Journal
BIOCHEMICAL PHARMACOLOGY
Volume 83, Issue 7, Pages 849-857Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2012.01.007
Keywords
ST6Gal I; EGFR; Colon cancer; Gefitinib; Sialylation
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Funding
- National Research Foundation of Korea (NRF)
- Korean Government (Ministry of Education, Science and Technology [M2AMA006]
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beta-Galactoside alpha 2,6-sialyltransferase (ST6Gal-I) has been shown to catalyze alpha 2,6 sialylation of N-glycan, an action that is highly correlated with colon cancer progression and metastasis. We have recently demonstrated that ST6Gal-I-induced alpha 2,6 sialylation is critical for adhesion and migration of colon cancer cells. Increase of alpha 2,6 sialylation also contributes to radioresistance of colon cancer. A number of studies have focused on the involvement of sialylation in tumorigenesis, but the mechanism underlying ST6Gal-I-induced cancer progression and the identity of enzyme substrates has received scant research attention. To provide further support for the relevance of ST6Gal-I in the malignancy of colon cancer, we prepared and characterized a ST6Gal-I-knockdown SW480 colorectal carcinoma cell line. We found that inhibition of ST6Gal-I expression increased cell proliferation and tumor growth in vitro and in vivo. An examination of the effect of sialylation on epidermal growth factor receptor (EGFR) activity and downstream signaling, which are highly correlated with cell proliferation, showed that the loss of ST6Gal-I augmented EGF-induced EGFR phosphorylation and activation of extracellular signal-regulated kinase (ERK) in colon cancer cells. Moreover, ST6Gal-I induced sialylation of both wild type and mutant EGFR. These studies provide the first demonstration that ST6Gal-I induces EGFR sialylation in human colon cancer cell lines. Importantly, the anticancer effect of the EGFR kinase inhibitor, gefitinib, was increased in ST6Gal-I-deficient colon cancer cells. In contrast, overexpression of ST6Gal I decreased the cytotoxic effect of gefitinib. These results suggest that sialylation of the EGFR affects EGF-mediated cell growth and induces chemoresistance to gefitinib in colon cancer cells. Crown Copyright (c) 2012 Published by Elsevier Inc. All rights reserved.
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