JNK-dependent Stat3 phosphorylation contributes to Akt activation in response to arsenic exposure.
Environmental exposure to arsenic, especially the trivalent inorganic form (As(3+)), has been linked to human cancers in addition to a number of other diseases including skin lesions, cardiovascular disorders, neuropathy, and internal organ injury. In the present study, we describe a novel signaling axis of the c-Jun NH2 kinase (JNK) and signal transducer and activator of transcription 3 (Stat3) and its involvement in As(3+)-induced Akt activation in human bronchial epithelial cells. As(3+) activates JNK and induces phosphorylation of the Stat3 at serine 727 (S727) in a dose- and time-dependent manner, which occurred concomitantly with Akt activation. Disruption of the JNK signaling pathway by treatment with the JNK inhibitor SP600125, siRNA knockdown of JNK, or genetic deficiency of the JNK1 or JNK2 gene abrogated As(3+)-induced S727 phosphorylation of Stat3, Akt activation, and the consequent release of vascular endothelial growth factor (VEGF) and migration of the cells. Similarly, pretreatment of the cells with Stat3 inhibitor or Stat3 siRNA prevented Akt activation and VEGF release from the cells in response to As(3+) treatment. Taken together, these data revealed a new signaling mechanism that might be pivotal in As(3+)-induced malignant transformation of the cells by linking the key stress signaling pathway, JNK, to the activation of Stat3 and the carcinogenic kinase, Akt.
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48201, USA.
Jia
J
Liu
Bailing
B
Chen
Yongju
Y
Lu
Youfei
Y
Guan
Fei
F
Chen
D001151:Arsenic / Q000494:pharmacology*; D002460:Cell Line; D018920:Coculture Techniques; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4; D001151:Arsenic