Cancer is associated with many molecular aberrations that support the malignant phenotype. In that regard, aberrant activation of epidermal growth factor receptor (EGFR), Src, and signal transducer and activator of transcription 3 (Stat3) occur concurrently in pancreatic cancer and are implicated in the disease phenotype. Notwithstanding, increasing evidence indicates that therapies that target only EGFR or Src are rather ineffective in modulating the cancer phenotype. The poor therapeutic outcome of the monotherapies targeting EGFR or Src may in part be due to the increased incidence of signaling cross-talks among aberrant signaling pathways in cancer. Molecular details of the signaling integration between EGFR, Src and Stat3, however, are lacking. Understanding how the aberrant EGFR, Src and Stat3 pathways are integrated in pancreatic cancer would facilitate the design of effective multipletargeted, clinically feasible therapeutic modalities. Our study shows that in pancreatic cancer cell lines, aberrant Src activity promotes abnormal EGFR activation through the phosphorylation of the EGFR motifs, Tyr845, Tyr1068 and Tyr1086. Furthermore, aberrantly-active EGFR and Src together induce constitutive activation of Stat3 in pancreatic cancer cells. Evidence further shows that EGFR, Src and Stat3 physically associated into a heteromeric complex. Significantly, the EGFR, Src and Stat3 heteromeric complex is detectable in the nucleus and functions as a transcriptionallyactive complex to induce the c-Myc gene. Of therapeutic significance, the concurrent inhibition of Stat3 and EGFR or Src promoted greater viability loss and apoptosis of pancreatic cancer cells in vitro, and induced stronger tumor growth inhibition in xenografts of human pancreatic cancer. Altogether, our studies suggest that the iii heteromeric EGFR, Src, and Stat3 complex may serve as an additional novel mechanism of support of the pancreatic cancer phenotype. Furthermore, our studies provide evidence that the concurrent targeting of Stat3 and EGFR or Stat3 and Src could be a more effective therapeutic approach for human pancreatic cancer.
| Identifer | oai:union.ndltd.org:ucf.edu/oai:stars.library.ucf.edu:etd-2619 |
| Date | 01 January 2010 |
| Creators | Jaganathan, Soumya |
| Publisher | STARS |
| Source Sets | University of Central Florida |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses and Dissertations |
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