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Departments of ¹ Biochemistry, ² Otolaryngology and Sensory Organ Surgery, and ³ Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan, and⁴ Department of Molecular Genetics, Kochi Medical School, Kochi, Japan

Request for Reprints:Naoyuki Taniguchi, Department of Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: +81-6-6879-3421; Fax: +81-6-6879-3429. E-mail: proftani{at}biochem.med.osaka-u.ac.jp

Multiple mechanisms are involved in the resistance of cancer cells to cisplatin, including the expression of multidrug resistance-associated protein (MRP) and enhanced DNA repair. Here, we report findings to show that oligosaccharide changes in 5ß1 integrin are associated with cisplatin resistance in a head and neck squamous cell carcinoma cell line, HSC-2. Cisplatin-resistant HSC-2 (HSC-2/CR) cells were established by stepwise treatment with various concentrations of cisplatin. The oligosaccharides containing ß1, 6-N-acetylglucosamine (ß1-6GlcNAc) branching, detected by leukoagglutinating phytohemagglutinin (L₄-PHA) lectin blot, were found to be dramatically decreased in 5ß1 integrin immunoprecipitated from HSC-2/CR cells. To better understand the mechanisms underlying cisplatin resistance and oligosaccharide alteration, we analyzed the downstream signaling of 5ß1 integrin, one of the target glycoproteins of ß1-6GlcNAc transferase [UDP-GlcNAc:-D-mannoside ß1, 6-N-acetylglucosaminyltransferase (GnT-V)]. Cell adhesion to fibronectin and phosphorylation of focal adhesion kinase (FAK), which are associated with 5ß1 integrin and involved in a cell survival signaling, were found to be increased in the cisplatin-resistant cells. Enhancement of the inhibition of cell adhesion and FAK phosphorylation also support the above data in GnT-V transfectants of HSC-2 cells. Interestingly, the differences in sensitivity to cisplatin and FAK phosphorylation between cisplatin-sensitive and -resistant cells were completely abolished by treatment with a neutral antibody of 5ß1 integrin. These results suggest that modification of oligosaccharides of 5ß1 integrin represents one of the possible mechanisms of drug resistance in head and neck cancer cells.

Grant support:Grant-in-Aid for Scientific Research (S) no. 13854010 from the Japan Society for the Promotion of Science; the 21st Century COE program and Grant-in-Aid for Cancer Research and Scientific Research on Priority Areas no. 15025238 from the Ministry of Education, Science, Sports and Culture of Japan.

Received 5/28/03; revised 7/28/03; accepted 8/28/03.

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