Abstract A29: Targeting adenylate kinase-4 modulation of HIF-1α: Stability identifies Withaferin-A suppresses lung cancer metastasis

Abstract

Abstract Aberrant activation of hypoxia inducible factor (HIF-1α) often plays a crucial role in promoting metabolic reprogramming and metastatic dissemination. Here we report functional evidences of adenylate kinase 4 (AK4), one of the hypoxia-responsive genes, in enhancing HIF-1α; transcriptional activity to drive epithelial-to-mesenchymal transition (EMT). By analyzing lung adenocarcinoma microarray datasets, we identified AK4-associated metabolic gene signature and revealed HIF-1α; was transcriptionally activated and associated with poor prognosis. Immunohistochemistry analysis confirms the positive correlation between AK4 and HIF-1α; in non-small cell lung (NSCLC) cancer patients. Overexpression of AK4 induces metabolic shift towards aerobic glycolysis and increases intracellular reactive oxygen species (ROS), which exaggerates HIF-1a; protein expression under hypoxia and concurrently induces EMT in a HIF-1α-dependent manner. Furthermore, overexpression of AK4 reduces hypoxic necrosis in tumors and promotes liver metastasis in vivo. Connectivity map analysis of AK4 gene signature identifies Withaferin-A as a potential inhibitor to inverse AK4 signature and proven to be a potent anti-metastatic agent in orthotopic xenograft model of lung cancer. Our findings offer an alternative strategy to treat metastatic lung cancer via targeting AK4-HIF-1α axis.α Citation Format: Michael Hsiao. Targeting adenylate kinase-4 modulation of HIF-1α: Stability identifies Withaferin-A suppresses lung cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A29.