Hydrophobic statins induce autophagy in cultured human rhabdomyosarcoma cells
Section snippets
Materials and methods
Materials. Simvastatin and pravastatin were purchased from Wako (Tokyo, Japan) and cerivastatin from Sequoia Research Products (Pangbourne, UK). Mevalonolactone was purchased from Tokyo-Kasei (Tokyo, Japan). Expression plasmid of GFP-LC3 (microtubule-associated protein 1 light chain 3, an autophagy marker protein) [10] was a gift from Prof. N. Mizushima (Tokyo Medical and Dental University, Tokyo, Japan).
Cell culture and transfection. Human rhabdomyosarcoma A204 cells were obtained from ATCC
Cerivastatin dose-dependently induces cellular autophagy
To examine the possibility that statins induce autophagy in muscle, we first established a human rhabdomyosarcoma cell line (A204) that constitutively expressed LC3 fused with GFP [10]. The fluorescent GFP-LC3 on autophagosome membranes that had been formed during autophagy was investigated with confocal microscopy to monitor the induction of autophagy. The cells inducing autophagy by starvation by incubating in Hank’s balanced salt solution (HBSS) served as a positive control, and the
Discussion
Microscopic observation and biochemical analysis revealed that hydrophobic cerivastatin and simvastatin but not hydrophilic pravastatin induced autophagy in cultured human rhabdomyosarcoma cells in a dose-dependent manner (Fig. 1). When compared with previous studies in which adverse effects of statins were investigated, the statin concentrations used in this study were low and the incubation period to detect the side effects was short: 0.1–1.0 μM cerivastatin in 12 h in this study vs 100 μM for 24
Acknowledgments
This work was supported in part by Meiyaku Open Research Project and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.
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2015, European Journal of PharmacologyCitation Excerpt :This selective statin-induced autophagy is due to inhibition of cholesterol synthesis and counteracts concomitant cholesterol depletion-dependent apoptotic demise of leukemic cells. Recently, we and others have shown that various statins, including simvastatin, lovastatin, atorvastatin, fluvastatin, pravastatin, cerivastatin, and rosuvastatin induce autophagy in hepatocellular and colorectal carcinoma, glioma, mesothelioma, rhabdomyosarcoma, prostate, thyroid, bladder and ovarian cancer cell lines (Araki et al., 2012; Araki and Motojima, 2008; Asakura et al., 2011; He et al., 2012; Jiang et al., 2014; Kang et al., 2014; Misirkic et al., 2012; Parikh et al., 2010; Robinson et al., 2013; Toepfer et al., 2011; Yang et al., 2010; Zeybek et al., 2011), as well as in normal fibroblasts and smooth muscle cells (Ghavami et al., 2011; Ghavami et al., 2014, 2012; Wei et al., 2013). As statin-induced autophagy has thus far not been studied in leukemic cells, we screened a panel of human cell lines, primary tumor samples, and normal human leukocytes to determine their sensitivity to statin treatment.