Abstract 1129: Adenylate kinase 4 promotes metabolic reprogramming and induces EMT in lung cancer through ROS-dependent stabilization of HIF1-α

Abstract

Abstract The metabolic alterations that are essential for cancer progression remain largely unknown. Previously, we have identified adenylate kinase 4 (AK4) as a marker for poor clinical outcome that promotes metastasis of lung cancer. However, the molecular mechanism of AK4-induced phenotype remains elusive. By microarray analysis, we found downstream targets of HIF1-α were differentially regulated upon AK4 overexpression in CL1-0 lung cancer cells. Furthermore, AK4 overexpression induces glycolysis and results in accelerated glucose consumption, ATP utilization and lactate production. Overexpression of AK4 also increases the levels of reactive oxygen species (ROS), which exaggerates HIF1-α protein expression under hypoxia and concurrently induces epithelial-to-mesenchymal transition (EMT) in a HIF1-α-dependent manner. IHC analysis showed an inverse correlation between AK4 and E-cadherin and a positive correlation between AK4 and nuclear HIF1-α in lung cancer patients. Moreover, patients with AK4 high/E-Cadherin low showed worse outcome compared to patients with AK4 low/E-cadherin high. Our study indicates that enhanced expression of AK4 is a critical factor to trigger aerobic glycolysis and induced HIF1-α-mediated EMT in lung cancer. Citation Format: Yi-Hua Jan, Michael Hsiao. Adenylate kinase 4 promotes metabolic reprogramming and induces EMT in lung cancer through ROS-dependent stabilization of HIF1-α. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1129. doi:10.1158/1538-7445.AM2014-1129