Quantitative Proteomic Analysis Revealed Lovastatin-induced Perturbation of Cellular Pathways in HL-60 Cells

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 similar to 3200 proteins with both forward and reverse SILAC labeling experiments, among which similar to 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 alpha, steroid receptor RNA activator 1, and other related proteins. Lovastatin also altered glutamate metabolism through down-regulation of glutamine synthetase and gamma-glutamylcysteine synthetase. Moreover, lovastatin treatment led to a marked down-regulation of carbonate dehydratase H (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.