The acceleration of oxidative phosphorylation, aerobic glycolysis and its parallel pentose phosphate pathway make glucose metabolism a possible target for cancer therapies by distinguishing their metabolic profiles from non-cancerous cells. These glucose-metabolising pathways are enhanced concomitantly to satisfy the increased glucose demand of proliferating cancer cells. Usually glycolysis is initiated in hypoxic environments and while many tumors are hypoxic in their core, the transition to glycolysis in these cells is not hypoxia-induced. The transition seems to be driven by dysregulated transcription factors affecting enzymes involved in glucose metabolism.
To realize the potential glucose metabolism has as a target for cancer therapy, interference with relevant enzymes must be performed in a selective manner that avoids system wide toxicity to normal tissues. Discovery of cancer-specific isozymes will be important for overcoming ubiquity related impediments inherent in targeting enzymes involved in glucose metabolism.
Enzymes involved in glucose metabolism are currently under research as potential targets
for cancer therapy. One obstacle to discovering effective targets is the metabolic plasticity of tumors. Cancer cells are extremely effective at finding alternative means to achieve growth and proliferation. Multiple homeostatic processes become disequilibrated at the expense of the patient and to the benefit of the tumor’s proliferation.
The utilization of intermediary metabolites to allosterically alter the normal actions of enzymes is a common method of achieving metabolic plasticity. Intermediary metabolites produced by glucose metabolizing enzymes often allosterically interact with other enzymes to overcome negative feedback loops in cancer cells that would otherwise inhibit glycolysis. An abundance of intracellular ATP usually initiates signalling cascades that restrict the glycolytic pathway. In cancer cells, for example, the intermediary metabolite fructose-2,6-phosphate allosterically activates the enzyme PFK-1 which helps cancer cells overcome negative feedback loops that inhibit glycolysis in the presence of abundant levels of ATP. As this example shows, inhibiting the expression of enzymes involved in glycolysis could result in the accumulation of glucose related intermediates that feed alternative biosynthetic pathways like the pentose phosphate pathway.
Metabolic plasticity is not the only or even the greatest challenge to targeting glucose metabolism as a means of cancer therapy. Avoiding ubiquity related impediments poses a serious challenge to researchers and is exceedingly difficult given the systemic requirement to metabolize glucose. Targeted delivery of therapeutics to cancer cells may be possible once cancer specific isoforms are recognized. PKM1 and PKM2 represent one interesting example of cancer-related isozyme recognition. Cancer cells naturally express greater amounts of PKM2 than PKM1 when compared to non-cancer cells. Developing a PKM2 targeted therapeutic mightavoid the ubiquity related impediments inherent to targeting glucose metabolism.
Given the systemic use of glucose, a vast amount of samples will likely need to be analyzed to identify cancer cell isozymes that are appropriate targets. FFPE tissue microarray is a promising avenue to isozyme detection. Biorepositories store large amounts of ffpe blocks containing human tissue samples and collection of protein, RNA and DNA samples from these biobanks could provide a wealth of data to elucidate isozymes found exclusively in cancer cells.
Sources
The Journal of Experimental Medicine - Targeting glucose metabolism for cancer therapy
US National Library of Medicine - Targeting glucose metabolism for cancer therapy
