title: Cell fate regulation by gelsolin in human gynecologic cancers.
abstract: Chemoresistance is a major hurdle in cancer treatment. Down-regulation of apoptosis pathways is one of the key determinants for chemoresistance. Here, we report higher gelsolin (GSN) levels in chemoresistant gynecological cancer cells compared with their sensitive counterparts. cis-Diammine dichloroplatinium (II) (CDDP)-induced GSN down-regulation is associated with its cleavage and apoptosis. Although the C-terminal GSN fragment (C-GSN) sensitized chemoresistant cells to CDDP, intact GSN and its N-terminal fragment (N-GSN) attenuated this response. GSN silencing also facilitated CDDP-induced apoptosis in chemoresistant cells. In contrast, intact GSN (I-GSN) was prosurvival in the presence of CDDP through a FLICE-like inhibitory protein (FLIP)-Itch interaction. This interaction was colocalized in the perinuclear region that could be dissociated by CDDP in sensitive cells, thereby inducing FLIP ubiquitination and degradation, followed by apoptosis. In resistant cells, GSN was highly expressed and CDDP failed to abolish the I-GSN-FLIP-Itch interaction, resulting in the dysregulation of the downstream responses. In addition, we investigated the association between GSN expression in ovarian serous adenocarcinoma and progression free survival and overall survival, as well as clinical prognosis. GSN overexpression was significantly associated with more aggressive behavior and more cancer deaths and supported our hypothesis that high GSN expression confers chemoresistance in cancer cells by altering the GSN-FLIP-Itch interaction. These findings are in agreement with the notion that GSN plays an important role in the regulation of gynecological cell fate as reflected in dysregulation in chemosensitivity.
authors.affiliation: Departments of Obstetrics and Gynaecology and Cellular and Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada K1H 8L6; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; Cellular and Molecular Medicine Research Center, Department of Pharmacology, Birjand University of Medical Sciences, Birjand 97178, Iran;
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Abedini
authors.affiliation: Institute of Basic Medical Science, Institute of Oral Medicine and Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan 704, Taiwan; and.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Huang
authors.affiliation: Departments of Obstetrics and Gynaecology and Cellular and Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada K1H 8L6; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6;
authors.forename: Mingju
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan 704, Taiwan; and btsang@ohri.ca dshieh@mail.ncku.edu.tw chougyn@mail.ncku.edu.tw.
authors.forename: Cheng-Yang
authors.initials: CY
authors.lastname: Chou
authors.affiliation: Institute of Basic Medical Science, Institute of Oral Medicine and Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; Advanced Optoelectronic Technology Center and Center for Micro/Nano Science and Technology, National Cheng Kung University, Tainan 704, Taiwan btsang@ohri.ca dshieh@mail.ncku.edu.tw chougyn@mail.ncku.edu.tw.
authors.forename: Dar-Bin
authors.initials: DB
authors.lastname: Shieh
authors.affiliation: Departments of Obstetrics and Gynaecology and Cellular and Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada K1H 8L6; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; btsang@ohri.ca dshieh@mail.ncku.edu.tw chougyn@mail.ncku.edu.tw.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Tsang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D005260:Female; D018260:Gelsolin / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018613:Microscopy, Confocal; D008875:Middle Aged; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018260:Gelsolin; D012097:Repressor Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin
keywords: cervical cancer; ovarian cancer