Y.T., SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress of tumor cells
Description
Glutaminase regulates glutaminolysis for cancer cell proliferation. However, the mechanism underlying glutaminase activity regulation is largely unknown. Here we demonstrated that the kidney-type glutaminase (GLS) is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens with correspondingly upregulated glutamine dependence for PDAC cell proliferation. In addition to regulation at its expression level, GLS K311 is succinylated by succinyl-CoA in a succinyl-CoA concentration-dependent manner, leading to enhanced GLS oligomerization and activity. Upon oxidative stress, succinyl-CoA synthetase ADP-forming subunit (SUCLA2) phosphorylated by p38 MAP kinase at S79 dissociates from GLS, resulting in enhanced GLS K311 succinylation. Activated GLS increases glutaminolysis and production of NADPH and glutathione, thereby counteracting oxidative stress-increased reactive oxygen species and apoptosis and promoting tumor cell proliferation and tumor growth in mice. In addition, the levels of SUCLA2 pS79 and GLS K311 succinylation, which were mutaully correlated, were markedly higher in the PDAC specimens than those in the adjacent normal tissue samples and positively correlated with the advanced stages of PDAC and inversely correlated with overall survival durations of the patients. Our findings uncover a critical regulation of GLS activity by SUCLA2-coupled GLS succinylation regulation and underscore the regulatory role of metabolites in glutaminolysis and PDAC development.