a functional nuclear epidermal growth factor receptor, src and stat3 heteromeric complex in pancreatic cancer cells功能核表皮生长因子受体、src和stat3 heteromeric复杂的胰腺癌细胞.pdfVIP

A Functional Nuclear Epidermal Growth Factor Receptor, Src and Stat3 Heteromeric Complex in Pancreatic Cancer Cells 1 1 1 2,3 2,3 Soumya Jaganathan , Peibin Yue , David C. Paladino , Jelena Bogdanovic , Qun Huo , James Turkson1* 1 Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America, 2 NanoScience Technology Center, University of Central Florida, Orlando, Florida, United States of America, 3 Department of Chemistry, University of Central Florida, Orlando, Florida, United States of America Abstract Evidence is presented for the nuclear presence of a functional heteromeric complex of epidermal growth factor (EGFR), Src and the Signal Transducer and Activator of Transcription (Stat)3 proteins in pancreatic cancer cells. Stat3 remains nuclear and associated with Src or EGFR, respectively, upon the siRNA knockdown of EGFR or Src, demonstrating the resistance of the complex to the modulation of EGFR or Src alone. Significantly, chromatin immunoprecipitation (ChIP) analyses reveal the nuclear EGFR, Src and Stat3 complex is bound to the c-Myc promoter. The siRNA knockdown of EGFR or Src, or the pharmacological inhibition of Stat3 activity only marginally suppressed c-Myc expression. By contrast, the concurrent modulation of Stat3 and EGFR, or Stat3 and Src, or EGFR and Src strongly suppressed c-Myc expression, demonstrating that the novel nuclear heteromeric complex intricately regulates the c-Myc gene. The prevalence of the transcriptionally functional EGFR, Src, and Stat3 nuclear complex provides an additional and novel mechanism for supporting the pancreatic cancer