Exploring the Role of Acetyl CoA Acetyltransferase 1 (ACAT1) in ROS Homeostasis in Lung Cancer

Abstract

Acetyl-CoA acetyltransferase 1 (ACAT1), also known as acetoacetyl-CoA thiolase is an enzyme that catalyzes the condensation reaction of two acetyl-CoA to produce acetoacetyl-CoA and CoA as well as its reverse reaction. Recent studies revealed that ACAT1 can inhibit pyruvate dehydrogenase complex (PDC) by acetylating K202 residue of PDHA as well as K321 residue of PDP1. ACAT1 is also known as a potential biomarker in advanced prostate cancer because its expression and activity are elevated as cancer progresses. However, the mechanism of ACAT1 is not fully understood in cancer progression and metastasis. To this end, I generated a cell-based loss of function model to investigate the mechanism by knocking down ACAT1 in lung cancer cell lines using the lentiviral shRNA system. First, I confirmed the generation of ACAT1 knock-down cell lines by Western blot analysis. By using the XFp extracellular flux analyzer, I observed upregulated glycolysis and mitochondrial respiration that might induce ROS production in lung cancer cells. Moreover, elevated ROS was measured by DCFDA staining as well as the elevated protein expressions of both superoxide dismutase 2 (SOD2) and catalase in the ACAT1 KD cells. Lastly, attenuated cell proliferation and slightly increased apoptosis and necrosis were observed which might be caused by the increased ROS production in the ACAT1 KD cells. Taken together, these findings suggest that the function of ACAT1 has critical roles in maintaining cellular ROS homeostasis in lung cancer which may suggest possible new therapeutic targets for cancer treatment.