Autophagic Activation and Decrease of Plasma Membrane Cholesterol Contribute to Anticancer Activities in Non-Small Cell Lung Cancer
| Autor: | Jih-Hwa Guh, Wohn-Jenn Leu, Jui-Ling Hsu, Nan-Shan Zhong |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
autophagy
Cell cycle checkpoint Lung Neoplasms Pharmaceutical Science Organic chemistry Antineoplastic Agents para-toluenesulfonamide Article Analytical Chemistry QD241-441 Lysosome Carcinoma Non-Small-Cell Lung Cell Line Tumor Drug Discovery Antineoplastic Combined Chemotherapy Protocols medicine Humans Physical and Theoretical Chemistry Lipid raft Protein kinase B PI3K/AKT/mTOR pathway non-small cell lung cancer Sulfonamides plasma membrane cholesterol Chemistry TOR Serine-Threonine Kinases Akt/mTOR/p70S6K pathway Autophagy Cell Membrane Ribosomal Protein S6 Kinases 70-kDa Gefitinib Cell cycle medicine.anatomical_structure Cholesterol Chemistry (miscellaneous) Apoptosis Cancer research Molecular Medicine Lysosomes Proto-Oncogene Proteins c-akt Toluene |
| Zdroj: | Molecules, Vol 26, Iss 5967, p 5967 (2021) Molecules Volume 26 Issue 19 |
| ISSN: | 1420-3049 |
| Popis: | Non-small cell lung cancer (NSCLC), an aggressive subtype of pulmonary carcinomas with high mortality, accounts for 85% of all lung cancers. Drug resistance and high recurrence rates impede the chemotherapeutic effect, making it urgent to develop new anti-NSCLC agents. Recently, we have demonstrated that para-toluenesulfonamide is a potential anti-tumor agent in human castration-resistant prostate cancer (CRPC) through inhibition of Akt/mTOR/p70S6 kinase pathway and lipid raft disruption. In the current study, we further addressed the critical role of cholesterol-enriched membrane microdomain and autophagic activation to para-toluenesulfonamide action in killing NSCLC. Similar in CRPC, para-toluenesulfonamide inhibited the Akt/mTOR/p70S6K pathway in NSCLC cell lines NCI-H460 and A549, leading to G1 arrest of the cell cycle and apoptosis. Para-toluenesulfonamide significantly decreased the cholesterol levels of plasma membrane. External cholesterol supplement rescued para-toluenesulfonamide-mediated effects. Para-toluenesulfonamide induced a profound increase of LC3-II protein expression and a significant decrease of p62 expression. Double staining of lysosomes and cellular cholesterol showed para-toluenesulfonamide-induced lysosomal transportation of cholesterol, which was validated using flow cytometric analysis of lysosome staining. Moreover, autophagy inhibitors could blunt para-toluenesulfonamide-induced effect, indicating autophagy induction. In conclusion, the data suggest that para-toluenesulfonamide is an effective anticancer agent against NSCLC through G1 checkpoint arrest and apoptotic cell death. The disturbance of membrane cholesterol levels and autophagic activation may play a crucial role to para-toluenesulfonamide action. |
| Databáze: | OpenAIRE |
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