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Involvement of oligosaccharide changes in alpha5beta1 integrin in a cisplatin-resistant human squamous cell carcinoma

Susumu Nakahara1, Eiji Miyoshi, Katsuhisa Noda

  • 1Department of Biochemistry, Osaka University Graduate School of Medicine, Osaka, Japan.

Molecular Cancer Therapeutics
|November 18, 2003
PubMed

Insights

Altered oligosaccharides in alpha5beta1 integrin are linked to cisplatin resistance in head and neck cancer. This suggests a new mechanism for drug resistance involving changes in cell adhesion and signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cisplatin resistance in cancer involves mechanisms like multidrug resistance-associated protein (MRP) expression and enhanced DNA repair.
  • Alpha5beta1 integrin plays a role in cell adhesion and survival signaling pathways.
  • Oligosaccharide modifications can influence protein function and cellular behavior.

Purpose of the Study:

  • To investigate the association between oligosaccharide changes in alpha5beta1 integrin and cisplatin resistance in head and neck squamous cell carcinoma.
  • To explore the downstream signaling pathways affected by these oligosaccharide alterations.
  • To identify potential therapeutic targets for overcoming cisplatin resistance.

Main Methods:

  • Establishment of cisplatin-resistant head and neck squamous cell carcinoma cell line (HSC-2/CR).
  • Leukoagglutinating phytohemagglutinin (L(4)-PHA) lectin blot analysis to detect beta1,6-N-acetylglucosamine (beta1-6GlcNAc) branching in alpha5beta1 integrin.
  • Analysis of cell adhesion to fibronectin and focal adhesion kinase (FAK) phosphorylation.
  • Functional studies using GnT-V transfectants and alpha5beta1 integrin antibody treatment.

Main Results:

  • Decreased beta1-6GlcNAc branching in alpha5beta1 integrin of cisplatin-resistant HSC-2/CR cells.
  • Increased cell adhesion to fibronectin and FAK phosphorylation in cisplatin-resistant cells.
  • Inhibition of cell adhesion and FAK phosphorylation in GnT-V transfectants.
  • Reversal of cisplatin sensitivity and FAK phosphorylation differences upon alpha5beta1 integrin antibody treatment.

Conclusions:

  • Oligosaccharide modification of alpha5beta1 integrin is a potential mechanism contributing to cisplatin resistance in head and neck cancer.
  • Altered alpha5beta1 integrin glycosylation impacts cell adhesion and FAK signaling, influencing drug sensitivity.
  • Targeting alpha5beta1 integrin glycosylation or its downstream signaling may offer strategies to overcome cisplatin resistance.

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