Lovastatin lactone elicits human lung cancer cell apoptosis via a COX-2/PPARγ-dependent pathway
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Udo Walther1,*, Kristin Emmrich1,*, Robert Ramer1, Nadine Mittag1 and Burkhard Hinz1
1 Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany
* These authors have contributed equally to this work
Burkhard Hinz, email:
Keywords: lovastatin lactone, cyclooxygenase-2, peroxisome proliferator-activated receptor γ, apoptosis, human lung cancer cells
Received: July 18, 2015 Accepted: January 01, 2016 Published: February 05, 2016
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.
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