Quantitative proteomic analysis reveals the perturbation of multiple cellular pathways in HL-60 cells induced by...

Arsenic is ubiquitously present in the environment; it is a known human carcinogen and paradoxically it is also a successful drug for the clinical remission of acute promyelocytic leukemia (APL). The cellular responses induced by arsenite treatment have been investigated for years; however, the precise mechanisms underlying its cytotoxicity and therapeutic activity remain unclear. Here we report the use of mass spectrometry together with stable isotope labeling by amino acids in cell culture (SILAC) for the comparative study of protein expression in HL-60 cells that were untreated or treated with a clinically relevant concentration of arsenite. Our results revealed that, among the 1067 proteins quantified in both forward and reverse SILAC measurements, 56 had significantly altered levels of expression induced by arsenite treatment. These included the up-regulation of core histones, neutrophil elastase, alpha-mannosidase as well as the down-regulation of fatty acid synthase and protein phosphatase 1 alpha. We further demonstrated that the arsenite-induced growth inhibition of HL-60 cells could be rescued by treatment with palmitate, the final product of fatty acid synthase, supporting that arsenite exerts its cytotoxic effect, in part, via suppressing the expression of fatty acid synthase and inhibiting the endogenous production of fatty acid. The results from the present study offered important new knowledge for gaining insights into the molecular mechanisms of action of arsenite.