Autophagic Activation and Decrease of Plasma Membrane Cholesterol Contribute to Anticancer Activities in Non-Small Cell Lung Cancer.
Jui-Ling HsuWohn-Jenn LeuNan-Shan ZhongJih-Hwa GuhPublished in: Molecules (Basel, Switzerland) (2021)
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.
Keyphrases
- cell death
- cell cycle
- small cell lung cancer
- low density lipoprotein
- cell proliferation
- cell cycle arrest
- advanced non small cell lung cancer
- signaling pathway
- oxidative stress
- high glucose
- diabetic rats
- endoplasmic reticulum stress
- endothelial cells
- poor prognosis
- mass spectrometry
- electronic health record
- cardiovascular disease
- risk assessment
- machine learning
- young adults
- cardiovascular events
- big data
- type diabetes
- high resolution
- epidermal growth factor receptor
- fluorescent probe
- single molecule
- tandem mass spectrometry
- solid phase extraction