Skip to 0 minutes and 14 secondsAll cells need energy in order to survive. For most normal cells, metabolism of glucose through glycolysis and into the citric acid cycle, also known as the Krebs cycle, provides the primary source for energy production with complete oxidation of each molecule of glucose generating a net output of 32 molecules of ATP. Beta oxidation of fatty acids and, to a lesser extent, oxidation of amino acids provide alternative sources for energy production. In cancer cells, however, this picture changes dramatically. To begin with, glucose is only partially broken down to pyruvate in many cancer types. And rather than entering the mitochondria, pyruvate is converted to lactate and secreted from the cell.
Skip to 0 minutes and 58 secondsThus, only two molecules of ATP are generated from each molecule of glucose in cancer cells. In part, to compensate for this decline in glucose-derived energy production, cancer cells make increased use of fatty acid and amino acid oxidation, taking up large quantities of glutamine, in particular, for entry into the citric acid cycle at the level of alpha-ketoglutarate. Why? One of the reasons cancer cells are thought to redirect metabolism in this manner is to provide precursor molecules for macromolecular biosynthesis. In order for a cell to replicate, it must first generate all of the physical materials needed to give rise to two daughter cells-- i.e., more proteins, more lipids, more ribosomes, and, of course, the complete replication of the cell's DNA.
Skip to 1 minute and 44 secondsAll of these molecules are comprised of precursors that can be traced back to central metabolism. The implications of these changes are that this impetus to replicate, impact the cells' energetic capacity in two ways. Firstly, by removing much of the fuel required for energy production and secondly, by increasing the demand for ATP as macromolecular synthesis is, itself, energetically very expensive. Thus, cancer cells typically exist in a state of energetic stress, forever trying to balance the voracious appetite with an often limited supply of nutrients. We and others believe that this state of energetic stress specific for cancer cells can be exploited, and we are trying to develop therapeutic approaches based on the principle of selectively inducing energetic catastrophe to treat cancer.
Skip to 2 minutes and 32 secondsFor example, we have shown that cancer cells that overexpress the c-myc oncogene are critically dependent upon efficient ATP homeostasis for survival. Genetic or pharmacological suppression of a kinase called ARK5, interferes with ATP homeostasis, and thereby selectively kills cells that overexpress myc. Our current work is aimed towards identifying cancers in which this phenomenon holds true, and developing small molecule inhibitors of ARK5 that may in the future be used to treat such susceptible cancers.
Cancer metabolism and targeted therapies
Dr Daniel Murphy introduces us to the idea of targeting cancer cells at the level of metabolic pathways. He describes the ‘energetic crisis’ that cancer cells find themselves experiencing and how this may allow us to selectively target and destroy them.
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