title: Sialylation of epidermal growth factor receptor regulates receptor activity and chemosensitivity to gefitinib in colon cancer cells.
abstract: β-Galactoside α2,6-sialyltransferase (ST6Gal-I) has been shown to catalyze α2,6 sialylation of N-glycan, an action that is highly correlated with colon cancer progression and metastasis. We have recently demonstrated that ST6Gal-I-induced α2,6 sialylation is critical for adhesion and migration of colon cancer cells. Increase of α2,6 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.
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Jung-Jin
authors.initials: JJ
authors.lastname: Park
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Yi
authors.forename: Yeung Bae
authors.initials: YB
authors.lastname: Jin
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.forename: Young-Gyu
authors.initials: YG
authors.lastname: Ko
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lee
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005434:Flow Cytometry; D000077156:Gefitinib; D019073:HT29 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012794:Sialic Acids / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D011799:Quinazolines; D034741:RNA, Small Interfering; D012794:Sialic Acids; D012799:Sialyltransferases; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase