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Potential role of lipophagy impairment for anticancer effects of glycolysis-suppressed pancreatic ductal adenocarcinoma cells

  • 0Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba, 260-8675, Japan.
Cell Death Discovery +

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April 5, 2024

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April 5, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Pancreatic cancer cells survive low-glycolysis by boosting fatty acid metabolism. Inhibiting this pathway, alongside glycolysis, shows promise for new pancreatic ductal adenocarcinoma (PDAC) treatments.

Area Of Science

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background

  • Pancreatic ductal adenocarcinoma (PDAC) cells exhibit unique metabolic flexibility, surviving even when glycolysis is suppressed.
  • Identifying therapeutic targets in these metabolically adaptable cancer cells is crucial for effective treatment.

Purpose Of The Study

  • To investigate the survival mechanisms of glycolysis-suppressed PDAC cells.
  • To identify novel therapeutic targets and strategies for PDAC treatment.

Main Methods

  • Screening of anticancer metabolic compounds, including lysine-specific histone demethylase 1A (LSD1) inhibitors.
  • Proteomic analyses to understand cellular adaptations under glucose starvation.
  • Assessment of autophagy and lipophagy pathways in response to drug treatment.

Main Results

  • SP-2509, an LSD1 inhibitor, reduced PDAC cell growth and demonstrated anti-tumoral effects in mice.
  • Glycolysis-suppressed PDAC cells enhance mitochondrial oxidative phosphorylation and fatty acid metabolism for survival.
  • SP-2509 and OG-L002 impaired fatty acid metabolism and lipophagy, leading to lipid droplet accumulation.

Conclusions

  • PDAC cell survival under suppressed glycolysis relies on enhanced mitochondrial fatty acid metabolism.
  • Inhibition of fatty acid metabolism and lipophagy presents a potential therapeutic strategy for PDAC.
  • Dual inhibition of glycolysis and fatty acid metabolism offers a promising avenue for novel PDAC therapies.

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