Decreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia
Yasushi Kojima, Emi Mishiro‐Sato, Teruaki Fujishita, Kiyotoshi Satoh, Rie Kajino‐Sakamoto, Isao Oze, Kazuki Nozawa, Yukiya Narita, Takatsugu Ogata, Keitaro Matsuo, Kei Muro, Makoto M. Taketo, Tomoyoshi Soga, Masahiro Aoki
Abstract
Cancer cachexia is a complex metabolic disorder accounting for ~20% of cancer-related deaths, yet its metabolic landscape remains unexplored. Here, we report a decrease in B vitamin-related liver enzymes as a hallmark of systemic metabolic changes occurring in cancer cachexia. Metabolomics of multiple mouse models highlights cachexia-associated reductions of niacin, vitamin B6, and a glycine-related subset of one-carbon (C1) metabolites in the liver. Integration of proteomics and metabolomics reveals that liver enzymes related to niacin, vitamin B6, and glycine-related C1 enzymes dependent on B vitamins decrease linearly with their associated metabolites, likely reflecting stoichiometric cofactor-enzyme interactions. The decrease of B vitamin-related enzymes is also found to depend on protein abundance and cofactor subtype. These metabolic/proteomic changes and decreased protein malonylation, another cachexia feature identified by protein post-translational modification analysis, are reflected in blood samples from mouse models and gastric cancer patients with cachexia, underscoring the clinical relevance of our findings.