The two faces of AMPK

Salk scientists unravel how enzyme long thought to suppress cancer may sometimes help tumors survive

Kristen Smith
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LA JOLLA, Calif.—Researchers at the Salk Institute for Biological Studies have unraveled the mystery of how an enzyme long known to suppress cancer can also help certain tumors thrive. AMP-activated protein kinase (AMPK) is a metabolic master switch that springs into gear when cells run low on energy, and revs up a cellular recycling program to free up essential molecular building blocks in times of need.
While scientists have known that AMPK could halt a tumor that may over-activate a cell’s engine, other research indicated that AMPK could also help other kinds of tumors to grow. The lab of Salk professor Dr. Reuben Shaw studied mice with and without the AMPK regulator to see how tumors developed. Their findings, recently published in the journal Cell Metabolism, suggest promising potential for targeted activation or deactivation of AMPK in different cancer types.
AMPK plays a key role as a master regulator of cellular energy homeostasis. It is a fuel-sensing enzyme that is activated in response to stresses that deplete cellular adenosine triphosphate (ATP) supplies, such as low glucose, hypoxia, ischemia and heat shock. Because mutant tumor cells are able to steal energy in order to grow, their presence can activate AMPK and trigger processes that slow its growth. AMPK can both increase ATP generation such as fatty-acid oxidation and glucose transport, and decrease others that consume ATP, but are not acutely required for survival, such as lipid and protein synthesis and cell growth and proliferation—inhibiting the tumor and helping to restore other normal cellular functions. The recent findings at Dr. Shaw’s lab, however, also found that the presence of AMPK could help larger existing tumors to grow.
“Our study shows that the same dysfunction in a genetic circuit that causes non-small cell lung cancer to begin with is necessary for more mature tumor cells to survive when they don’t have enough nutrients,” says Shaw, director of the Salk Cancer Center and the paper’s senior author. “It’s exciting because not only does it solve a genetic ‘whodunnit,’ but it also points to a potential new therapeutic target for a cancer that is often diagnosed very late.”
In studying the mice, they observed how tumors developed and progressed in mice with AMPK, and others without, and which genes from the same mouse were being activated under differing conditions. They noticed that when a tumor reached a certain size, AMPK actually stimulated a gene (Tfe3) responsible for recouping cellular materials and reusing them—when interior cells could no longer access the needed energy to grow, AMPK signaled Tfe3 to cannibalize pieces of the cell so the tumor could grow. 
“We found that tumors grew much more slowly when AMPK was not present,” says research associate Dr. Lillian Eichner, the first author of the paper. “That means that AMPK is not always functioning as a tumor suppressor, as we originally thought. Previously, we were focused on how we could activate AMPK. Now that we’ve identified this mechanism, we can shift to how to inhibit it in certain cancers.”
According to the published paper, the team is not suggesting they have discovered a unifying function of AMPK in cancer, but rather that its role differs based on the context—it can inhibit or promote tumor growth, depending on the cancer type. “Whether AMPK is required to support or inhibit tumorigenesis is context dependent and most likely relies on the temporal energetic demands of the tumor,” reads the paper. “Taken together, our study describing the requirement for AMPK to promote the growth of NSCLC warrants further investigation into AMPK function in different cancers to enhance our understanding of the complex and dynamic relationship between AMPK, metabolism and cancer.”

Kristen Smith

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