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

• Published in: The journal of clinical endocrinology and metabolism Vol. 101; no. 10; pp. 3616 - 3627
• Main Authors: Fotouhi, Omid, Kjellin, Hanna, Larsson, Catharina, Hashemi, Jamileh, Barriuso, Jorge, Juhlin, C. Christofer, Lu, Ming, Höög, Anders, Pastrián, Laura G, Lamarca, Angela, Soto, Victoria Heredia, Zedenius, Jan, Mendiola, Marta, Lehtiö, Janne, Kjellman, Magnus
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.10.2016; Copyright by The Endocrine Society
• Subjects: Antineoplastic Agents - pharmacology; Cell Line, Tumor; Humans; Inhibitor of Apoptosis Proteins - drug effects; Medicin och hälsovetenskap; Neuroendocrine Tumors - drug therapy; Original; Peptides, Cyclic - pharmacology; Proteomics - methods; Somatostatin - analogs & derivatives; Somatostatin - analysis; Somatostatin - pharmacology
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2016-2028

Context: 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. Setting and Design: 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. Results: 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. Conclusions: 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. A link between lanreotide treatment, APC and survivin was identified in proteome-wide and functional studies of NET cells, and shorter survival of NET patients was associated with survivin expression.