Effect of Dietary ω-3 Polyunsaturated Fatty Acid DHA on Glycolytic Enzymes and Warburg Phenotypes in Cancer

Figure 1

Schematic illustration of the mechanism by which DHA may interfere with the molecular signalling by activating glycolytic phenotype. The PI3K-Akt-mTORC1 pathway promotes the glycolytic phenotype, principally activating the transcription factor HIF-1α. HIF-1α is activated also by hypoxia, as well as by mutations of its regulator VHL. The accumulation of HIF-1α in the cytosol determines its heterodimerization with the subunit HIF-1β, forming the active HIF-1 complex. HIF-1 upregulates a wide network of genes by binding to hypoxia response elements (HRE). DHA interferes at various sites of this pathway, and then it is able to attenuate bioenergetic function and Warburg metabolism. DHA treatment increases the LKB1 protein expression and AMP cytosolic levels, necessary events to activate the AMPK pathway. Active AMPK inhibits mTORC1 signalling, via phosphorylation of TSC protein. Moreover, DHA alters cancer cell metabolism by interfering with the processes implicated in the stabilization of HIF-1α. Indeed, the reduction of cytosolic ATP levels induced by DHA prevents the proper functioning of HSP90, molecular chaperon necessary for folding of HIF-1α. Moreover, DHA destabilizes HIF-1α promoting its proteolytic degradation via PPARα activation.