{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:41:04Z","timestamp":1768506064719,"version":"3.49.0"},"posted":{"date-parts":[[2023,4,8]]},"group-title":"Cancer Biology","reference-count":38,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,4,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. SBNETs express high levels of tryptophan hydroxylase 1 (Tph1), a key enzyme in serotonin biosynthesis. Patients with high serotonin level may develop carcinoid syndrome, which can be treated with somatostatin analogues and the Tph1 inhibitor telotristat ethyl in severe cases. Although the active drug telotristat can efficiently reduce serotonin levels, its effect on tumor growth is unclear. This study determined the effect of serotonin inhibition on tumor cell growth\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  . The levels of Tph1 in various neuroendocrine neoplasms (NENs) were determined and the biological effects of Tph1 inhibition\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  using genetic and pharmacologic approaches was tested. Gene and protein expression analyses were performed on patient tumors and cancer cell lines. shRNAs targeting\n                  <jats:italic>TPH1<\/jats:italic>\n                  were used to create stable knockdown in BON cells. Control and knockdown lines were assessed for their growth rates\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  , angiogenesis potential, serotonin levels, endothelial cell tube formation, tumor weight, and tumor vascularity.\n                  <jats:italic>TPH1<\/jats:italic>\n                  is highly expressed in SBNETs and many cancer types.\n                  <jats:italic>TPH1<\/jats:italic>\n                  knockdown cells and telotristat treated cells showed similar growth rates as control cells\n                  <jats:italic>in vitro<\/jats:italic>\n                  . However,\n                  <jats:italic>TPH1<\/jats:italic>\n                  knockdown cells formed smaller tumors\n                  <jats:italic>in vivo<\/jats:italic>\n                  and tumors were less vascularized. Although Tph1 inhibition with telotristat showed no effect on tumor cell growth\n                  <jats:italic>in vitro<\/jats:italic>\n                  , Tph1 inhibition reduced tumor formation\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Serotonin inhibition in combination with other therapies is a promising new avenue for targeting metabolic vulnerabilities in NENs.\n                <\/jats:p>","DOI":"10.1101\/2023.04.07.536013","type":"posted-content","created":{"date-parts":[[2023,4,9]],"date-time":"2023-04-09T01:35:11Z","timestamp":1681004111000},"source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of serotonin biosynthesis in neuroendocrine neoplasm suppresses tumor growth\n                  <i>in vivo<\/i>"],"prefix":"10.64898","author":[{"given":"Dane H.","family":"Tow","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine G.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis C.","family":"Borbon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maclain","family":"Ridder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiying","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Courtney A.","family":"Kaemmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen","family":"Abusada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aswanth Harish","family":"Mahalingam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anguraj","family":"Sadanandam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chandrikha","family":"Chandrasekaran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Dillon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas R.","family":"Spitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawn E.","family":"Quelle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos H.F.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Bellizzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James R.","family":"Howe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Po Hien","family":"Ear","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023041202300710000_2023.04.07.536013v1.1","doi-asserted-by":"publisher","DOI":"10.1593\/neo.81630"},{"key":"2023041202300710000_2023.04.07.536013v1.2","doi-asserted-by":"crossref","first-page":"107423","DOI":"10.1016\/j.pharmthera.2019.107423","article-title":"Inhibition of serotonin synthesis: A novel therapeutic paradigm","volume":"205","year":"2020","journal-title":"Pharmacol Ther"},{"key":"2023041202300710000_2023.04.07.536013v1.3","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/PAP.0000000000000256","article-title":"An Algorithmic Immunohistochemical Approach to Define Tumor Type and Assign Site of Origin","volume":"27","year":"2020","journal-title":"Adv Anat Pathol"},{"key":"2023041202300710000_2023.04.07.536013v1.4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.soc.2019.11.003","article-title":"Pathologic Considerations in Gastroenteropancreatic Neuroendocrine Tumors","volume":"29","year":"2020","journal-title":"Surg Oncol Clin N Am"},{"key":"2023041202300710000_2023.04.07.536013v1.5","doi-asserted-by":"crossref","unstructured":"Blazevic, A. , Iyer, A. M. , Van Velthuysen, M. F. , Hofland, J. , Van Koestveld, P. M. , Franssen, G. J. H. , Feelders, R. A. , Zajec, M ., Luider, T. M. , De Herder, W. W. & Hofland, L. J. 2022. Aberrant tryptophan metabolism in stromal cells is associated with mesenteric fibrosis in small intestinal neuroendocrine tumors. Endocr Connect, 11.","DOI":"10.1530\/EC-22-0020"},{"key":"2023041202300710000_2023.04.07.536013v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2010.01643.x"},{"key":"2023041202300710000_2023.04.07.536013v1.7","doi-asserted-by":"crossref","unstructured":"Chaudhary, P. , Guragain, D. , Chang, J. H. & Kim, J. A . 2021. TPH1 and 5-HT(7) Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma. Cancers (Basel), 13.","DOI":"10.3390\/cancers13215305"},{"key":"2023041202300710000_2023.04.07.536013v1.8","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.2217\/fon-2017-0340","article-title":"Telotristat ethyl: a novel agent for the therapy of carcinoid syndrome diarrhea","volume":"14","year":"2018","journal-title":"Future Oncol"},{"key":"2023041202300710000_2023.04.07.536013v1.9","doi-asserted-by":"crossref","first-page":"4934","DOI":"10.1002\/cncr.24533","article-title":"Autoregulatory effects of serotonin on proliferation and signaling pathways in lung and small intestine neuroendocrine tumor cell lines","volume":"115","year":"2009","journal-title":"Cancer"},{"key":"2023041202300710000_2023.04.07.536013v1.10","first-page":"393","article-title":"The human carcinoid cell line","volume":"733","year":"1994","journal-title":"BON. A model system for the study of carcinoid tumors. Ann N Y Acad Sci"},{"key":"2023041202300710000_2023.04.07.536013v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(91)90004-5"},{"key":"2023041202300710000_2023.04.07.536013v1.12","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s12943-016-0559-6","article-title":"Tryptophan hydroxylase 1 and 5-HT(7) receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling","volume":"15","year":"2016","journal-title":"Mol Cancer"},{"key":"2023041202300710000_2023.04.07.536013v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0546-8"},{"key":"2023041202300710000_2023.04.07.536013v1.14","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"},{"key":"2023041202300710000_2023.04.07.536013v1.15","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu393"},{"key":"2023041202300710000_2023.04.07.536013v1.16","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1159\/000502200","article-title":"Effect of the Tryptophan Hydroxylase Inhibitor Telotristat on Growth and Serotonin Secretion in 2D and 3D Cultured Pancreatic Neuroendocrine Tumor Cells","volume":"110","year":"2020","journal-title":"Neuroendocrinology"},{"key":"2023041202300710000_2023.04.07.536013v1.17","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3389\/fcell.2019.00045","article-title":"The Use of Live Cell Imaging and Automated Image Analysis to Assist With Determining Optimal Parameters for Angiogenic Assay in vitro","volume":"7","year":"2019","journal-title":"Front Cell Dev Biol"},{"key":"2023041202300710000_2023.04.07.536013v1.18","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-2346"},{"key":"2023041202300710000_2023.04.07.536013v1.19","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1053\/j.gastro.2017.03.008","article-title":"Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice","volume":"153","year":"2017","journal-title":"Gastroenterology"},{"key":"2023041202300710000_2023.04.07.536013v1.20","doi-asserted-by":"crossref","first-page":"10252","DOI":"10.1038\/s41598-021-89866-1","article-title":"Development and comparison of novel bioluminescent mouse models of pancreatic neuroendocrine neoplasm metastasis","volume":"11","year":"2021","journal-title":"Sci Rep"},{"key":"2023041202300710000_2023.04.07.536013v1.21","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-14-0173"},{"key":"2023041202300710000_2023.04.07.536013v1.22","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41590-020-00850-9","article-title":"IL-2 regulates tumor-reactive CD8(+) T cell exhaustion by activating the aryl hydrocarbon receptor","volume":"22","year":"2021","journal-title":"Nat Immunol"},{"key":"2023041202300710000_2023.04.07.536013v1.23","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2015-0455"},{"key":"2023041202300710000_2023.04.07.536013v1.24","doi-asserted-by":"crossref","first-page":"6607","DOI":"10.2147\/CMAR.S261257","article-title":"Antiproliferative Effects of Telotristat Ethyl in Patients with Neuroendocrine Tumors: The TELEACE Real-World Chart Review Study","volume":"12","year":"2020","journal-title":"Cancer Manag Res"},{"key":"2023041202300710000_2023.04.07.536013v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2005.01.003"},{"key":"2023041202300710000_2023.04.07.536013v1.26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.3.674"},{"key":"2023041202300710000_2023.04.07.536013v1.27","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0202"},{"key":"2023041202300710000_2023.04.07.536013v1.28","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s11033-022-07693-7","article-title":"Glutamine increases stability of TPH1 mRNA via p38 mitogen-activated kinase in mouse mastocytoma cells","volume":"50","year":"2023","journal-title":"Mol Biol Rep"},{"key":"2023041202300710000_2023.04.07.536013v1.29","doi-asserted-by":"crossref","unstructured":"Park, S. , Kim, Y. , Lee, J. , Lee, J. Y. , Kim, H. , Lee, S. & Oh, C. M . 2021. A Systems Biology Approach to Investigating the Interaction between Serotonin Synthesis by Tryptophan Hydroxylase and the Metabolic Homeostasis. Int J Mol Sci, 22.","DOI":"10.3390\/ijms22052452"},{"key":"2023041202300710000_2023.04.07.536013v1.30","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-17-0455"},{"key":"2023041202300710000_2023.04.07.536013v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-018-0110-y"},{"key":"2023041202300710000_2023.04.07.536013v1.32","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abc8188"},{"key":"2023041202300710000_2023.04.07.536013v1.33","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.03.007"},{"key":"2023041202300710000_2023.04.07.536013v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/335254a0"},{"key":"2023041202300710000_2023.04.07.536013v1.35","doi-asserted-by":"crossref","unstructured":"Soldevilla, B. , Lopez-Lopez, A. , Lens-Pardo, A. , Carretero-Puche, C. , Lopez-Gonzalvez, A. , La Salvia, A. , Gil-Calderon, B. , Riesco-Martinez, M. C. , Espinosa-Olarte, P. , Sarmentero, J. , Rubio-Cuesta, B. , Rincon, R. , Barbas, C. & Garcia-Carbonero, R. 2021. Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance. Cancers (Basel ), 13.","DOI":"10.3390\/cancers13112634"},{"key":"2023041202300710000_2023.04.07.536013v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.25049"},{"key":"2023041202300710000_2023.04.07.536013v1.37","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1016\/j.febslet.2012.05.047","article-title":"Serotonin activates angiogenic phosphorylation signaling in human endothelial cells","volume":"586","year":"2012","journal-title":"FEBS Lett"},{"key":"2023041202300710000_2023.04.07.536013v1.38","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1186\/s12885-022-09569-2","article-title":"Tryptophan hydroxylase 1 drives glioma progression by modulating the serotonin\/L1CAM\/NF-kappaB signaling pathway","volume":"22","year":"2022","journal-title":"BMC Cancer"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.04.07.536013","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:31:48Z","timestamp":1768451508000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.04.07.536013"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,8]]},"references-count":38,"URL":"https:\/\/doi.org\/10.1101\/2023.04.07.536013","relation":{},"subject":[],"published":{"date-parts":[[2023,4,8]]},"subtype":"preprint"}}