title: Restoration of BRAK / CXCL14 gene expression by gefitinib is associated with antitumor efficacy of the drug in head and neck squamous cell carcinoma.
abstract: Clinical efficacy of gefitinib (ZD1839, Iressa), which is an inhibitor specific for epidermal growth factor (EGF) receptor tyrosine kinase, has been shown in non-small-cell lung carcinoma patients with EGF receptor mutations, so these mutations are useful marker(s) to find a responder for the drug. Recent studies have shown that the EGF receptor gene mutation is rare in squamous cell carcinoma in the esophageal and head and neck regions. We previously reported that the expression of the chemokine BRAK/CXCL14 in head and neck squamous cell carcinoma (HNSCC) cells was down-regulated by EGF treatment, and that forced expression of BRAK in tumor cells decreased the tumorigenicity of the cells in xenografts. Thus, we investigated the relationship between restoration of BRAK expression by gefitinib and the efficacy of the drug for tumor suppression. We found that EGF down-regulated BRAK expression through the MEK-extracellular signal regulated kinase pathway and that this down-regulated expression was restored by gefitinib in vitro. Oral administration of gefitinib significantly (P < 0.001) reduced tumor growth of xenografts of three HNSCC cell lines (HSC-2, HSC-3, and HSC-4), in female athymic nude mice, accompanied by an increase in BRAK expression specifically in tumor tissue. This tumor-suppressing effect of the drug was not observed in the case of BRAK non-expressing cells. Furthermore introduction of BRAK shRNA vector reduced both the expression levels of BRAK in HSC-3 cells and the antitumor efficacy of gefitinib in vivo. Our data showing an inverse relationship between BRAK expression levels in tumor cells and the tumor growth rate indicate that the gefitinib-induced increase in BRAK expression is beneficial for tumor suppression in vivo.
authors: Department of Biochemistry and Molecular Biology, Kanagawa Dental College, Yokosuka, Japan.
authors: Shigeyuki
authors: S
authors: Ozawa
authors: Yasumasa
authors: Y
authors: Kato
authors: Shin
authors: S
authors: Ito
authors: Reika
authors: R
authors: Komori
authors: Naoto
authors: N
authors: Shiiki
authors: Keiichi
authors: K
authors: Tsukinoki
authors: Satoru
authors: S
authors: Ozono
authors: Yojiro
authors: Y
authors: Maehata
authors: Takahide
authors: T
authors: Taguchi
authors: Yukari
authors: Y
authors: Imagawa-Ishiguro
authors: Mamoru
authors: M
authors: Tsukuda
authors: Eiro
authors: E
authors: Kubota
authors: Ryu-Ichiro
authors: R
authors: Hata
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019743:Chemokines, CXC / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D011799:Quinazolines; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib