A Metabolic Switch Blocks the Fuel of Cancer Cells
An international study conducted by the “A. Rossi Fanelli” Department of Biochemical Sciences, in collaboration with the “Charles Darwin” Department of Biology and Biotechnology, the CNR Institute for Molecular Biology and Pathology, the Barcelona Centre for Genomic Regulation and the Catalan Oncology Institute in Girona, has shed new light on the role of the enzyme Serine hydroxymethyl transferase (SHMT) in promoting the high proliferative ability of cancer cells.
The results of the research project, which was funded by the Italian Association for Cancer Research (AIRC), have been published in Nucleic Acids Research.
In order to understanding the mechanisms underlying the propagation of cancer cells, especially in particularly aggressive tumours such as lung cancer, it is fundamental to comprehend how cancer cells reprogram their metabolism to satisfy their elevated energy needs. The researchers observed that a specific RNA can bind to the SHMT metabolic enzyme in the cytoplasm of cells, controlling its enzymatic functions and also regulating the expression of the enzyme's form present in the mitochondrion, the cell’s energy plant.
“We have observed that the metabolic enzymes involved in the metabolism of folates can conduct unorthodox functions in cancer cells, such as binding RNA and modulating other proteins,” explains Francesca Cutruzzolà, Project Coordinator. “And we have revealed that this RNA binding activity specifically addresses cellular metabolism, allowing the optimal exploitation of the nutrients required by cancer cells.”
“We were surprised to discover that the enzyme-RNA interaction,” explains Sapienza Researcher Giulia Guiducci, “could also act as a selective modulator of enzymatic activity, promoting the synthesis of serine rather than glycine, an observation that may lead to new approaches to a cure.”
The research team is already working to understand how to design specific nucleic acid molecules that can operate as metabolic switches, blocking the production of the fuel necessary to cancer cells and interrupting their proliferation. This discovery opens up new, completely innovative therapeutic routes in the field of chemotherapy to modulate cellular metabolism, a critical factor in tumour aggressiveness.
The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism – Guiducci, G., Paone, A., Tramonti, A., Giardina, G., Rinaldo, S., Bouzidi, A., Magnifico, M.C., Marani, M., Menendez, J.A., Fatica, A., Macone, A., Armaos, A., Tartaglia, G.G., Contestabile, R., Paiardini, A., Cutruzzolà, F. - Nucleic Acids Research 2019 DOI: 10.1093/nar/gkz129.
Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome