A scientific team led by a University of Cincinnati (UC) cancer researcher has shown that a specific enzyme is responsible for sensing the available supply of guanosine triphosphate (GTP) that can fuel the uncontrolled growth of cancer cells. The research underscores the enzyme's potential to become a therapeutic target for future cancer drugs, according to the investigators.
Atsuo Sasaki, Ph.D., assistant professor in the division of hematology oncology at the UC College of Medicine, Toshiya Senda, Ph.D., professor at the High Energy Accelerator Research Organization in Tsukuba, Japan, and colleagues showed that PI5P4Kβ (phosphatidylinositol-5-phosphate 4-kinase-β) acts like the arrow on a fuel gauge. The enzyme senses and communicates via a second messenger the amount of GTP fuel that is available to a cell at any given time. Until now, the molecular identity of a GTP sensor has remained unknown.
“Energy sensing is vital to the successful proliferation of cancer cells,” says Dr. Sasaki. “A large amount of GTP is required in rapidly dividing cells, and cells need to know that the fuel is available to them. If we can interfere with the ability of PI5P4Kβ to sense fuel availability and communicate that information, we may be able to slow or halt the growth of cancers, including the aggressive brain cancer glioblastoma multiforme and cancers that have metastasized to the brain.”
The study (“The Lipid Kinase PI5P4Kβ Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis”), published in Molecular Cell, is Dr. Sasaki's first to address PI5P4Kβ as a molecular sensor of GTP concentration. Initially, he and his team reportedly faced skepticism regarding the existence of GTP energy-sensing.
GTP is one of two energy molecules used by cells. The other is adenosine triphosphate. ATP handles the bulk of a cell's energy requirements, while GTP is required for protein synthesis and is a signaling molecule that helps direct processes within the cell. When GTP levels are increased and utilized as fuel by cancer cells, its ability to perform its primary goals is compromised.
Dr. Sasaki and his team identified PI5P4Kβ as a GTP sensor by demonstrating, in a laboratory setting its ability to bind to GTP and by showing, at the atomic level by X-ray structural analysis, the molecular mechanism by which it recognizes GTP. They then designed PI5P4Kβ mutant cells that were unable to sense GTP concentration and, as a result, impaired the ability of PI5P4Kβ to promote tumor growth.
His next step is to use both pharmacological and molecular approaches that target PI5P4Kβ in a cell culture and in animal tumor models.
“By unveiling PI5P4Kβ's role as a GTP sensor, we now have a potential new therapeutic target for patients,” explains Dr. Sasaki. “If we can find drugs that stop PI5P4Kβ from acting as the fuel indicator, we could get these aggressive and tragic cancers into energy-depleted status.”