title: Smoothened is a poor prognosis factor and a potential therapeutic target in glioma.
abstract: Malignant gliomas are associated with a high mortality rate. Thus, there is an urgent need for the development of novel targeted therapeutics. Aberrant Hedgehog signaling has been directly linked to glioma. GDC-0449 is a novel small molecule inhibitor of Hedgehog signaling that blocks the activity of smoothened (Smo). In this study, we evaluated the in vitro and in vivo effects of the smoothened inhibitor GDC-0449 on cell proliferation in human gliomas. We found that high expression of smoothened in glioma is a predictor of short overall survival and poor patient outcome. Our data suggest that GDC-0449 significantly inhibits the proliferation of glioma cells by inducing cell cycle arrest at the G1 phase. Our results demonstrate that GDC-0449 can effectively inhibit the migration and invasion of glioma cells. Furthermore, GDC-0449 treatment significantly suppressed glioma cell xenograft tumorigenesis. Mechanistically, GDC-0449 treatment markedly decreases the expression levels of key Hedgehog pathway component genes (Shh, Patched-1, Patched-2, smoothened, Gli1 and Gli2). These results indicate that GDC-0449 works through targeting the Hedgehog pathway. Taken together, our study suggests that smoothened could be used as a prognostic marker and molecular therapeutic target for glioma.
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Jiangsu Key Laboratory of Bone Marrow Stem Cell, Blood Diseases Institute, Xuzhou, Medical University, Xuzhou, Jiangsu, China.
authors.forename: Mingshan
authors.initials: M
authors.lastname: Niu
authors.affiliation: Department of Neurosurgery, Huai'an Hospital Affiliated of Xuzhou Medical University and Huai'an Second People's Hospital, Huaian, Jiangsu, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xie
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Yue
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Zhenglei
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Brain Hospital, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Gao
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Brain Hospital, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Liu
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Brain Hospital, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Brain Hospital, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Rutong
authors.initials: R
authors.lastname: Yu
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Brain Hospital, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Liu
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D014408:Biomarkers, Tumor; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D011379:Prognosis; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D014408:Biomarkers, Tumor; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; C491023:SMO protein, human; D000072086:Smoothened Receptor