Hyaluronan Constitutively Regulates Activation of COX-2-mediated Cell Survival Activity in Intestinal Epithelial and Colon Carcinoma Cells

Hyaluronan is a major component of the pericellular matrix surrounding tumor cells, including colon carcinomas. Elevated cycooxygenase-2 levels have been implicated in several malignant properties of colon cancer. We now show for the first time a strong link between hyaluronan-CD44 interaction and c...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-05, Vol.283 (21), p.14335-14344
Main Authors: Misra, Suniti, Obeid, Lina M., Hannun, Yusuf A., Minamisawa, Susumu, Berger, Franklin G., Markwald, Roger R., Toole, Bryan P., Ghatak, Shibnath
Format: Article
Language:English
Subjects:
beta Catenin - metabolism
Cell Survival
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Cyclooxygenase 2 - genetics
Cyclooxygenase 2 - metabolism
Enzyme Activation - drug effects
Epithelial Cells - cytology
Epithelial Cells - metabolism
Gene Expression Regulation, Enzymologic
Humans
Hyaluronic Acid - biosynthesis
Intestinal Mucosa - metabolism
Intestines - cytology
Mechanisms of Signal Transduction
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Receptor, ErbB-2 - metabolism
Signal Transduction
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Summary:Hyaluronan is a major component of the pericellular matrix surrounding tumor cells, including colon carcinomas. Elevated cycooxygenase-2 levels have been implicated in several malignant properties of colon cancer. We now show for the first time a strong link between hyaluronan-CD44 interaction and cyclooxygenase-2 in colon cancer cells. First, we have shown that increased expression of hyaluronan synthase-2 induces malignant cell properties, including increased proliferation, anchorage-independent growth, and epithelial-mesenchymal transition in HIEC6 cells. Second, constitutive hyaluronan-CD44 interaction stimulates a signaling pathway involving ErbB2, phosphoinositide 3-kinase/AKT, β-catenin, and cyclooxygenase-2/prostaglandin E2 in HCA7 colon carcinoma cells. Third, the HA/CD44-activated ErbB2 → phosphoinositide 3-kinase/AKT → β-catenin pathway stimulates cell survival/cell proliferation through COX-2 induction in hyaluronan-overexpressing HIEC6 cells and in HCA7 cells. Fourth, perturbation of hyaluronan-CD44 interaction by hyaluronan oligomers or CD44-silencing RNA decreases cyclooxygenase-2 expression and enzyme activity, and inhibition of cyclooxygenase-2 decreases hyaluronan production suggesting the possibility of an amplifying positive feedback loop between hyaluronan and cyclooxygenase-2. We conclude that hyaluronan is an important endogenous regulator of colon cancer cell survival properties and that cyclooxygenase-2 is a major mediator of these hyaluronan-induced effects. Defining hyaluronan-dependent cyclooxygenase-2/prostaglandin E2-associated signaling pathways will provide a platform for developing novel therapeutic approaches for colon cancer.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M703811200