Sasaki says researchers saw an elevated level of inosine monophosphate dehydrogenase (IMPDH) in cancer cells, which accelerates GTP production and in turn fuels nucleolus growth. This is a major step toward solving the mystery surrounding nucleolus growth in cancer cells, he says.
To conduct the research, the multidisciplinary team zeroed in on the energy production pathways in malignant brain tumors and glioblastoma, the deadliest type of brain cancer, in animal models, followed by cohort studies for human specimens. The results showed a significant increase of GTP, which is a form of energy, in glioblastoma. Experts took a deeper look at brain tumor cells and determined that the significantly elevated level of IMPDH in cancer cells accelerates GTP production.
The close relationship between IMPDH and the nucleolus was discovered and prompted Sasaki’s team to develop a new method of metabolic analysis, which enabled researchers to obtain critical data for demonstrating that GTP produced from IMPDH activities is used for the nucleolus’s ribosome synthesis; this led to the discovery of a clear correlation between the suppression of glioblastoma cell growth and IMPDH inhibition, which prolonged animal models’ lives.
“Thanks to our multinational cross-disciplinary collaboration and the team’s hard work, we were able to unlock the mechanism through which cancerous cells hijack GTP metabolism to take control over the nucleoli. We are excited to continue our research on GTP for the development of therapies to annihilate the ‘eye of cancer’ in patients,” Sasaki says.
Co-collaborators on the study include Tomoyoshi Soga, PhD, Hideyuki Saya, MD, PhD, and Makoto Suematsu, MD, PhD, all of Keio University; Ralph DeBerardinis, MD, PhD, and Robert Bachoo, MD, PhD, both of UT Southwestern; Wataru Yasui, MD, PhD, Hiroshima University; Ichiro Nakano, MD, PhD, University of Alabama; Hiroaki Wakimoto, MD, PhD, Harvard Medical School; William Young, PhD, UCLA; Craig Horbinski, MD, PhD, Northwestern University; Risa Kawaguchi, PhD, National Institute of Advanced Industrial Science and Technology of Japan; and Ingrid Grummt, PhD, and Holger Bierhoff, PhD, of the German Cancer Research Center.
The work is supported in-part by a UC College of Medicine Research Innovation grant, Molecular Therapeutics Program UC Brain Tumor Center grant, Mayfield Education and Research Foundation grant, Marlene Harris Ride Cincinnati grant, American Brain Tumor Association Discovery Grant, B*Cured research grant, Ohio Cancer Research grant and National Institutes of Health grants R21NS100077 and R01NS089815 (ATS).
*Featured photo: Colleen Kelley / UC Creative Services