Modulation of gold(III) porphyrin 1a-induced apoptosis by mitogen-activated protein kinase signaling pathways

Abstract

Gold(III) porphyrin 1a is a novel gold(III) complex with selective anticancer effect in a number of human carcinoma cell lines. We have previously shown that gold(III) porphyrin 1a mediated mitochondrial transmembrane potential (ΔΨm) depletion, leading to cytochrome c release, nucleus translocation of apoptosis-inducing factor (AIF), and generation of reactive oxygen species (ROS). The current study addressed gold(III) porphyrin 1a-induced phosphoproteome alterations and modulation of cell death by the mitogen-activated protein kinase (MAPK) family proteins. ERK and p38MAPK were transiently activated upon gold(III) porphyrin 1a treatment. Inhibition of p38MAPK phosphorylation rescued gold(III) porphyrin 1a-induced cell death upstream of caspase activation. Attenuation of ΔΨm was the primary effect of gold(III) porphyrin 1a leading to p38MAPK phosphorylation. Further functional proteomic study suggested that differential regulation of phosphotyrosine proteins were related to p38MAPK activation in gold(III) porphyrin 1a-induced signal transduction cascade. In summary, p38MAPK modulated gold(III) porphyrin 1a-induced cell death downstream of mitochondria, and phosphorylation of multiple proteins also involved in this process. These results suggested that gold(III) porphyrin 1a is a promising anticancer agent directed toward the mitochondria. © 2007 Elsevier Inc. All rights reserved.