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Steven J. Wang, MD; Lilly Y. W. Bourguignon, PhD

Arch Otolaryngol Head Neck Surg. 2006;132:19-24.

Objective  To investigate whether hyaluronan (HA)–CD44 promotes head and neck squamous cell carcinoma (HNSCC) cisplatin resistance and whether HA-CD44 promotes phospholipase C (PLC)–mediated Ca²⁺ signaling to alter cisplatin sensitivity in HNSCC.

Design  Cell line study.

Main Outcome Measures  Tumor cell growth with the chemotherapeutic drug cisplatin was measured in the presence or absence of HA, anti-CD44 antibody plus HA, and other inhibitors of the PLC-mediated Ca²⁺ signaling pathway. Ca²⁺ mobilization was measured with fluorescence spectrophotometry using the Ca²⁺ binding dye Fura/2AM.

Results  In the absence of HA, cisplatin inhibited tumor cell growth. The addition of HA, but not HA plus anti-CD44 antibody, resulted in a 5-fold reduced ability of cisplatin to cause HNSCC cell death, suggesting that HA can promote CD44-dependent cisplatin resistance. Fluorescence spectrophotometry demonstrated that HA can promote CD44-dependent Ca²⁺ mobilization in HNSCC. On the other hand, the presence of U73122, a PLC inhibitor, and 2-aminoethoxydiphenyl borate, an inositol-1,4,5-triphosphate receptor inhibitor, eliminated HA-mediated Ca²⁺ mobilization and HA-mediated cisplatin resistance in these cell lines.

Conclusions  Our results indicate that HA-CD44 signaling influences cisplatin sensitivity in HNSCC cell growth. In particular, HA-CD44 promotion of PLC-mediated Ca²⁺ signaling plays a role in cisplatin resistance in HNSCC cells. Perturbation of this HA-CD44–mediated signaling pathway may be a promising target to overcome cisplatin resistance in HNSCC.

Author Affiliations: Department of Otolaryngology–Head and Neck Surgery (Dr Wang) and Endocrine Unit (Dr Bourguignon), Department of Medicine, University of California–San Francisco, and Veterans Affairs Medical Center, San Francisco (Dr Bourguignon).

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