Wnt signaling controls radiosensitivity via cyclooxygenase-2-mediated Ku expression in head and neck cancer.
It has been proposed that Wnt signaling pathway may be a key radioprotective mechanism in irradiated cancer cells; however, the specific radioresistance mechanisms remain not to be fully clarified. Here we elucidate a novel signaling pathway of radioresistance in head and neck cancer (HNC) cell lines involving interactions among the Wnt signaling pathway, cyclooxygenase-2 (COX-2) and Ku expression. Activation of the Wnt signaling pathway by (2'Z,3'E)-6-bromoindirubin-3'-oxime (BIO) resulted in beta-catenin cytoplasmic accumulation and translocation to the nucleus, upregulated Ku expression and increased radioresistance in the COX-2-expressing HNC cell line. In contrast, Wnt singaling activation by BIO had no effects on Ku expression and radiosensitivity in a HNC cell line negative for COX-2. Interactions between Wnt singaling and Ku were indirectly regulated by COX-2. Blockage of COX-2 signaling led to the suppression of beta-catenin-induced Ku expression, and to consequent recovery of the radiosensitivity in HNC cells. Our results conclusively suggest that beta-catenin plays a pivotal role in the regulation of Ku expression via the proposed COX-2 intracellular pathway, thus supporting a novel radioresistance mechanism of HNC.
Chang
Hyo Won
HW
Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
Roh
Jong-Lyel
JL
Jeong
Eun-Jeong
EJ
Lee
Sang-wook
SW
Kim
Seung-Whan
SW
Choi
Seung-Ho
SH
Park
Sung-Kyung
SK
Kim
Sang Yoon
SY
D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology; D000072200:Ku Autoantigen; D010091:Oximes / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C483321:6-bromoindirubin-3'-oxime; D007211:Indoles; D010091:Oximes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen