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

Although elevated aerobic glycolysis is typical in a variety of cancers, pancreatic ductal adenocarcinoma (PDAC) cells can survive a condition of glycolysis suppression. We aimed to recognize potential therapeutic targets in glycolysis-covered up PDAC cells. By screening anticancer metabolic compounds, we identified SP-2509, an inhibitor of lysine-specific histone demethylase 1A (LSD1), which dramatically decreased the development of PDAC PANC-1 cells and demonstrated an anti-tumoral effect in tumor-bearing rodents. The development of glycolysis-covered up PANC-1 cells seemed to be inhibited by another LSD1 inhibitor, OG-L002. Similarly, another two PDAC cells (PK-1 and KLM-1) with covered up glycolysis exhibited anticancer effects against SP-2509. However, the anticancer effects on PDAC cells were unrelated to LSD1. To research how PDAC cells survive inside a glycolysis-covered up condition, we conducted proteomic analyses. These results coupled with our previous findings recommended that glucose-starvation causes PDAC cells to boost mitochondrial oxidative phosphorylation. Particularly, mitochondrial essential fatty acid metabolic process was recognized as a vital factor adding towards the survival of PDAC cells under glycolysis suppression. We further shown that SP-2509 and OG-L002 disturbed essential fatty acid metabolic process and caused fat droplet accumulation with the impairment of lipophagy, although not bulk autophagy. These bits of information indicate a substantial potential association of lipophagy and anticancer effects in glycolysis-covered up PDAC cells, offering suggestions for new therapeutic techniques for PDAC by dual inhibition of glycolysis and essential fatty acids metabolic process.