Cancer cell metabolism veers off the normal metabolic path at one place or another, but exactly where hasn’t been clear. It’s not as though metabolic detours are marked with flares or flashing signs. One detour has been identified, however, by scientists based at the University of Wisconsin-Madison. They used a protein interaction assay in a breast cancer cell line and found that a protein called CARM1, or co-activator-associated arginine methyltransferase 1, chemically modifies a metabolic enzyme called PKM2, or pyruvate kinase isoform M2, changing its function, causing it to direct cell metabolism down a cancerous path.
The scientists, led by Wei Xu, Ph.D., the Marian A. Messerschmidt Professor in Cancer Research at the UW Carbone Cancer Center and McArdle Laboratory for Cancer Research, propose that this cancer sign be taken down. They have even experimented with a peptide that interferes with the modification caused by CARM1. The results looked promising enough that the scientists hope that additional work will help keep the normal metabolic path passable, thus preventing cancer.
“Cancer cells often change their nutrient utilization and energy production, so many efforts are being made to develop drug inhibitors of cancer cell metabolism to starve them,” said Xu. “We have found that inhibiting a chemical modification of a cancer-associated metabolism protein is enough to inhibit the aggressive nature of cancer cells.”
Cancer biologists have identified nearly a dozen “hallmarks of cancer,” or large-scale changes that send a precancerous cell over the tipping point to become a cancerous one. One hallmark of cancer is the loss of properly regulated energy metabolism, a process referred to as the Warburg effect after the Nobel laureate Otto Warburg, who identified it.
Other hallmarks of cancer include continuous activation of growth pathways, the inability to respond to signals that put the brakes on cell growth, and a gain of invasion and spread to distant organs.
“My lab studies a protein, CARM1, which is associated with worse outcomes in breast cancer patients, though it has also been found expressed in many other cancer types,” Xu explained. “CARM1 chemically modifies its target proteins to alter their function, and in doing so directly leads to the activation of several hallmarks of cancer.”
Details about the CARM1 mechanism appeared October 23 in the journal Nature Cell Biology, in an article entitled “PKM2 Methylation by CARM1 Activates Aerobic Glycolysis to Promote Tumorigenesis.” The article describes the metabolic “fork in the road” that may lead to a healthy energy path or a cancer energy path.
“PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells,” the article’s authors wrote. “Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked.”
After discovering that CARM1 methylates the key glycolytic enzyme PKM2, Xu and colleagues found that methylated PKM2, by interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), inhibits the influx of calcium from the endoplasmic reticulum to mitochondria.
The investigators then engineered cells to express “normal” PKM2 or a mutated form that was not modifiable. They learned that PKM2 appears to be the deciding factor in picking the direction cell metabolism takes at that fork in the road. The CARM1-modified PKM2 shifted cells toward the cancer cell metabolism path while cells with PKM2 that could not be modified took the metabolic path associated with noncancerous cells.
“Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis,” the Nature Cell Biology article indicated. “Collectively, the CARM1–PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions.”
With a clearer picture of how cancer cells shift their metabolism, the researchers next used a mouse model of breast cancer and a competitor drug that prevents CARM1 from effectively modifying PKM2 to test what would happen.
“When we block PKM2 modification by CARM1, the metabolic energy balance in cancer cells is reversed, and we see a decrease of cell growth and cell spreading potential,” Xu says. “This study, then, identifies another therapeutic target to help reverse several hallmarks of cancer.”
In addition to targeting PKM2 modification by CARM1, Xu's lab is investigating how CARM1 recognizes all of its many target proteins, with the goal of disrupting those protein modifications from driving aggressive cancers.