Other HIF-independent pathways that enhance resistance to chemotherapeutic agents by suppressing apoptotic signals under hypoxia have also been reported in A549 lung adenocarcinoma cells, including the cyclooxygenase-2 (COX-2)–prostaglandin E2 (PGE2) pathway and the Sphingosine Kinase 2 (SphK2)–Sphingosine-1-Phosphate (S1P)–MAPK pathway [145,146]. This evidence concerns the gene SPHK2 and lung adenocarcinoma.