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


METHODS
Cell line study.


METHODS
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.
Wang
Steven J
SJ
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. swang@ohns.ucsf.edu
Bourguignon
Lilly Y W
LY
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D006820:Hyaluronic Acid / Q000502:physiology*; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects; D014062:Tongue Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism*
D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D010738:Type C Phospholipases; D002945:Cisplatin; D002118:Calcium