title: TCEB2 confers resistance to VEGF-targeted therapy in ovarian cancer.
abstract: Targeted therapy has revolutionized the therapeutic landscape in oncology in recent years and anti-VEGF agent has been approved for ovarian cancer (OC). Unfortunately, the efficacy of this treatment is limited due to the development of resistance, while the molecular mechanisms underlying OC resistance to anti-VEGF therapy are less clear. In this study, we observed a differential response of OC cells to anti-VEGF agent bevacizumab (BV) by using xenograft models. Gene expression analysis showed that TCEB2 gene was significantly upregulated in the OC tumors with acquired resistance compared with the sensitive tumors. Further mechanism dissections demonstrated that TCEB2 played a critical role in the development of acquired resistance to BV in OC cells via promoting HIF-1α degradation and suppressing VEGF-A expression. In TCEB2 overexpressing cells, interleukin-8 (IL-8) was elevated and functioned as a compensatory angiogenesis signaling which was sensitive to IL-8 monoclonal antibody (IL-8 Ab). The combination of BV and IL-8 Ab exhibited synergistic effect of growth inhibition on both OC and endothelial cells. Thus, this study provides an alternative strategy of simultaneously targeting VEGF-A and IL-8 for combating OC.
authors.affiliation: Center for Translational Medicine and, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Translational Medicine and, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Han
authors.affiliation: Center for Translational Medicine and, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000075065:Elongin; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C000616396:ELOB protein, human; C000616401:Elob protein, mouse; D000075065:Elongin; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D014157:Transcription Factors; D000068258:Bevacizumab