4-Methylumebelliferone Enhances Radiosensitizing Effects of Radioresistant Oral Squamous Cell Carcinoma Cells via Hyaluronan Synthase 3 Suppression
Kazuki Hasegawa,
Ryo Saga,
Kentaro Ohuchi,
Yoshikazu Kuwahara,
Kazuo Tomita,
Kazuhiko Okumura,
Tomoaki Sato,
Manabu Fukumoto,
Eichi Tsuruga,
Yoichiro Hosokawa
Affiliations
Kazuki Hasegawa
Department of Radiation Science, Graduate School of Health Sciences, Hirosaki University, Hirosaki 036-8564, Japan
Ryo Saga
Department of Radiation Science, Graduate School of Health Sciences, Hirosaki University, Hirosaki 036-8564, Japan
Kentaro Ohuchi
Department of Oral and Maxillofacial Surgery, School of Dentistry, Health Sciences University of Hok-Kaido, Tobetsu-cho 061-0293, Japan
Yoshikazu Kuwahara
Department of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 983-8536, Japan
Kazuo Tomita
Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
Kazuhiko Okumura
Department of Oral and Maxillofacial Surgery, School of Dentistry, Health Sciences University of Hok-Kaido, Tobetsu-cho 061-0293, Japan
Tomoaki Sato
Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
Manabu Fukumoto
Pathology Informatics Team, RIKEN Center for Advanced Intelligence Project, Tokyo 103-0027, Japan
Eichi Tsuruga
Department of Radiation Science, Graduate School of Health Sciences, Hirosaki University, Hirosaki 036-8564, Japan
Yoichiro Hosokawa
Department of Radiation Science, Graduate School of Health Sciences, Hirosaki University, Hirosaki 036-8564, Japan
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.
