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Arch Otolaryngol Head Neck Surg. 2006 Jan;132(1):19-24.

Hyaluronan-CD44 promotes phospholipase C-mediated Ca2+ signaling and cisplatin resistance in head and neck cancer.

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Department of Otolaryngology-Head and Neck Surgery and Endocrine Unit, Department of Medicine, University of California-San Francisco, 4150 Clement Street #112B, San Francisco, CA 94121, USA.



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.


Cell line study.


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.


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.


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.

[Indexed for MEDLINE]

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