title: Differentiation and apoptosis induction by lovastatin and γ-tocotrienol in HL-60 cells via Ras/ERK/NF-κB and Ras/Akt/NF-κB signaling dependent down-regulation of glyoxalase 1 and HMG-CoA reductase.
abstract: Glyoxalase 1 (GLO1) and HMG-CoA reductase (HMGCR) are highly expressed in most tumor cells and little in normal cells. In this study, treatment of HL-60 cells with lovastatin induced characteristic apoptosis in a dose-dependent manner. We demonstrated that lovastatin treatment inhibited Ras and Raf protein translocation to cell membrane and eliminated the phosphorylation of the downstream effectors Akt and ERK, and the subsequent NF-κB translocation into nucleus. Specific inhibitors and γ-tocotrienol confirmed the Ras/Raf/ERK/NF-κB/GLO1 and Ras/Akt/NF-κB/GLO1 pathways. Data revealed that lovastatin induced HL-60 cell death was attenuated by mevalonate treatment. We demonstrated also that γ-tocotrienol showed its apoptotic effect on the HL-60 cell through the same pathway. γ-Tocotrienol enhanced the apoptotic effect of lovastatin through the down-regulation of GLO1 and HMGCR resulting in an increase of methylglyoxal and a decrease of cholesterol and led to the apoptosis of HL-60 cells. Data also revealed that both lovastatin and gamma-tocotrienol induced significant HL-60 cell differentiation. These results suggest that both lovastatin and gamma-tocotrienol could induce differentiation and followed by apoptosis.
authors.affiliation: Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan. Electronic address: tkc720901@gmail.com.
authors.forename: Chun-Chia
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan. Electronic address: yubaby118@hotmail.com.
authors.forename: Tzu-Yu
authors.initials: TY
authors.lastname: Liu
authors.affiliation: Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan. Electronic address: wenily0617@gmail.com.
authors.forename: Shih-Pin
authors.initials: SP
authors.lastname: Huang
authors.affiliation: Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA. Electronic address: ho@aesop.rutgers.edu.
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.affiliation: Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan. Electronic address: tchuang@mail.npust.edu.tw.
authors.forename: Tzou-Chi
authors.initials: TC
authors.lastname: Huang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007791:Lactoylglutathione Lyase / Q000096:biosynthesis*; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D048490:raf Kinases / Q000378:metabolism
chemical_list: D002839:Chromans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D014810:Vitamin E; C013649:plastochromanol 8; D011765:Pyruvaldehyde; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); C000597196:GLO1 protein, human; D007791:Lactoylglutathione Lyase; D008798:Mevalonic Acid
keywords: Apoptosis; Differentiation; Glyoxalase 1; HMG-CoA reductase; Leukemia; Lovastatin; γ-Tocotrienol