title: Cardamonin induces apoptosis by suppressing STAT3 signaling pathway in glioblastoma stem cells.
abstract: Glioblastoma stem cells (GSCs) are the initiating cells in glioblastoma multiforme (GBM) and contribute to the resistance of GBM to chemotherapy and radiation. In the present study, we investigated the effects of cardamonin (3,4,2,4-tetrahydroxychalcone) on the self-renewal and apoptosis of GSCs, and if its action is associated with signal transducer and activator of transcription 3 (STAT3) pathway. CD133(+) GSCs, a kind of GSCs line, was established from human glioblastoma tissues. Cardamonin inhibited the proliferation and induced apoptosis in CD133+ GSCs. The proapoptotic effects of temozolomide (TMZ) were further enhanced by cardamonin in CD133+ GSCs and U87 cells in vitro. For in vivo study, injection of 5 × 10(5) cells of CD133+ GSCs subcutaneously (s.c.) into nude mice, 100 % of large tumors were developed within 8 weeks in all mice; in contrast, only one out of five mice developed a small tumor when 5 × 10(5) cells of CD133(-) GMBs cells were injected. Cardamonin also inhibited STAT3 activation by luciferase assay and suppressed the expression of the downstream genes of STAT3, such as Bcl-XL, Bcl-2, Mcl-1, survivin, and VEGF. Furthermore, cardamonin locked nuclear translocation and dimerization of STAT3 in CD133(+) GSCs. Docking analysis confirmed that cardamonin molecule was successfully docked into the active sites of STAT3 with a highly favorable binding energy of -10.78 kcal/mol. The study provides evidence that cardamonin is a novel inhibitor of STAT3 and has the potential to be developed as a new anticancer agent targeting GSCs. This study also reveals that targeting STAT3 signal pathway is an important strategy for the treatment of human GBM.
authors.affiliation: Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: College of Medicine, Qingdao University, Qingdao, 266021, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Qingdao Medical University Affiliated Hospital, Qingdao, 266070, China.
authors.forename: Xiangzhong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Qingdao Medical University Affiliated Hospital, Qingdao, 266070, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Chifeng Saliont Pharmaceutical Co., Ltd, Chifeng, Inner Mongolia Autonomous Region, China.
authors.forename: Shousong
authors.initials: S
authors.lastname: Cao
authors.affiliation: Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China. shidayong@qdio.ac.cn.
authors.forename: Dayong
authors.initials: D
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Capital Medical University, Beijing, 100069, China. xiukunlin@126.com.
authors.forename: Xiukun
authors.initials: X
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D047188:Chalcones / Q000008:administration & dosage* / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D011487:Protein Conformation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047188:Chalcones; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C436747:cardamonin
keywords: Apoptosis; Cardamonin; Glioblastoma stem cell; STAT3; Self-renewal; Temozolomide