Question

4. Numerous lines of evidence suggest that mitochondrial bioenergetics and signaling are required for tumorigenesis. Does targeting mitochondrial metabolism represent a viable therapeutic strategy? Discuss the evidence both for and against targeting mitochondrial metabolism for the treatment of cancer. (1/2 page max, 5pts)

Answer 1

The role of mitochondrial bioenergetics is evident in cancer as it participates in ATP synthesis, macromolecular biosynthesis as well as activation of signalling pathways, which make mitochondrial bioenergetics a potent target for cancer therapeutics.

• To meet the energy requirements of robustly growing cancer cells, there is constitutive glycolysis which is the result of dysfunctional signalling pathways in cancer and activation of oncogenes for eg. C-Myc.
• Mitochondrial ATP production can be targeted in inner areas of solid tumors as they have insufficient supply of glucose and energy with oxygen levels below 0.3% in which ETC is unable to generate ATP.
• Majority of the cancers are dependent on oxidative phosphorylation for ATP synthesis/oxidative glycolysis (Warburg effect), therefore targeting oxidative phosphorylation will result in failure of compensation of glycolysis.
• Production of intermediates of TCA cycle in mitochondrial matrix are the precursors of nucleotides which are required highly by cancer cells, and ability of cancer cells to oxidatively process glutamine, making them glutamine addicted, therefore intermediates of TCA cycle can be targeted for inhibiting growth of Cancer cells.
• Reactive oxygen species (ROS) are generated during metabolic pathways in the mitochondria which stimulate the activation of oncogenic signalling pathwayss but there is an accumulation of ROS in larger amounts cell undergoes cell death therefore mechanism for accumulating ROS in mitochondria can be upregulated in Cancer cells so that cancer cells can undergoes cell death.
• For counteracting the effect of accumulating reactive oxygen species, cells produces NADPH, therefore NADPH formation is targeted in order to deteriorate the antioxidant activities in the cells.
• Targeting mitochondrial bioenergetics for cancer therapeutics may result in cancer evolution and generation of clones having cancer stem cells like characteristics which bypass the normal pathways for energy production and formation of metabolic intermediates making it more difficult to treat.