title: Quantitative proteomic analysis revealed lovastatin-induced perturbation of cellular pathways in HL-60 cells.
abstract: Lovastatin, a member of the statin family of drugs, is widely prescribed for treating hypercholesterolemia. The statin family of drugs, however, also shows promise for cancer treatment and prevention. Although lovastatin is known to be an inhibitor for HMG-CoA reductase, the precise mechanisms underlying the drug's antiproliferative activity remain unclearly defined. Here we utilized mass spectrometry, in conjunction with stable isotope labeling by amino acids in cell culture (SILAC), to analyze the perturbation of protein expression in HL-60 cells treated with lovastatin. We were able to quantify ∼3200 proteins with both forward and reverse SILAC labeling experiments, among which ∼120 exhibited significant alterations in expression levels upon lovastatin treatment. Apart from confirming the expected inhibition of the cholesterol biosynthesis pathway, our quantitative proteomic results revealed that lovastatin perturbed the estrogen receptor signaling pathway, which was manifested by the diminished expression of estrogen receptor α, steroid receptor RNA activator 1, and other related proteins. Lovastatin also altered glutamate metabolism through down-regulation of glutamine synthetase and γ-glutamylcysteine synthetase. Moreover, lovastatin treatment led to a marked down-regulation of carbonate dehydratase II (a.k.a. carbonic anhydrase II) and perturbed the protein ubiquitination pathway. Together, the results from the present study underscored several new cellular pathways perturbed by lovastatin.
authors.affiliation: Department of Chemistry, University of California, Riverside, California 92521-0403, United States.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Dong
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Xiao
authors.forename: Xinning
authors.initials: X
authors.lastname: Jiang
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D002256:Carbonic Anhydrases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism; D002853:Chromatography, Liquid; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism; D007553:Isotope Labeling / Q000379:methods; D008148:Lovastatin / Q000494:pharmacology*; D013058:Mass Spectrometry; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D020543:Proteome / Q000032:analysis* / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D012717:Sesquiterpenes / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D011106:Polyisoprenyl Phosphates; D020543:Proteome; D012717:Sesquiterpenes; C548898:steroid receptor RNA activator, human; C004808:farnesyl pyrophosphate; D002784:Cholesterol; D008148:Lovastatin; D006904:Hydroxymethylglutaryl-CoA Synthase; D002256:Carbonic Anhydrases; D005974:Glutamate-Ammonia Ligase; D005721:Glutamate-Cysteine Ligase