The influence of hyaluronan-CD44 interaction on topoisomerase II activity and etoposide cytotoxicity in head and neck cancer

Arch Otolaryngol Head Neck Surg. 2007 Mar;133(3):281-8. doi: 10.1001/archotol.133.3.281.


Objective: To investigate the downstream molecular targets of hyaluronan (HA)-CD44 and phospholipase C (PLC)-mediated calcium ion (Ca(2+)) signaling in head and neck squamous cell carcinoma (HNSCC). Hyaluronan is a ligand for the CD44 receptor, which interacts with multiple signaling pathways to influence cellular behavior. We recently determined that HA-CD44 interaction promotes PLC-mediated Ca(2+) signaling and cisplatin resistance in HNSCC.

Design: Proliferation of HNSCC tumor cells and topoisomerase (Topo) II enzymatic activity, including DNA-cleavable complex formation and DNA decatenation, were analyzed in the presence or absence of HA, the Topo II poison etoposide (VP-16), and various inhibitors of PLC and Ca(2+)-calmodulin kinase II (CaMKII) signaling.

Results: Treatment with HA promoted Topo II phosphorylation, suggesting that HA can modulate Topo II activity. Topoisomerase II-mediated DNA cleavable complex formation was increased by VP-16, and this increase was significantly enhanced by noncytotoxic doses of the PLC inhibitor U73122 and the CaMKII inhibitor KN-62, implicating PLC and CaMKII in Topo II regulation. However, the drug- and inhibitor-mediated increase in DNA cleavable complex formation was reduced with HA pretreatment. Inhibitors of PLC and CaMKII also enhanced VP-16 inhibition of Topo II-mediated DNA decatenation. Treatment with HA reduced VP-16 cytotoxic activity. On the other hand, U73122 and KN-62 enhanced VP-16 cytotoxic activity and reduced the ability of HA to promote VP-16 resistance.

Conclusion: Our results suggest that HA, PLC, and CaMKII are upstream regulators of Topo II-mediated DNA metabolism in HNSCC and that this signaling pathway could be a promising target for the development of novel therapies against HNSCC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents, Phytogenic / adverse effects*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Calcium Signaling / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / pharmacology
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Line, Tumor
  • DNA Topoisomerases, Type II / drug effects*
  • DNA Topoisomerases, Type II / metabolism
  • Etoposide / adverse effects*
  • Etoposide / therapeutic use
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / metabolism*
  • Hyaluronic Acid / pharmacology
  • Male
  • Phosphorylation
  • Signal Transduction
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / pharmacology


  • Antineoplastic Agents, Phytogenic
  • Hyaluronan Receptors
  • Etoposide
  • Hyaluronic Acid
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Type C Phospholipases
  • DNA Topoisomerases, Type II