Scientists in Montreal discover a new enzymatic complex that can stop cells from aging, opening the way to possible new cancer therapies.
Researchers at Université de Montréal and McGill University have discovered a new multi-enzyme complex that reprograms metabolism and overcomes “cellular senescence,” when aging cells stop dividing.
In their study published on September 16, 2021, in Molecular Cell, the researchers show that an enzyme complex named HTC (hydride transfer complex) can inhibit cells from aging.
“HTC protects cells from hypoxia, a lack of oxygen that normally leads to their death,” said senior author Gerardo Ferbeyre, an UdeM biochemistry professor and principal scientist at the CRCHUM, the university’s affiliated teaching hospital research center.
“Importantly, HTC can be hijacked by certain cancer cells to improve their metabolism, resist to a hypoxic environment and proliferate,” said Ferbeyre, who made the discovery with Sebastian Igelmann, a PhD student in his lab and first author of the study.
HTC is made up of three enzymes: pyruvate carboxylase, malate dehydrogenase 1, and malic enzyme 1. They were all highly expressed in samples from a prostate cancer mouse model generated at the University of Veterinary Medicine Vienna, in Austria, and in tissue samples from prostate cancer patients.
“Most interestingly, inhibition of these enzymes stopped the growth of prostate cancer cells, suggesting that HTC could be a key target to develop new therapeutics for a variety of cancers, including prostate cancer,” said Ferbeyre.
Most key metabolic cycles were identified more than 50 years ago, but HTC remained hidden to researchers. “We found it by performing state-of-the art metabolomic analysis, the study of chemical processes of cell metabolism,” said co-author Ivan Topisirovic, a McGill researcher and medical professor.
The scientists were able to assemble the enzyme complex from purified proteins and obtain biophysical data about its composition. Their next step will be to generate a detailed high-resolution structure of the enzyme complex in order to design drugs able to modulate its functions.
Reference: “A hydride transfer complex reprograms NAD metabolism and bypasses senescence” by Sebastian Igelmann, Frédéric Lessard, Oro Uchenunu, Jacob Bouchard, Ana Fernandez-Ruiz, Marie-Camille Rowell, Stéphane Lopes-Paciencia, David Papadopoli, Aurélien Fouillen, Katia Julissa Ponce, Geneviève Huot, Lian Mignacca, Mehdi Benfdil, Paloma Kalegari, Haytham M. Wahba, Jan Pencik, Nhung Vuong, Jordan Quenneville, Jordan Guillon, Véronique Bourdeau, Laura Hulea, Etienne Gagnon, Lukas Kenner, Richard Moriggl, Antonio Nanci, Michael N. Pollak, James G. Omichinski, Ivan Topisirovic and Gerardo Ferbeyre, 16 September 2021, Molecular Cell.