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J Clin Endocrinol Metab. 2016 Oct;101(10):3616-3627. Epub 2016 Jul 26.

Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors.

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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.



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.

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