The Influence of Hyaluronan-CD44 Interaction on Topoisomerase II Activity and Etoposide Cytotoxicity in Head and Neck Cancer

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Abstract

Objective

To investigate the downstream molecular targets of hyaluronan (HA)-CD44 and phospholipase C (PLC)-mediated calcium ion (Ca2+) 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 Ca2+ 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 Ca2+-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.

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