Preprint
Inhibition of serotonin biosynthesis in neuroendocrine neoplasm suppresses tumor growth in vivo
bioRxiv
Cold Spring Harbor Laboratory
04/08/2023
DOI: 10.1101/2023.04.07.536013
PMCID: PMC10104152
PMID: 37066322
Abstract
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
in vitro
and
in vivo
. The levels of Tph1 in various neuroendocrine neoplasms (NENs) were determined and the biological effects of Tph1 inhibition
in vitro
and
in vivo
using genetic and pharmacologic approaches was tested. Gene and protein expression analyses were performed on patient tumors and cancer cell lines. shRNAs targeting
TPH1
were used to create stable knockdown in BON cells. Control and knockdown lines were assessed for their growth rates
in vitro
and
in vivo
, angiogenesis potential, serotonin levels, endothelial cell tube formation, tumor weight, and tumor vascularity.
TPH1
is highly expressed in SBNETs and many cancer types.
TPH1
knockdown cells and telotristat treated cells showed similar growth rates as control cells
in vitro
. However,
TPH1
knockdown cells formed smaller tumors
in vivo
and tumors were less vascularized. Although Tph1 inhibition with telotristat showed no effect on tumor cell growth
in vitro
, Tph1 inhibition reduced tumor formation
in vivo
. Serotonin inhibition in combination with other therapies is a promising new avenue for targeting metabolic vulnerabilities in NENs.
Details
- Title: Subtitle
- Inhibition of serotonin biosynthesis in neuroendocrine neoplasm suppresses tumor growth in vivo
- Creators
- Dane H. Tow - University of IowaCatherine G. Tran - University of IowaLuis C. Borbon - University of IowaMaclain Ridder - University of IowaGuiying Li - University of IowaCourtney A. Kaemmer - University of IowaEllen Abusada - University of IowaAswanth Harish Mahalingam - Institute of Cancer ResearchAnguraj Sadanandam - Institute of Cancer ResearchChandrikha ChandrasekaranJoseph Dillon - University of IowaDouglas R. Spitz - University of IowaDawn E. Quelle - University of IowaCarlos H.F. Chan - University of IowaAndrew Bellizzi - University of IowaJames R. Howe - University of IowaPo Hien Ear - University of Iowa
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- Publisher
- Cold Spring Harbor Laboratory
- DOI
- 10.1101/2023.04.07.536013
- PMID
- 37066322
- PMCID
- PMC10104152
- Language
- English
- Date posted
- 04/08/2023
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Surgery; Internal Medicine; Pathology; Neuroscience and Pharmacology; Radiation Oncology
- Record Identifier
- 9984398211602771
Metrics
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