Loss of tyrosine phosphatase-dependent inhibition promotes activation of tyrosine kinase c-Src in detached pancreatic cells.

Abstract

Despite an intense focus on novel therapeutic strategies, pancreatic adenocarcinoma remains one of the deadliest human malignancies. The frequent and rapid mortality associated with pancreatic cancer may be attributed to several factors, including late diagnosis, rapid tumor invasion into surrounding tissues, and formation of distant metastases. Both local invasion and metastasis require disruption of tumor cell contacts with the extracellular matrix. Detachment of normal cells from the extracellular matrix leads to a form of programmed cell death termed anoikis. Pancreatic cancer cells avert anoikis by activation of signaling pathways that allow for adhesion-independent survival. In the present studies, cellular signaling pathways activated in detached pancreatic cancer cells were examined. We demonstrate a rapid and robust activation of Src kinase in detached pancreatic cancer cells, relative to adherent. Src autophosphorylation rapidly returned to baseline levels upon reattachment to tissue culture plastic, in the presence or absence of specific extracellular matrix proteins. Treatment of pancreatic cancer cells with tyrosine phosphatase inhibitors increased steady-state Src autophosphorylation in adherent cells and abrogated the detachment-induced increase in Src autophosphorylation. Src was found to co-immunoprecipitate with the Src homology 2 (SH2) domain containing protein tyrosine phosphatase (SHP-2) in pancreatic cancer cells, suggesting that SHP-2 may participate in regulation of Src autophosphorylation in adherent cells. Src family kinase (SFK) dependent increases in Akt and Jun N-terminal kinase (JNK) phosphorylation were observed in detached cells, indicating the potential for Src-dependent activation of survival and stress pathways in pancreatic cancer cells that have detached from the extracellular matrix.

• Authors: Sarah F Connelly, Beth A Isley, Cheryl H Baker, Gary E Gallick, Justin M Summy
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 49 Issue 12 Pg. 1007-21 (Dec 2010) ISSN: 1098-2744 [Electronic] United States
• PMID: 20945416 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 Wiley-Liss, Inc.

Chemical References

• Extracellular Matrix Proteins
• src-Family Kinases
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase 4
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Protein Tyrosine Phosphatases

Topics

• Adenocarcinoma (enzymology)
• Anoikis
• Cell Adhesion
• Cell Line, Tumor
• Cell Survival
• Enzyme Activation
• Extracellular Matrix Proteins (metabolism)
• Gene Knockdown Techniques
• Humans
• MAP Kinase Kinase 4 (metabolism)
• Pancreatic Neoplasms (enzymology)
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (genetics, metabolism)
• Protein Tyrosine Phosphatases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• src-Family Kinases (metabolism)