Scientists Develop Fluorescent Sensors That May Pave Way for New Cancer Therapies
BUFFALO, N.Y. — For several decades, scientists have recognized the key role that a molecule known as GTP, one of the building blocks of RNA, plays in the development of cancer and other diseases. But they had no way to monitor this important nucleotide in live cells, and thus to understand — and disrupt — its contribution to tumor growth and aggressiveness. New research led by a team from Roswell Park Comprehensive Cancer Center and published in the journal Nature Methods reports the development of genetically encoded GTP sensors that can rapidly detect changes in GTP levels in living cells. It’s a finding, the authors say, that could enable the development of new approaches for treating a wide variety of solid-tumor cancers, and perhaps other diseases as well.
These unique sensors — which the team refers to as GEVALs, or GTP evaluators — rely on fluorescent protein technology.
“GTP plays an essential role in multiple cellular processes, including protein synthesis, cytoskeleton maintenance and function, nuclear and intracellular transport and intracellular signaling,” notes the paper’s first author, Anna Bianchi-Smiraglia, PhD, a postdoctoral researcher with the Department of Cell Stress Biology at Roswell Park. “By inserting a yellow fluorescent protein into a particular bacterial protein and monitoring the comparative change in fluorescence that results when GTP binds to our sensors, we are able to detect and track changes in GTP levels.”
These GEVAL sensors are the first tool for GTP measurement that can be performed in live cells, and the first to reveal the spatio-temporal dynamics driving changes in GTP levels and activity.
“Our sensors represent a new and unique tool for assessing changes in GTP levels in cell populations and individual cells, which may in turn point the way to effective strategies for suppressing or even preventing tumor growth,” says Mikhail Nikiforov, PhD, Professor of Oncology in the Department of Cell Stress Biology at Roswell Park and the paper’s senior author. “This is an early finding that will have to be further developed through additional research, but it suggests opportunities for developing therapies that interfere with GTP metabolism by targeting key enzymes —perhaps existing therapies as well as new drugs yet to be developed.”
The team’s collaborators include scientists from the University of Texas Health Science Center at San Antonio.
This research was supported by grants from the National Cancer Institute (project nos. R21CA151128, R01CA197996, R01CA120244, R01CA193981, R01CA190533, F32CA189622 and F99CA212455), National Institute of General Medical Sciences (project no. R01GM118933), Empire State Development Corp. and Jennifer Linscott Tietgen Family Foundation. The paper, “Internally ratiometric fluorescent sensors for evaluation of intracellular GTP levels and distribution,” is available at nature.com/nmeth.
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