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Sodium taurocholate cotransporting polypeptide mediates dual actions of deoxycholic acid in human hepatocellular carcinoma cells: enhanced apoptosis versus growth stimulation

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Abstract

Purpose

The hydrophobic bile acid, deoxycholic acid (DC), can induce apoptosis in hepatocytes. The roles of DC and its transporter are not yet established in hepatocellular carcinoma (HCC) cells. We investigated DC-induced alterations in HCC cell growth, with a particular focus on the effect of the expression of bile acid (BA)-transporting Na+-dependent taurocholic cotransporting polypeptides (NTCPs).

Methods

We determined NTCP expression in four human HCC cell lines: Huh-BAT, Huh-7, SNU-761, and SNU-475. NTCP expression and apoptotic signaling cascades were examined by immunoblot analyses. Cell viability was assessed using the 3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assay. Wound healing and invasion assays were performed to evaluate cell migration and invasion abilities. Real-time polymerase chain reaction was performed to measure IL-8 expression levels. Nuclear factor kappa B (NF-κB) activity was evaluated by enzyme-linked immunosorbent assay.

Results

The HCC cell lines revealed varying NTCP expression levels, and DC treatment had dual effects, depending on NTCP expression. DC induced apoptosis in NTCP-positive HCC cells, especially under hypoxic conditions. In NTCP-negative HCC cells, simultaneous treatment with DC and cyclooxygenase inhibitor markedly decreased aggressive cellular behaviors via the inhibition of NF-κB/COX-2/IL-8 pathways.

Conclusion

Hydrophobic bile acid offers therapeutic potential for patients with advanced HCC via different mechanisms depending on NTCP expression levels within the tumor.

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Abbreviations

BA:

Bile acid

DC:

Deoxycholic acid

HCC:

Hepatocellular carcinoma

NTCP:

Na+-dependent taurocholic cotransporting polypeptides

COX:

Cyclooxygenase

IL:

Interleukin

TACE:

Transarterial chemoembolization

CDC:

Chenodeoxycholate

DC:

Deoxycholate

GCDC:

Glycochenodeoxycholate

EGFR:

Epidermal growth factor receptor

TGR5:

G-protein-coupled bile acid receptor

FXR:

Farnesoid-X-receptor

NFκB:

Nuclear factor kappa B

DMEM:

Dulbecco’s Modified Eagle’s Medium

RPMI:

Roswell Park Memorial Institute

FBS:

Fetal bovine serum

eIF2α:

Eukaryotic initiation factor 2α

JNK:

c-Jun N-terminal Kinase

siRNAs:

Small interfering RNA

MTS:

3,4-(5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt

ELISA:

Enzyme-linked immunosorbent assay

HBSS:

Hank’s balanced salt solution

PCR:

Polymerase chain reaction

RNA:

Ribonucleic acid

cDNA:

Complementary deoxyribonucleic acid

MoMLV:

Moloney murine leukemia virus

mRNA:

Messenger RNA

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

SD:

Standard deviation

ER:

Endoplasmic reticulum

Mcl-1:

Induced myeloid leukemia cell differentiation protein

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant No. 20100007381) and by the Liver Research Foundation of Korea.

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Authors and Affiliations

  1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehakro, Chongno-gu, Seoul, 110-744, Republic of Korea

    Eun Sun Jang, Jung-Hwan Yoon, Sung-Hee Lee, Soo-Mi Lee, Jeong-Hoon Lee, Su Jong Yu, Yoon Jun Kim, Hyo-Suk Lee & Chung Yong Kim

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  1. Eun Sun Jang
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Jang, E.S., Yoon, JH., Lee, SH. et al. Sodium taurocholate cotransporting polypeptide mediates dual actions of deoxycholic acid in human hepatocellular carcinoma cells: enhanced apoptosis versus growth stimulation. J Cancer Res Clin Oncol 140, 133–144 (2014). https://doi.org/10.1007/s00432-013-1554-6

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