Finnish Study Shows Cell Metabolism is Key to Cancer
By Sharon Kingman
LONDON – A new study has connected known differences in the metabolism typical of cancer cells to the pathway leading to apoptosis, or cell death. Researchers working in Finland have, for the first time, linked metabolic changes in cancer cells to the mechanism that, in normal cells, prevents abnormal cellular proliferation.
The discovery is likely to encourage drug developers to consider whether existing drugs that modify cellular metabolism could be used in the future to treat cancer.
Juha Klefström, Finnish Academy Research Fellow and principal investigator at the University of Helsinki in Finland, told BioWorld Today: "Our work connects the typical altered metabolism of the cancer cell to cell death pathways, which opens up new possibilities to fight cancer with targeted therapies. There are already many clinically tested drugs that inhibit or activate metabolic pathways and the most desired future outcome would be to be able to use such drugs against cancer."
Eventually, he added, it may be possible to combine therapies to treat cancer, using drugs that target the metabolic differences present in cancer cells in combination with those that push cancer cells into the cell death pathway, toward apoptosis.
An account of the study appeared in the April 15, 2013, issue of the Proceedings of the National Academy of Sciences, in a paper, titled "Myc-induced AMPK-phospho p53 pathway activates Bak to sensitize mitochondrial apoptosis."
For a couple of decades, Klefström has been studying the factors that cause cancer cells to undergo apoptosis. "It has long been known that low ATP levels make cells sensitive to apoptosis," he said. "But there was no molecular connection between the two."
The team decided to investigate further. Working with cancer cells, the researchers observed what happened if they activated the Myc oncoprotein. "The Myc oncoprotein not only boosts tumor cell proliferation but it also makes the cells vulnerable to apoptosis," Klefström said. "We wanted to understand the pathways that cause this vulnerability."
Experiments showed that a protein associated with apoptosis, called BAK, became active in the mitochondria when Myc was activated. With BAK active, the cells did not start to die, but they were known to be very sensitive to many triggers that can cause apoptosis.
The next step was to probe what other molecules BAK was interacting with. "We found that BAK was interacting with p53, so the next question for us was to find out exactly how Myc activates this interaction between BAK and p53 at the mitochondria," Klefström said. "We did a small screen of different kinases, to find out which one was responsible for triggering phosphorylation and activation of p53, and turning on apoptosis-promoting BAK activity. It turned out that AMP kinase, or AMPK, was the only hit."
Having confirmed that AMPK activates p53, they still needed to find out how Myc activates AMPK. "This turned out to be quite simple," Klefström said, "as it was already known that AMPK is activated by decreasing ATP levels." They went on to confirm that activation of Myc decreases levels of ATP in cells.
The work, therefore, links the apoptosis-promoting activation of p53 in the mitochondria to activation of AMPK in the cytosol to activation of Myc in the nucleus. "This is a new pathway," Klefström said. "People previously thought that when AMPK is active in cancer cells, the cells would starve to death, but we now think there is a more direct connection between AMPK activation and the triggering of apoptosis."
Next steps include evaluating the many drug-like compounds that the team used in their study reported in PNAS, to see how effective they are as AMPK activators. "We will also look at drugs such as metformin, which is known to be an activator of AMPK and is being tried as an anticancer drug, to see the effects on mouse models of cancer," Klefström said. "We want to test our hypothesis that activation of the AMPK pathway will prevent the formation of tumors in animal models. If we can understand how to direct an aspect of cancer cell metabolism so that the cell enters apoptosis, this will allow us to kill cancer cells in a highly targeted way."