title: Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors.
abstract: Somatostatin analogs are established in the treatment of neuroendocrine tumors (NETs) including small intestinal NET; however, the molecular mechanisms are not well known. Here, we examined the direct effects of lanreotide in NET cell line models.
  
  
  
  The cell lines HC45 and H727 were treated with 10nM lanreotide for different time periods and alterations of the proteome were analyzed by in-depth high-resolution isoelectric focusing tandem liquid chromatography-mass spectrometry. We next investigated whether the observed suppression of survivin was mediated by adenomatous polyposis coli (APC) and possible effects on tumor proliferation in vitro. Expression of survivin was assessed by immunohistochemistry in 112 NET cases and compared with patient outcome.
  
  
  
  We quantified 6451 and 7801 proteins in HC45 and H727, respectively. After short time lanreotide treatment APC was increased and survivin reduced. Overexpression of APC in H727 cells decreased, and APC knock-down elevated the survivin level. The lanreotide regulation of APC-survivin could be suppressed by small interfering RNA against somatostatin receptor 2. Although lanreotide only gave slight inhibition of proliferation, targeting of survivin with the small molecule YM155 dramatically reduced proliferation. Moderate or high as compared with low or absent total survivin expression was associated with shorter progression-free survival, independent of tumor stage, grade, and localization.
  
  
  
  We report a proteome-wide analysis of changes in response to lanreotide in NET cell lines. This analysis suggests a connection between somatostatin analog, APC, and survivin levels. Survivin is a possible prognostic factor and a new potential therapeutic target in NETs.
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Omid
authors.initials: O
authors.lastname: Fotouhi
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kjellin
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Jamileh
authors.initials: J
authors.lastname: Hashemi
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barriuso
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Pastrián
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Lamarca
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Victoria Heredia
authors.initials: VH
authors.lastname: Soto
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Jan
authors.initials: J
authors.lastname: Zedenius
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Mendiola
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
authors.affiliation: Departments of Oncology-Pathology (O.F., C.L., J.H., C.C.J., M.L., A.H., J.L.) and Molecular Medicine and Surgery (H.K., J.Z., M.K.), Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska (O.F., C.L., J.H., C.C.J., M.L., A.H.), Karolinska University Hospital, Stockholm, Sweden; Cancer Proteomics Mass Spectrometry (H.K., J.L.), Science for Life Laboratory, Stockholm, Sweden SE-171 76; Faculty of Biology (J.B.), Medicine and Health, University of Manchester, M13 9PT, Manchester, United Kingdom; Laboratory of Molecular Pathology and Therapeutic Targets, and Translational Oncology Research Group (J.B., A.L., V.H.S., M.M.), Instituto de Investigación; Department of Pathology (L.G.P.); and Molecular Pathology Section (M.M.), Instituto de Genética Médica, Hospital Universitario La Paz 28046, Madrid, Spain; and Department of Medical Oncology (A.L.), The Christie NHS Trust, M20 4BX, Manchester, United Kingdom.
authors.forename: Magnus
authors.initials: M
authors.lastname: Kjellman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects*; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000032:analysis* / Q000494:pharmacology; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D010456:Peptides, Cyclic; D000077022:Survivin; C060347:lanreotide; D013004:Somatostatin