title: HMG-CoA reductase inhibitors induce apoptosis of lymphoma cells by promoting ROS generation and regulating Akt, Erk and p38 signals via suppression of mevalonate pathway.
abstract: Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are widely used cholesterol-lowering drugs. Convincing evidence indicates that statins stimulate apoptotic cell death in several types of proliferating tumor cells in a cholesterol-lowering-independent manner. The objective here was to elucidate the molecular mechanism by which statins induce lymphoma cells death. Statins (atorvastatin, fluvastatin and simvastatin) treatment enhanced the DNA fragmentation and the activation of proapoptotic members such as caspase-3, PARP and Bax, but suppressed the activation of anti-apoptotic molecule Bcl-2 in lymphoma cells including A20 and EL4 cells, which was accompanied by inhibition of cell survival. Both increase in levels of reactive oxygen species (ROS) and activation of p38 MAPK and decrease in mitochondrial membrane potential and activation of Akt and Erk pathways were observed in statin-treated lymphoma cells. Statin-induced cytotoxic effects, DNA fragmentation and changes of activation of caspase-3, Akt, Erk and p38 were blocked by antioxidant (N-acetylcysteine) and metabolic products of the HMG-CoA reductase reaction, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These results suggests that HMG-CoA reductase inhibitors induce lymphoma cells apoptosis by increasing intracellular ROS generation and p38 activation and suppressing activation of Akt and Erk pathways, through inhibition of metabolic products of the HMG-CoA reductase reaction including mevalonate, FPP and GGPP.
authors: Key Laboratory for Regenerative Medicine of Ministry of Education, and Department of Developmental and Regenerative Biology, Ji Nan University School of Life Science and Technology, Guangzhou, People's Republic of China.
authors: X-F
authors: XF
authors: Qi
authors: L
authors: L
authors: Zheng
authors: K-J
authors: KJ
authors: Lee
authors: D-H
authors: DH
authors: Kim
authors: C-S
authors: CS
authors: Kim
authors: D-Q
authors: DQ
authors: Cai
authors: Z
authors: Z
authors: Wu
authors: J-W
authors: JW
authors: Qin
authors: Y-H
authors: YH
authors: Yu
authors: S-K
authors: SK
authors: Kim
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000633:toxicity; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000633:toxicity; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D007211:Indoles / Q000633:toxicity; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011758:Pyrroles / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000633:toxicity; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D000077340:Fluvastatin; D000069059:Atorvastatin; D019821:Simvastatin; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D008798:Mevalonic Acid; D000111:Acetylcysteine