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Differential Regulation of EGFR–MAPK Signaling by Deoxycholic Acid (DCA) and Ursodeoxycholic Acid (UDCA) in Colon Cancer

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Abstract

A high-fat diet coincides with increased levels of bile acids. This increase in bile acids, particularly deoxycholic acid (DCA), has been strongly associated with the development of colon cancer. Conversely, ursodeoxycholic acid (UDCA) may have chemopreventive properties. Although structurally similar, DCA and UDCA present different biological and pathological effects in colon cancer progression. The differential regulation of cancer by these two bile acids is not yet fully understood. However, one possible explanation for their diverging effects is their ability to differentially regulate signaling pathways involved in the multistep progression of colon cancer, such as the epidermal growth factor receptor (EGFR)–mitogen-activated protein kinase (MAPK) pathway. This review will examine the biological effects of DCA and UDCA on colon cancer development, as well as the diverging effects of these bile acids on the oncogenic signaling pathways that play a role in colon cancer development, with a particular emphasis on bile acid regulation of the EGFR–MAPK pathway.

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Abbreviations

15-PGDH:

15-Hydroxyprostaglandin dehydrogenase

AKT:

Protein kinase B

AOM:

Azoxymethane

AP-1:

Activator protein 1

AR:

Amphiregulin

ATF-2:

Activating transcription factor 2

BRE:

Brain and reproductive organ-expressed protein

CA:

Cholic acid

CCK:

Cholecystokinin

CDCA:

Chenodeoxycholic acid

CDK2:

Cyclin-dependent kinase 2

COX-2:

Cyclooxygenase-2

CYP7a:

Cholesterol 7 alpha-hydroxylase

DSH:

Disheveled

EGFR:

Epidermal growth factor receptor

ELK-1:

E twenty six-like transcription factor 1

ERK1/2:

Extracellular signal-regulated kinases 1 and 2

FXR-α:

Farnesoid X receptor-alpha

GCDC:

Glycochenodeoxycholate

GUDCA:

Glycoursodeoxycholate

HDAC6:

Histone deacetylase 6

HIF-1α:

Hypoxia-inducible factor 1 alpha

IAP:

Intestinal alkaline phosphatase

IκBα:

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha

IL-8:

Interleukin 8

Irs-1:

Insulin receptor substrate 1

JNK:

c-Jun N-terminal kinase

LCA:

Lithocholic acid

MAPK:

Mitogen-activated protein kinase

MDM2:

Murine double minute 2

MMP-9:

Matrix metallopeptidase 9

MNNG:

N-Methyl-N′-nitro-N-nitrosoguanidine

MUC2:

Mucin 2

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

Nur77:

Nuclear receptor subfamily 4 group A member 1

PARP:

Poly (ADP-ribose) polymerase

PGE2:

Prostaglandin E2

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

PLA2:

Phospholipase A2

PXR:

Pregnane X receptor

ROS:

Reactive oxygen species

TCA:

Taurocholic acid

TCDC:

Taurochenodeoxycholate

TDCA:

Taurodeoxycholic acid

TGF-α:

Transforming growth factor alpha

TGR5:

G Protein-coupled receptor

TUDCA:

Tauroursodeoxycholate

uPA:

Urokinase-type plasminogen activator

uPAR:

Urokinase-type plasminogen activator receptor

VDR:

Vitamin D receptor

VEGF:

Vascular endothelial growth factor

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Acknowledgments

We are thankful to Cecil J. Gomes, BS, who assisted in the editing of this manuscript and also to Josh Brownlee, BS, for assistance with production of 3-dimensional figures. This work was supported by the RO1 CA129688 and the minority supplement CA129688 S1 awarded by the National Institute of Health, to Jesse D. Martinez.

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  1. Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, 1515 N. Campbell Ave., PO Box 245024, Tucson, AZ, 85724-5024, USA

    Sara M. Centuori & Jesse D. Martinez

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Correspondence to Jesse D. Martinez.

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Centuori, S.M., Martinez, J.D. Differential Regulation of EGFR–MAPK Signaling by Deoxycholic Acid (DCA) and Ursodeoxycholic Acid (UDCA) in Colon Cancer. Dig Dis Sci 59, 2367–2380 (2014). https://doi.org/10.1007/s10620-014-3190-7

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