PPARs: Interference with Warburg’ Effect and Clinical Anticancer Trials

Figure 3

Illustration of how biased HIF-1 signaling in cancer cells may cause Warburg’ effect and lead to modified protein content and subcellular localization (a), metabolism (b), and cancer-specific therapeutic opportunities (c). The role of aberrant HIF-1 signalling in cancer cells by encoding proteins (a) which modify the intermediary metabolism in a way that favors the emergence of glycolytic metabolism even in normoxic conditions (b). Note the convergence of the HIF-1-driven increase of proteins, convergence which favors tumor vascularization (Figure 2(a)), and aerobic glycolysis (this figure). Panel (c) illustrates therapeutic opportunities related to cancer cell metabolism. Inhibition of glucose transport and activation disrupts Warburg’s effect, depriving cancer cells of their preferential metabolic substrate. Inhibition of hexokinase may in addition lead to its detachment from mitochondrial VDAC. Blocking the utilization of glucose 6-phosphate by increasing its concentrations secondarily leads to hexokinase inhibition and hence its detachment from VDAC (reopening this channel). Direct interaction with VDAC might also disrupt the closed state of the channel. The closed channel may be, however, bypassed by small permeant compounds such as pyruvate methyl ester (pme) and dichloroacetate (dca). When VDAC is closed, pyruvate methyl ester, in contrast to pyruvate, can enter the mitochondrial matrix where an esterase produces pyruvate, following this the action of residual pyruvate dehydrogenase generates an electron flux towards the respiratory chain (at the level of complex I), a feature capable of triggering mitochondrial apoptosis. Dichloroacetate inhibits pyruvate dehydrogenase kinase activity and then restores substantial pyruvate dehydrogenase activity and subsequent flux towards respiratory chain. Lipopphilic cationic compounds are attracted by cancer cell mitochondria which present abnormally high negative electric charges consequently to reduced electron chain proton efflux and to the closed state of VDAC (resulting in accumulation of small negative metabolites trapped within the mitochondria). Lipohilic cations may cross mitochondrial membranes, bypassing VDAC and being insensitive to the closed state of this channel. The intramitochondrial accumulation of lipophilic cations induces destruction and depletion of mitochondrial DNA. Abbreviations are GLUT1, glucose transporter 1; LDHA, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase1; HKII, hexokinase II; VDAC, voltage-dependent anionic channel; pme, pyruvic methyl ester; dca, dichloracetate; RC, respiratory chain.