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Metabolic protein linked to cancer and autoimmunity

Tuesday, July 19, 2016

Cancer researchers exploring the role of a metabolic protein have discovered it may also be a piece of the immune system puzzle, with potential implications for patients with autoimmune diseases as well as cancer.

Scientists in the lab of Lewis Cantley, Ph.D., director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian, found that a little gene with a long name – type 2 phosphatidylinositol-5-phosphate 4-kinase gamma (PIP4K2C) and its associated protein PI5P4Kγ- plays a role in the regulation of the immune system.

By stopping its function, the scientists were able to induce hyperactivation of the immune system in mice.

“This suggests that drugs that inhibit PIP4K2C function could be useful to enhance cancer immunotherapy,” said first author Hyeseok Shim, Ph.D., a former postdoctoral researcher in Cantley’s lab, now at Petra Pharma.

The immune system is a complex network that evolved to protect organisms from invasion of various microbes. Whereas an active immune system provides protection, overactivation can result in autoimmunity, in which the body attacks its own healthy cells and tissues.

An understanding of the molecular underpinnings of an overactive or underactive immune system is important for developing therapies for immune-related diseases, from immunodeficiency to autoimmune disorders such as celiac disease, Type 1 diabetes, lupus and rheumatoid arthritis, and even cancers.

The Cantley lab primarily focuses on cell metabolism, and was investigating PI5P4Kγ because it is one of three PI5P4K enzymes that have been implicated in cell metabolism, growth control, and a variety of stress responses. The other two – PI5P4Kα and PI5P4Kβ have been more closely studied; the Cantley study, published July 5 in the Proceedings of the National Academy of Sciences, is the first to detail what happens when PI5P4Kγ is lost.

They found that without a PIP4K2C gene, mice had increased inflammation and more T-cell activation as they aged. T-cells are types of white blood cells that can assist and regulate immune responses. Some help destroy infected cells, while others signal the formation of killer immune cells and point them towards their targets, or provide the immune system with a “memory” of infection to facilitate future response to re-exposure. Still others perform a regulatory function, to shut down the immune response at the appropriate time.

In the case of the mice missing the PIP4K2C gene, they had an increase in T-helper-cell populations and a decrease in regulatory T-cell populations, with overall increased proliferation of T-cells.

Shim said the protein’s link to immunity was not a complete surprise, since its location on the genome is adjacent to other nucleotide snippets whose mutations have been correlated with rheumatoid arthritis.

Further study into the mechanism behind the reaction found it was linked to the mTORC1 signaling pathway. mTORC1 is a protein complex that functions as a nutrient-energy-reduction/oxidation sensor, and controls protein synthesis. It is a central regulator of cell survival, growth and metabolism; it also plays a critical role in the regulation of immune cells. The mTOR pathway is activated during various cellular processes, including the activation of T-cells, insulin resistance, and tumor formation.

The Cantley team figured out that the PIP4K2C gene manipulated the mTORC1 signaling pathway, and that mTORC1 became highly activated when the gene was absent.

This could be a welcome, short-term solution for those in need of an immune boost, such as cancer patients. Adding PIP4K2C inhibitors to the treatment regimen of some patients could enhance the effectiveness of immunotherapy, Shim said.

Long-term hyperactive immune activity and prolonged inflammation are not as welcome for those with a permanent loss of PIP4K2C function, however. But the new findings may provide them with new hope too.

The Cantley team found that the immunosuppressive drug rapamycin, which is currently used clinically to prevent transplant rejection, successfully decreased the chronic inflammation response in the PIP4K2C deficient mice.

“Further study is needed to elucidate more of the mechanisms behind this hyperactivation, but this indicates that drugs that target mTORC1 signaling, such as rapamycin, are likely to be effective for patients with familial autoimmunity that correlates with a nucleotide variation near the PIP4K2C locus,” Shim said.