Another avenue for attacking cancerous tumors may have opened up with a breakthrough in manipulation of an enzyme long known to be involved in cancer-cell glucose metabolism.
In a paper published online in Science, Anastasiou et al. (2011) took an important line of cancer research a step forward. Their research also furthers what is known about reactive oxygen species (ROS, also known as oxidants or “free radicals”), which are of interest to those studying general health and nutrition. Although anti-oxidants are a big part of the annual twenty-billion-dollar supplement industry, because they bind to ROS which are believed to play a role in aging, their complete range of physiological roles is still clearly not understood.*
But we know that it is true that ROS are damaging to cells, because it is based on this very principle that chemotherapy drugs were and continue to be developed: they attack dividing cells using free radicals. Conversely, protection against ROS helps cells to grow and proliferate. The ability of cancer cells to proliferate is exactly the problem with them, as it is uncontrolled growth of cancerous tumors that can ultimately impair organ function and lead to death. Ironically, conditions leading to the growth of cancerous tumors actually produce extra ROS, so cancer cells have to be especially good at thwarting their effects to continue to survive and grow uninhibited.
Glucose is the energy form used by cells to grow and proliferate. All food we eat is eventually converted to glucose for this purpose.
Pyruvate kinase (PK) is an enzyme that helps to enable glucose utilization by proliferating cells. There are two major variants of this enzyme: PKM1, found in many normal body tissues, and PKM2, which is associated with cancer cells. When Anastasiou et al. treated both PKM1 and PKM2 with oxidants, they observed very different effects. The activity of PKM1 did not change, but PKM2 was inhibited by the presence of oxidants, and this diverted glucose into a different metabolic pathway which resulted in detoxification of the ROS, which reduced damage to the cells. That is, the changing activity of PKM2 under different oxidation conditions makes cancer cells especially resistant to ROS; when oxidants are present, they tend to shut down, rendering those oxidants ineffective. This shows why cancer cells are pre-adapted to resist many of the chemicals we use to treat them. Anyone who has suffered through months of chemotherapy and all its attendant complications only to learn that their cancer was unaffected or even proliferated further understands the grave implications of this. (Most cancer patients also learn that the reason for the worst side-effects of chemotherapy drugs – hair loss, mouth sores, nausea – is that chemotherapy drugs attack dividing cells, and the cells associated with these parts of the body are dividing a lot more than other cells. This is why fasting before chemotherapy is now being explored as a method to mitigate side effects: it tends to shut down normal cell activity, making them divide less, thus making them more resistant to the oxidizing action of the drugs.)
The researchers were able to use a method to keep PKM2 activated in mice in the presence of oxidants to show that taking away the ability of this enzyme to shut down results in much reduced tumor activity, because the cells are no longer protected from ROS. Scientists are very far, of course, from developing a therapeutic version of their procedure but it could be a fruitful avenue to pursue. They envision that it may be possible in the future to use PKM2 activators in conjunction with chemotherapy. One would expect that this would result in much lower doses of chemotherapy being effective against cancer, which would alleviate a lot of needless suffering. Then again, several therapies which have shown promise in vitro have not panned out in the real world, showing that we have a long way to go in knowing enough about cancer – in all its many variants – to be able to control it.
* Multiple studies on anti-oxidants and other supplements over the last several years have shown increasing evidence that they are bad for your health. A meta analysis by Bjelakovic et al. (2007) showed increased mortality associated with supplement use, and most recently a study on older women (Mursu et al., 2011) grabbed media attention for its similar conclusions. A further paper on anti-oxidants and exercise (Ristow et al. 2009), previously discussed on Bioblog, demonstrated that ROS may have important positive functions being overlooked in the anti-aging, supplement craze.
Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ, Vander Heiden MG, Cantley LC. 2011. Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Antioxidant Responses. Science. Nov 3. [Epub ahead of print]
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C., 2007. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. Feb 28;297(8):842-57.
Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr., 2011. Dietary Supplements and Mortality Rate in Older Women: The Iowa Women’s Health Study. Arch Intern Med. Oct 10;171(18):1625-33.
Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Blüher M. 2009. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. May 26;106(21):8665-70.
Image courtesy Richard Wheeler (Zephyris) 2006 (Wikimedia Commons).