Because proprotein convertases (PCSKs) activate growth factors and matrix metalloproteinase, these enzymes have been implicated in non-small cell lung cancer tumor progression and aggressiveness. Previous studies indicate that one PCSK member, FURIN is overexpressed in NSCLC, but little is known regarding the mechanisms driving PCSKs expression during malignant change. We sought to determine whether prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (PTGS2) (aka COX2), whose expression is also frequently increased in NSCLC, differentially regulates PCSK expression and activity between normal (NHBE) and NSCLC epithelial cells (NCI-H292, NCI-H441, A549). NSCLC cells exhibit significantly greater cell-associated and secreted PCSK activity as compared with NHBE. The heightened activity is consistent with increased FURIN, PCSK4, and PCSK6 protein in the NCSLC cells. Inhibition of PTGS2 activity using NS-398 and siRNA decreased FURIN mRNA, protein, activity along with cell proliferation in NCI-H292 cells but not NHBE cells. NSCLC also expressed elevated levels of the transcription factor E2F1. When NCI-H292 cells were transfected with E2F1 siRNA, both PTGS2 expression and PCSK activity were attenuated, arguing a pivotal role for E2F1 in the differential regulation of PCSKs by PTGS2. Our results highlight a novel role for PTGS2 in NSCLC and may provide a mechanism, whereby PTGS2 inhibitors suppress lung cancer cell growth. © 2012 Wiley Periodicals, Inc.