Quinasas TOR/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
OBJECTIVES: Declining gait speed is common in the elderly population and is associated with age-related conditions. Because telomere length is a reflection of aging and known to affect degenerative changes in organ systems, gait speed may be associated with telomere length. We therefore investigated the relationship between gait speed and leukocyte telomere length in elderly Korean women. STUDY DESIGN: Cross-sectional study. MAIN OUTCOME MEASURES: A total of 117 Korean elderly women participated. Metabolic variables were assessed along with gait speed calculated as walking distance (6m) divided by time. Leukocyte telomere length was measured by real-time quantitative polymerase chain reaction. RESULTS: Gait speed correlated with telomere length (r=0.38, p<0.01), fasting insulin (r=-0.19, p=0.04), homeostasis model assessment of insulin resistance index (HOMA-IR; r=-0.22, p=0.02), triglyceride (r=-0.20, p=0.03), and Korean Mini-Mental State Examination (K-MMSE; r=0.20, p=0.03) after adjusting for age. On step-wise multiple regression analysis, telomere length (ß=0.35, p<0.01), K-MMSE (ß=0.16, p=0.02), age (ß=-0.23, p=0.01), and HOMA-IR (ß=-0.19, p=0.03) were identified as independent variables associated with gait speed. CONCLUSIONS: This study suggested that telomere length may have a role in maintaining overall health status as well as preserving gait speed in the elderly population. Further studies are required to better understand the significance of our findings.