4-Methylumebelliferone Enhances Radiosensitizing Effects of Radioresistant Oral Squamous Cell Carcinoma Cells via Hyaluronan Synthase 3 Suppression

Abstract

Radioresistant (RR) cells are poor prognostic factors for tumor recurrence and metastasis after radiotherapy. The hyaluronan (HA) synthesis inhibitor, 4-methylumbelliferone (4-MU), shows anti-tumor and anti-metastatic effects through suppressing HA synthase (HAS) expression in various cancer cells. We previously reported that the administration of 4-MU with X-ray irradiation enhanced radiosensitization. However, an effective sensitizer for radioresistant (RR) cells is yet to be established, and it is unknown whether 4-MU exerts radiosensitizing effects on RR cells. We investigated the radiosensitizing effects of 4-MU in RR cell models. This study revealed that 4-MU enhanced intracellular oxidative stress and suppressed the expression of cluster-of-differentiation (CD)-44 and cancer stem cell (CSC)-like phenotypes. Interestingly, eliminating extracellular HA using HA-degrading enzymes did not cause radiosensitization, whereas HAS3 knockdown using siRNA showed similar effects as 4-MU treatment. These results suggest that 4-MU treatment enhances radiosensitization of RR cells through enhancing oxidative stress and suppressing the CSC-like phenotype. Furthermore, the radiosensitizing mechanisms of 4-MU may involve HAS3 or intracellular HA synthesized by HAS3.

Melatonin inhibits the stemness of head and neck squamous cell carcinoma by modulating HA synthesis via the FOSL1/HAS3 axis

“…It has been reported that the HA synthase HAS3 expression and HA levels were increased in human glioma tissues and associated with the poor prognosis of glioma 47 . Suppression of HAS3 expression by 4‐MU enhanced the radiosensitivity of radioresistant HNSCC cells 48 . In addition, HA promoted CSC functions in HNSCC by regulating the Oct4–Sox2–Nanog complex through interaction with its receptor CD44 49 .…”

“…47 Suppression of HAS3 expression by 4-MU enhanced the radiosensitivity of radioresistant HNSCC cells. 48 In addition, HA promoted CSC functions in HNSCC by regulating the Oct4-Sox2-Nanog complex through interaction with its receptor CD44. 49 Thus, blocking the interaction between HA and tumor cells may prevent tumor growth.…”