Sialylation of epidermal growth factor receptor regulates receptor activity and chemosensitivity to gefitinib in colon cancer cells

Jung Jin Park, Jae Youn Yi, Yeung Bae Jin, Yoon Jin Lee, Jae Seon Lee, Yun Sil Lee, Young-Gyu Ko, Minyoung Lee

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)849-857
Number of pages9
JournalBiochemical Pharmacology
Volume83
Issue number7
DOIs
Publication statusPublished - 2012 Apr 1

Fingerprint

Epidermal Growth Factor Receptor
Colonic Neoplasms
Cells
Cell proliferation
Epidermal Growth Factor
gefitinib
beta-D-galactoside alpha 2-6-sialyltransferase
Cell Proliferation
Sialyltransferases
Galactosides
Cell Line
Neoplasms
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Cell growth
Growth
Polysaccharides
Tumors
Colorectal Neoplasms
Carcinogenesis

Keywords

  • Colon cancer
  • EGFR
  • Gefitinib
  • Sialylation
  • ST6Gal I

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Sialylation of epidermal growth factor receptor regulates receptor activity and chemosensitivity to gefitinib in colon cancer cells. / Park, Jung Jin; Yi, Jae Youn; Jin, Yeung Bae; Lee, Yoon Jin; Lee, Jae Seon; Lee, Yun Sil; Ko, Young-Gyu; Lee, Minyoung.

In: Biochemical Pharmacology, Vol. 83, No. 7, 01.04.2012, p. 849-857.

Research output: Contribution to journalArticle

Park, Jung Jin ; Yi, Jae Youn ; Jin, Yeung Bae ; Lee, Yoon Jin ; Lee, Jae Seon ; Lee, Yun Sil ; Ko, Young-Gyu ; Lee, Minyoung. / Sialylation of epidermal growth factor receptor regulates receptor activity and chemosensitivity to gefitinib in colon cancer cells. In: Biochemical Pharmacology. 2012 ; Vol. 83, No. 7. pp. 849-857.
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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.",
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AU - Ko, Young-Gyu

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AB - 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.

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