Pharmacological Activation of Hypoxia-Inducible Factor Decreases Proliferation and Migration of Human Non-small Cell Lung Cancer Cell Line (A549)

The cellular transcriptional response to hypoxia is regulated by hypoxia-inducible factor (HIF). In lung cancer, elevated levels of HIF expression are linked to poor prognosis and aggressive disease. Inhibitors of the HIF prolyl hydroxylases (PHDs) induce a hypoxic response by upregulating HIF and are currently used to treat anemia associated with chronic kidney disease by stimulating erythropoietin production. However, it is unclear whether high HIF levels induced by these PHD inhibitors (PHIs) could promote cancer progression. Here, the effects of pharmacological HIF upregulation on the proliferation and migration of human nonsmall cell lung carcinoma cell line (A549) were investigated. HIF was upregulated using dimethyloxalylglycine (DMOG), IOX2 (a validated chemical probe for the PHDs), and two clinically approved PHIs (Daprodustat and Roxadustat). All the tested PHIs, except IOX2 decreased A549 proliferation in a dose-dependent manner. DMOG, Daprodustat, and IOX2 reduced A549 migration, whereas Roxadustat increased migration only at the highest concentration tested. The changes in the expression of E-cadherin (an epithelial marker) as an indicator of epithelial-to-mesenchymal transition are largely consistent with the observed effects on cell migration. Overall, these findings suggest that pharmacological activation of HIF does not promote nonsmall cell lung cancer progression.