Modulation of gold(III) porphyrin 1a-induced apoptosis by mitogen-activated protein kinase signaling pathways.
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 (DeltaPsi(m)) 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 p38(MAPK) were transiently activated upon gold(III) porphyrin 1a treatment. Inhibition of p38(MAPK) phosphorylation rescued gold(III) porphyrin 1a-induced cell death upstream of caspase activation. Attenuation of DeltaPsi(m) was the primary effect of gold(III) porphyrin 1a leading to p38(MAPK) phosphorylation. Further functional proteomic study suggested that differential regulation of phosphotyrosine proteins were related to p38(MAPK) activation in gold(III) porphyrin 1a-induced signal transduction cascade. In summary, p38(MAPK) 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.
Wang
Ying
Y
Department of Chemistry and Open Laboratory of Chemical Biology, The University of Hong Kong, Hong Kong SAR, China.
He
Qing-Yu
QY
Che
Chi-Ming
CM
Tsao
Sai Wah
SW
Sun
Raymond Wai-Yin
RW
Chiu
Jen-Fu
JF
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008665:Metalloporphyrins / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; C508665:gold (III) porphyrin 1a; D019000:Phosphotyrosine; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9