Abstract
Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are well-established agents to treat hyperlipidemic states. Experimental and epidemiological evidence further implies an anticancer effect of these substances. This study investigates the mechanism underlying human lung cancer cell death by lovastatin and the role of the prostaglandin (PG)-synthesizing enzyme cyclooxygenase-2 (COX-2) in this process. In A549 and H358 lung carcinoma cells the lipophilic prodrug lovastatin lactone led to a concentration-dependent decrease of viability and induction of DNA fragmentation, whereas its HMG-CoA-inhibitory, ring-open acid form was inactive in this respect. Apoptotic cell death by lovastatin was accompanied by high intracellular levels of the lactone form, by upregulation of COX-2 mRNA and protein, as well as by increased formation of peroxisome proliferator-activated receptor γ (PPARγ)-activating PGD2 and 15-deoxy-Δ12,14-PGJ2. Cells were significantly less sensitive to lovastatin-induced apoptotic cell death, when the expression or activity of COX-2 was suppressed by siRNA or by the COX-2 inhibitor NS-398. Apoptosis by lovastatin was likewise reversed by the PPARγ antagonist GW9662. Fluorescence microscopy analyses revealed a lovastatin-induced cytosol-to-nucleus translocation of PPARγ that was inhibited by NS-398. Collectively, this study demonstrates COX-2 induction and subsequent COX-2-dependent activation of PPARγ as a hitherto unknown mechanism by which lovastatin lactone induces human lung cancer cell death.
Highlights
Belonging to the most commonly prescribed drugs worldwide, statins are therapeutically used to treat primary and secondary hypercholesterolemia
The present study demonstrates induction of COX-2 expression and subsequent activation of peroxisome proliferatoractivated receptor γ (PPARγ) by COX2-derived PGs as key events within the proapoptotic action of lovastatin lactone on human lung cancer cells
Lovastatin lactone caused a profound upregulation of COX-2 mRNA and protein expression in the lung cancer cell lines A549 and H358
Summary
Belonging to the most commonly prescribed drugs worldwide, statins are therapeutically used to treat primary and secondary hypercholesterolemia. Statins are administered in its active ring-open hydroxy-acid form (e.g., pravastatin, atorvastatin) or as inactive lactone prodrugs (lovastatin, simvastatin) with the latter group of drugs becoming metabolized to a ring-open hydroxy-acid form that inhibits HMG-CoA reductase activity (for review see [1]). Besides their use as cholesterol-lowering agents, statins are currently considered and evaluated as potential drugs for cancer therapy [2]. Several epidemiological studies have proven an association between statin use and diminished cancer incidence [3,4,5] as well as mortality [6]. In vitro experiments with cancer cells revealed statins to exhibit pronounced antiproliferative [8, 9], proapoptotic [10, 11], anti-invasive [12,13,14] and antiangiogenic effects [15,16,17]
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