FIGURE 1 ! Figure 1. Lactate metabolism in tumors: a simplified cartoon showing lactate being shuttled to and from cancer cells and its potential role as a signaling molecule in driving angiogenesis. Increasing pyruvate inhibits formation of 2- oxoglutarate, with the net effect of less degradation of HIF-ia in the proteasome and increased VEGF and angiogenesis. Note that pyruvate can be increased by hypoxia “backing up” the TCA cycle, or by importation of lactate via MCT1s. Some lactate shuttling likely is present between cancer cells and (1) other cancer cells within the tumor, (2) tumor stromal cells, and/or (3) non-tumor cells both local and distant from the tumor. Note that the traditional “Warburg Effect” describes tumors relying heavily on glucose uptake (via GLUTS) with subsequent lactate exportation (via MCT45) in normoxia. A “Reverse Warburg Effect” describes lactate production from stromal cells, which is then taken up and used by local cancer cells. Some unique combination of these pathways is likely present within each tumor, highlighting the need for further in vivo experimentation. (Note that MCTS can transport lactate either direction; MCTs are typically expressed in cells importing lactate, while MCT4s are expressed in cells exporting lactate.)

iii. In Figure 1 of the article, pyruvate is shown entering the TCA cycle in the mitochondria (represented by the green structure). This is in fact a simplification as pyruvate must be converted into an intermediary product that can then enter the TCA cycle. What is this intermediary and where does this conversion occur? (2 marks) iv. Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate. Aside from pyruvate, what other product of glycolysis is required for this reaction and what general name can be used to describe this type of reaction? (3 marks)