Enhanced sensitivity of pancreatic cancer cells to concurrent inhibition of aberrant signal transducer and activator of transcription 3 and epidermal growth factor receptor or Src.
Many molecular aberrations occur in pancreatic cancer. Although aberrant epidermal growth factor receptor (EGFR), Src, and signal transducer and activator of transcription 3 (Stat3) are implicated in pancreatic cancer, therapies that target only one of these entities are undermined by signaling cross-talk. In the human pancreatic cancer lines, Panc-1 and Colo-357, pY845EGFR, pY1068EGFR, pY1086EGFR, and pY1173EGFR levels and pY416c-Src are concurrently elevated with aberrantly active Stat3 in a complex signaling cross-talk. Thus, understanding the signaling integration would facilitate the design of effective multiple-targeted therapeutic modalities. In Panc-1 and Colo-357 lines, pY845EGFR, pY1068EGFR, and pY1086EGFR levels are responsive to c-Src inhibition in contrast to pY1173EGFR, which is EGFR kinase-dependent. Constitutively active Stat3 is sensitive to both EGFR and Src inhibition, but the early suppression of aberrantly active Stat3 in response to the inhibition of EGFR and Src is countered by a Janus kinase (Jaks)-dependent reactivation, suggesting that Jaks activity is a compensatory mechanism for Stat3 induction. The inhibition of EGFR, Src, or Stat3 alone induced weak biological responses. By contrast, the concurrent inhibition of Stat3 and EGFR or Src induced greater viability loss and apoptosis and decreased the migration/invasion of pancreatic cancer cells in vitro. Significantly, the concurrent inhibition, compared with monotargeting modality, induced stronger human pancreatic tumor growth inhibition in xenografts. We infer that the tumor growth inhibition in vivo is caused by the simultaneous suppression of the abnormal functions of Stat3 and EGFR or Src. These studies strongly suggest that the concurrent targeting of Stat3 and EGFR or Src could be a beneficial therapeutic approach for pancreatic cancer.
Jaganathan
Soumya
S
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32826, USA.
Yue
Peibin
P
Turkson
James
J
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D019061:src-Family Kinases
D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D051058:Oncogene Protein v-akt; D020929:Mitogen-Activated Protein Kinase Kinases