# Serotonergic antidepressants as liver tumor preventives

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $425,094

## Abstract

PROJECT SUMMARY/ABSTRACT
The number of Americans at risk for hepatocellular carcinoma (HCC) is increasing due to the growing obesity
epidemic and its association with fatty liver disease, steatohepatitis, and cirrhosis. No medications have been
shown to prevent HCC in high-risk patients with chronic liver disease. The long-term goal is to define
mechanisms of hepatocarcinogenesis, providing a foundation for improved preventives, diagnostic tools, and
treatments for HCC. The overall objective of this proposal is to identify cellular and molecular mechanisms by
which serotonin promotes and antidepressants inhibit liver growth and tumor formation. The central hypothesis
of this proposal is that 1) serotonin promotes liver growth and tumorigenesis by stimulating the serotonin
receptor HTR2A on hepatocytes; and 2) serotonergic antidepressants inhibit liver growth and tumorigenesis by
antagonism of HTR2A. The following specific aims are proposed to test this hypothesis: 1) Determine the
cellular and molecular role of HTR2A in promoting liver tumor cell viability and liver growth; 2) Determine if
amitriptyline suppresses liver growth and tumor formation via HTR2A; 3) Identify downstream genes that
mediate amitriptyline’s effects on -catenin-driven liver growth and tumorigenesis and determine whether
amitriptyline’s effects required activated -catenin. In Aim 1, the hypothesis that HTR2A mediates serotonin’s
growth-promoting effects on HCC cells will be tested by measuring the effect of HTR2A knockdown on
serotonin responsiveness of human liver cancer cell lines. In parallel, HTR2A orthologs will be knocked down
in a zebrafish HCC model to determine the receptor and cell type(s) that mediate serotonin’s growth-promoting
effects on hepatocytes in vivo. In Aim 2, the hypothesis that amitriptyline suppresses liver growth and tumor
formation via inhibition of HTR2A will be tested using complementary approaches in human liver cancer cell
lines and zebrafish as in Aim 1. In Aim 3, a prioritized list of genes, downregulated by amitriptyline treatment in
mouse HCC, will be characterized for effects on liver growth and tumorigenesis and response to amitriptyline
using zebrafish and mouse HCC models. The hypothesis that amitriptyline’s actions require activated -catenin
will be tested. We expect the proposed studies to define how serotonin signaling and serotonergic
antidepressants modulate liver growth and tumorigenesis. This research is significant because it will form the
basis for identifying drugs to prevent liver cancer in high-risk patients, which could save thousands of lives
each year.

## Key facts

- **NIH application ID:** 9827489
- **Project number:** 5R01CA222570-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Kimberley Jane Evason
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,094
- **Award type:** 5
- **Project period:** 2017-12-13 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9827489

## Citation

> US National Institutes of Health, RePORTER application 9827489, Serotonergic antidepressants as liver tumor preventives (5R01CA222570-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9827489. Licensed CC0.

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