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Autophagic Activation and Decrease of Plasma Membrane Cholesterol Contribute to Anticancer Activities in Non-Small

Jui-Ling Hsu1,2, Wohn-Jenn Leu1, Nan-Shan Zhong3

  • 1School of Pharmacy, National Taiwan University, No. 33, Linsen S. Rd., Zhongzheng Dist., Taipei 100, Taiwan.

Molecules (Basel, Switzerland)
|October 13, 2021
PubMed

Insights

Para-toluenesulfonamide shows promise as an anti-cancer drug for non-small cell lung cancer (NSCLC). It works by disrupting cell membrane cholesterol and activating autophagy, leading to cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Non-small cell lung cancer (NSCLC) has high mortality and recurrence rates, necessitating novel therapeutic agents.
  • Drug resistance limits the efficacy of current chemotherapies for NSCLC.
  • Para-toluenesulfonamide has previously shown anti-tumor potential in prostate cancer.

Purpose of the Study:

  • To investigate the anti-cancer effects of para-toluenesulfonamide on NSCLC.
  • To elucidate the role of cholesterol-enriched membrane microdomains and autophagy in para-toluenesulfonamide's action against NSCLC.

Main Methods:

  • Inhibition of the Akt/mTOR/p70S6K pathway in NSCLC cell lines (NCI-H460, A549).
  • Assessment of plasma membrane cholesterol levels and the effect of cholesterol supplementation.
  • Analysis of autophagy markers (LC3-II, p62) and lysosomal cholesterol transport.
  • Evaluation of the impact of autophagy inhibitors on para-toluenesulfonamide's efficacy.

Main Results:

  • Para-toluenesulfonamide induced G1 cell cycle arrest and apoptosis in NSCLC cells.
  • The compound significantly reduced plasma membrane cholesterol levels, an effect reversed by cholesterol supplementation.
  • Para-toluenesulfonamide increased LC3-II and decreased p62 expression, indicating autophagy induction.
  • Lysosomal transport of cholesterol was observed, and autophagy inhibition reduced the drug's anti-cancer effects.

Conclusions:

  • Para-toluenesulfonamide is a potential anti-cancer agent for NSCLC, inducing G1 arrest and apoptosis.
  • Disruption of membrane cholesterol levels and activation of autophagy are key mechanisms underlying para-toluenesulfonamide's efficacy in NSCLC.
Keywords:
Akt/mTOR/p70S6K pathwayautophagynon-small cell lung cancerpara-toluenesulfonamideplasma membrane cholesterol

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