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Prostaglandins promote colon cancer cell invasion; signaling by cross‐talk between two distinct growth factor receptors
Author(s) -
Pai Rama,
Nakamura Toshikazu,
Moon Woo S.,
Tarnawski Andrzej S.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-1011com
Subject(s) - hepatocyte growth factor , urokinase receptor , cancer research , colorectal cancer , metastasis , epidermal growth factor receptor , epidermal growth factor , biology , cancer , medicine , c met , receptor , endocrinology
Colorectal cancer is the second most frequent cancer in the Western world, often lethal when invasion and/or metastasis occur. In addition to hepatocyte growth factor (HGF), colon cancer invasion may be driven by prostaglandins, especially the E 2 series (PGE 2 ), generated by the cyclooxygenase‐2 (Cox‐2) enzyme. While concentration of PGE 2 as well as expression of Cox‐2, HGF receptor (c‐Met‐R), epidermal growth factor receptor (EGFR), and β‐catenin are all dramatically increased in colon cancers and implicated in their growth and invasion, the precise role of PGE 2 in the latter process remains unclear. Here we provide evidence that PGE 2 transactivates c‐Met‐R (contingent upon functional EGFR), increases tyrosine phosphorylation and nuclear accumulation of β‐catenin, and induces urokinase‐type plasminogen activator receptor (uPAR) mRNA expression. This is accompanied by increased β‐catenin association with c‐Met‐R and enhanced colon cancer cell invasiveness. Inactivation of EGFR and c‐Met‐R significantly reduced PGE 2 ‐induced cancer cell invasiveness. Clinical relevance of these findings is confirmed by our immunohistochemical studies demonstrating that cancer cells in the invasive front overexpress Cox‐2, c‐Met‐R, and β‐catenin. Our findings explain a functional relationship between prostaglandins, EGFR, and c‐Met‐R in colon cancer growth and invasion.—Pai, R., Nakamura, T., Moon, W. S., Tarnawski, A. S. Prostaglandins promote colon cancer cell invasion; signaling by cross‐talk between two distinct growth factor receptors. FASEB J. 17, 1640–1647 (2003)