Statin drugs, such as lovastatin and simvastatin, block cholesterol synthesis by inhibiting the function of HMG-CoA reductase in the cellular cholesterol biosynthesis pathway. In a recent large case-control study, statins reduced the risk of lung cancer suggesting the utility of statins for lung cancer chemoprevention. In our studies, while both lovastatin and simvastatin dose-dependently decreased proliferation in both histologically normal and K-ras mutated human bronchial epithelial cells (HBECs), it also unexpectedly increased expression of PGE2 in mutated HBECs. The statin-mediated upregulation of PGE2 is most pronounced in K-ras mutated HBECs compared to P53 deleted or EGFR mutated HBECs. Treatment with the cholesterol precursor, mevalonic acid, inhibited statin mediated up-regulation of PGE2 indicating that the effect of the statins on PGE2 is sterol-dependent. We found that the suppression of proliferation by statins is also sterol dependent. Statins up-regulate the production of PGE2 by up-regulating mRNA and protein expression of COX-2. The addition of the MEK inhibitor (U0126) revealed the potential involvement of the ERK pathway for statin-mediated upregulation of PGE2 in HBECs. The combination of statins and a low dose of celecoxib (0.1 micro molar), a COX-2 inhibitor, suppressed the increased production of PGE2 by K-ras mutated HBECs. Studies are underway to determine the effect of statin-mediated upregulation of PGE2 on apoptosis resistance and invasion in K-ras mutated HBECs. Our studies suggest that the combination of statins with a low dose of celecoxib overcomes the upregulation of PGE2 induced by statins alone. Thus the combination represents a potentially effective lung cancer chemopreventative regimen worthy of further investigation.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):B57.