Abstract
BackgroundPancreatic cancer is recognized as one of the most fatal tumors due to its aggressiveness and resistance to therapy. Statins were previously shown to inhibit the proliferation of cancer cells via various signaling pathways. In healthy tissues, statins activate the heme oxygenase pathway, nevertheless the role of heme oxygenase in pancreatic cancer is still controversial. The aim of this study was to evaluate, whether anti-proliferative effects of statins in pancreatic cancer cells are mediated via the heme oxygenase pathway.MethodsIn vitro effects of various statins and hemin, a heme oxygenase inducer, on cell proliferation were evaluated in PA-TU-8902, MiaPaCa-2 and BxPC-3 human pancreatic cancer cell lines. The effect of statins on heme oxygenase activity was assessed and heme oxygenase-silenced cells were used for pancreatic cancer cell proliferation studies. Cell death rate and reactive oxygen species production were measured in PA-TU-8902 cells, followed by evaluation of the effect of cerivastatin on GFP-K-Ras trafficking and expression of markers of invasiveness, osteopontin (SPP1) and SOX2.ResultsWhile simvastatin and cerivastatin displayed major anti-proliferative properties in all cell lines tested, pravastatin did not affect the cell growth at all. Strong anti-proliferative effect was observed also for hemin. Co-treatment of cerivastatin and hemin increased anti-proliferative potential of these agents, via increased production of reactive oxygen species and cell death compared to individual treatment. Heme oxygenase silencing did not prevent pancreatic cancer cells from the tumor-suppressive effect of cerivastatin or hemin. Cerivastatin, but not pravastatin, protected Ras protein from trafficking to the cell membrane and significantly reduced expressions of SPP1 (p < 0.05) and SOX2 (p < 0.01).ConclusionsAnti-proliferative effects of statins and hemin on human pancreatic cancer cell lines do not seem to be related to the heme oxygenase pathway. While hemin triggers reactive oxygen species-induced cell death, cerivastatin targets Ras protein trafficking and affects markers of invasiveness.
Highlights
Pancreatic cancer is recognized as one of the most fatal tumors due to its aggressiveness and resistance to therapy
We previously reported that most statins protect green fluorescent protein (GFP)-K-Ras from its anchoring to the cell membrane, affecting the signaling pathways and leading to suppression of cancer cell growth in pancreatic cancer cells in vitro [4]
Bovine serum albumin (BSA), hemin, reduced nicotinamide adenine dinucleotide (NADPH), sulfosalicylic acid, Dulbecco’s Modified Essential Media (DMEM), and RPMI-1640 were purchased from Sigma-Aldrich
Summary
Pancreatic cancer is recognized as one of the most fatal tumors due to its aggressiveness and resistance to therapy. Competitive inhibitors of 3-hydroxyl-methylglutaryl coenzyme A (HMG CoA) reductase, are widely used for treatment of hypercholesterolemia Their therapeutic role surpasses the cholesterol lowering capacity, utilizing anti-inflammatory, anti-oxidant and anti-thrombotic actions [1]. Several studies suggested the antiproliferative role of statins in various cancer cell lines, including lung [2], colorectal [3] and pancreatic cancer [4,5,6,7]. These effects could be partly mediated by the depletion of several important intermediates of cholesterol biosynthesis involved in posttranslational protein prenylation. This process is especially important for modification of small GTPases, such as Ras [8, 9], which is essential for their
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