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Review

The farnesoid X receptor and colon cancer

Guofeng Xie, Jean-Pierre Raufman
Division of Gastroenterology and Hepatology, Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine,
Baltimore, MD 21201, USA.
Correspondence to: Dr. Guofeng Xie, Division of Gastroenterology and Hepatology, Veterans Affairs Maryland Health Care System, University of
Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201, USA. E-mail: gxie@medicine.umaryland.edu

A B S T R AC T
Worldwide, colorectal cancer (CRC) is a leading cause of cancer death, primarily because of limited therapeutic options for those
with advanced disease. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated
transcription factors. Besides its prominent role in bile acid synthesis, and lipoprotein and glucose metabolism, recent data indicate
that FXR also plays a key role in regulating intestinal cell proliferation and carcinogenesis. Here, we review the role of FXR as a
tumor suppressor in CRC, with particular emphasis on the molecular mechanisms underlying FXR-dependent tumorigenesis and
its regulation, FXR-bile acid relationships and FXR-targeted drugs as potential therapeutic agents.

Key words: Colon cancer; farnesoid X receptor; nuclear receptor; tumor suppressor

INTRODUCTION discontinuation of treatment.

Despite advances in screening and treatment, colorectal FARNESOID X RECEPTOR AND ITS LIGANDS
cancer (CRC) results in over 50,000 deaths yearly and
may soon surpass lung cancer as the overall leading Farnesoid X receptor (FXR) [nuclear receptor subfamily
cause of cancer-related death in the USA alone. [1,2] Despite 1, group H, member 4 (NR1H4)] is a member of the
increased efforts to improve access and compliance, nuclear receptor superfamily of ligand-activated transcription
many people neglect CRC screening. In addition, factors and acts as a bile acid sensor. [12-14] FXR regulates
the efficacy of colon cancer screening is limited by the the expression of genes involved in bile acid synthesis, and
limited sensitivity of tests, “miss” rates on colonoscopy cholesterol and triglyceride metabolism by binding to their
and other factors. Chemoprevention using non-steroidal promoters as a homo- or hetero-dimer with a common partner of
anti-inflammatory drugs is marginally effective [3,4] but nuclear receptors, retinoid X receptor. FXR agonists include
limited by gastrointestinal (GI) and cardiovascular naturally-occurring bile acids (e.g. chenodeoxycholic acid
[5]
[6]
toxicity that led to the withdrawal of rofecoxib. Non- [CDCA; EC50 of 10-50 µmol/L]), synthetic compounds
[7]
[15]
surgical treatments (e.g. chemotherapy and radiation) for GW4064 (EC50 of 15 nmol/L), 6E-CDCA (EC50 of
[16]
advanced colon cancer have limited efficacy. Although 99 nmol/L), WAY-362450 (EC50 of 4 nmol/L) and
[17]
[18]
the use of biologicals that target vascular endothelial fexaramine (EC50 of 25 nmol/L); FXR antagonists include
[19]
growth factor and epidermal growth factor receptor plant-derived guggulsterone and synthetic AGN34. The
[20]
[21]
(EGFR) (i.e. bevacizumab, cetuximab and panitumumab) FXR agonist fexaramine is poorly absorbed following oral
may increase survival with advanced CRC by several administration; thus, it acts as an intestine-restricted FXR
months, these agents have a limited impact on 5-year agonist without systemic side-effects. Oral administration
[19]
survival, on the order of only 10%. [8-10] Moreover, their of fexaramine results in serum levels that are an order of
use is limited by off-target toxicity that commonly magnitude lower than those obtained following intraperitoneal
reduces patient tolerance; EGFR, which is expressed injection of the drug, and it activates FXR target genes only
widely in non-intestinal epithelial cells (e.g. dermal in the GI tract. [19]
epithelial cells), causes skin reactions that may force
[11]
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How to cite this article: Xie G, Raufman JP. The farnesoid X receptor
DOI: and colon cancer. J Cancer Metastasis Treat 2016;2:24-8.
10.4103/2394-4722.164288
Received: 29-04-2015; Accepted: 21-07-2015
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© 2016 Journal of Cancer Metastasis and Treatment ¦ Published by OAE Publishing Inc.