Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis

Abstract

SummarySuppressing glutaminolysis does not always induce cancer cell death in glutamine-dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis. We conducted metabolic profiling in the triple-negative breast cancer cell line MB-MDA-231, treated with different dosages of glutaminase inhibitor C.968 at multiple time points. We found that multiple molecules involved in lipid catabolism responded directly to glutamate deficiency as a presumed compensation for energy deficit. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. We therefore simultaneously inhibited glutaminolysis and autophagy, which induced cancer cell death. Our study emphasizes the potential of non-targeted metabolomics to characterize and identify metabolic escape mechanisms contributing to cancer cell survival under treatment. Our findings add to the increasing evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers.

Metabolomics, Transcriptomics and Functional Glycomics Reveals Bladder Cancer Cells Plasticity and Enhanced Aggressiveness Facing Hypoxia and Glucose Deprivation

“…To some extent, this also challenges the pivotal role played by lactate in the aggressiveness of hypoxic cancer cells suggested by many studies 96,97 . We have also found strong indications of mitochondrial autophagy, which has been previously described as a concomitant cancer survival mechanism under nutrient deprivation 98,99 . These adaptions allowed cancer cells to support low energy requirement and cellular basal functions and are consistent with drastic stop in proliferation.…”

Survival/Adaptation of Bone Marrow-Derived Mesenchymal Stem Cells After Long-Term Starvation Through Selective Processes

“…Consequently, it is feasible to suggest that β-oxidation of lipids, confirmed by CPTII, FBPase, and LXRα/β expression and a reduction in the amount of free triglycerides at day 75, is the source of energy which supports gluconeogenesis and the glucose found in starving conditions. In addition, the AhR pathway activation prediction during starvation, and the results obtained treating the cells with troglitazone, a well-known gluconeogenesis and β-oxidation inhibitor [8,24,39], enabled confirmation of a direct involvement of β-oxidation as alternative energetic source, also highlighted by recently published papers [40,41]. Among the modulated pathways analyzed, we found Jak/Stat.…”

Neural signaling modulates metabolism of gastric cancer

“…The so-called ''metabolic escape'' has been suggested as a mechanism by cancer cells to avoid cell death in response to inhibited glutaminolysis. Thus, tumors that suffer from glucose/glutamine starvation frequently activate fatty acid catabolism for survival (Halama et al, 2018;Wise et al, 2008;Li and Zhang, 2016). The results of the present study might suggest that the metabolic escape takes place after vagotomy, leading to an activation of Acetyl-CoA with increased levels of lysolipids and polyunsaturated fatty acids in GC but not in WT mice.…”