Aerobic glycolysis, motility, and cytoskeletal remodeling.

Cancer cell motility and cytoskeletal remodeling are ubiquitous processes essential in cancer progression to metastasis. The role of metabolism in driving motility processes and cytoskeletal rearrangements is not fully understood, but abnormal usage of cellular energetics is a well-documented hallmark of cancer. Shiraishi and colleagues now provide evidence that energy utilized for cancer cell motility and cytoskeletal rearrangement processes is derived primarily from aerobic glycolysis and not mitochondrial oxidative phosphorylation, indicative of a deep metabolic compartmentalization program within cancer cells ().

Figure 1.

Energy for cancer cell movement is derived from glycolysis.

The authors demonstrate that more aggressive mesenchymal prostate cancer cells (PC3-EMT) exhibit an increased level of basal aerobic glycolysis relative to less aggressive epithelial prostate cancer cells (PC3-Epi) and non-cancerous human prostate epithelial cells (PrECs). These findings are consistent with the Warburg effect, which describes a high rate of aerobic glycolysis as a major consequence of tumorigenesis. Mitochondrial respiration is unchanged between the aggressive and less aggressive prostate cancer cells but provides the bulk of cellular energy in both groups. This finding highlights a widely held misconception about the Warburg Effect; despite the increased rate of aerobic glycolysis in tumor cells, mitochondrial respiration still provides the majority of cellular ATP. In addition, a higher glycolytic capacity in PC3-EMT cells (maximal rate of glycolysis) relative to PC3-Epi and PrECs was observed. Complementary studies were executed with the breast cancer cell line MDA-MB-231 (mesenchymal) and MDA-MB-231-EPI (overexpressing the transcription factors OVOL1 and OVOL2 which drive a mesenchymal to epithelial transition). The stable expression of OVOL1 and OVOL2 led to a decrease in proton production rate (PPR), a surrogate measurement for aerobic glycolysis, in MDA-MB-231 cells. Consistent with previous findings, these studies highlight the metabolic shift toward aerobic glycolysis in cells that display an aggressive phenotype.

Given the importance of actin polymerization and subsequent turnover during cellular motility and cellular invasion in cancer progression, cytoskeletal (CSK) rearrangement was measured by measuring contractile moment, cellular movement, and focal adhesion formation. PC3-EMT cells display a greater net contractile moment and a greater capacity to remodel their cytoskeleton than PC3-Epi cells. By tracking cellular displacement over time, PC3-EMT cells displayed greater motility relative to PC3-Epi cells. Cancer cell motility in both cancer cell lines is attenuated upon addition of 2-deoxy-D-Glucose (2-DG), a potent inhibitor of aerobic glycolysis, but not upon addition of oligomycin A, an inhibitor of mitochondrial respiration (). Focal adhesion formation and cellular contractile moment are also dramatically decreased upon addition of 2-DG but not oligomycin A. These findings are surprising given that actin is an ATPase and that mitochondrial respiration provides the majority of cellular ATP for these cells. Taken together, these findings indicate that aerobic glycolysis but not mitochondrial respiration is necessary for cellular movement (). Additionally, these studies underscore the importance of aerobic glycolysis in CSK rearrangement and focal adhesion formation. This study demonstrates a direct link between aerobic glycolysis and cellular movement consistent with previous studies that describe glycolytic enzyme co-localization at sites of active actin turnover. Surprisingly, the source of fuel for motility appears to be more important than the amount of energy provided by a given fuel type () indicative of cellular compartmentalization of metabolic flux.

These findings suggest that targeting aerobic glycolysis therapeutically could curb cancer cell motility and subsequent metastasis.