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

    Authors

    S. Jaganathan; P. B. Yue;J. Turkson

    Comments

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    Abbreviated Journal Title

    J. Pharmacol. Exp. Ther.

    Keywords

    CONSTITUTIVE ACTIVATION; ADENOCARCINOMA CELLS; KINASE-ACTIVITY; STAT3; EXPRESSION; SITES; OVEREXPRESSION; METASTASIS; CARCINOMA; THERAPY; Pharmacology & Pharmacy

    Abstract

    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.

    Journal Title

    Journal of Pharmacology and Experimental Therapeutics

    Volume

    333

    Issue/Number

    2

    Publication Date

    1-1-2010

    Document Type

    Article

    Language

    English

    First Page

    373

    Last Page

    381

    WOS Identifier

    WOS:000276777900003

    ISSN

    0022-3565

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