title: RanBP9/TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src-mediated Akt signaling in osteosarcoma.
abstract: Suppression of anoikis is a prerequisite for tumor cell metastasis, which is correlated with chemoresistance and poor prognosis. We characterized a novel interaction between RanBP9 SPRY domain and TSSC3 PH domain by which RanBP9/TSSC3 complex exerts transcription and post-translation regulation in osteosarcoma. RanBP9/TSSC3 complex was inversely correlated with a highly anoikis-resistant phenotype in osteosarcoma cells and metastasis in human osteosarcoma. RanBP9 cooperated with TSSC3 to inhibit anchorage-independent growth and to promote anoikis in vitro and suppress lung metastasis in vivo. Moreover, RanBP9 SPRY domain was required for RanBP9/TSSC3 complex-mediated anoikis resistance. Mechanistically, RanBP9 formed a ternary complex with TSSC3 and Src to scaffold this interaction, which suppressed both Src and Src-dependent Akt pathway activations and facilitated mitochondrial-associated anoikis. Collectively, the newly identified RanBP9/TSSC3 complex cooperatively suppress metastasis via downregulation of Src-dependent Akt pathway to expedite mitochondrial-associated anoikis. This study provides a biological basis for exploring the therapeutic significance of dual targeting of RanBP9 and TSSC3 in osteosarcoma.
authors.affiliation: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing, People's Republic of China.|Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Huanzi
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yang-Fan
authors.initials: YF
authors.lastname: Lv
authors.affiliation: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Guang-Ning
authors.initials: GN
authors.lastname: Yan
authors.affiliation: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing, People's Republic of China.|Department of Pathology, Southwest Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Meng
authors.affiliation: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing, People's Republic of China.|Department of Pathology, Southwest Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Qiao-Nan
authors.initials: QN
authors.lastname: Guo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000818:Animals; D023102:Anoikis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008297:Male; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D012516:Osteosarcoma / Q000201:enzymology / Q000473:pathology*; D010641:Phenotype; D011485:Protein Binding; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D055815:Young Adult; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C116005:Ran binding protein 9; C109277:TSSC3 protein; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt