Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
October 2012 Volume 28 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
October 2012 Volume 28 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells

  • Authors:
    • Sung-Chul Lim
    • Hong-Quan Duong
    • Keshab Raj Parajuli
    • Song Iy Han
  • View Affiliations / Copyright

    Affiliations: Research Center for Resistant Cells, Chosun University, Gwangju 501-759, Republic of Korea
  • Pages: 1429-1434
    |
    Published online on: July 19, 2012
       https://doi.org/10.3892/or.2012.1918
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Ursodeoxycholic acid (UDCA) has been regarded as a suppressor of gastrointestinal cancer, but the mechanisms underlying its antitumor effects are not fully understood. Previously, we reported the antitumor effect of UDCA by demonstrating that UDCA induces apoptosis of gastric cancer cells. Bile acids are known to activate the ERK pathway and ERK is a representative oncogenic kinase in cancer cells. Here, we investigated the role of ERK in UDCA-induced gastric cancer cell apoptosis. We found that UDCA enhanced the phosphorylation of ERK1/2 and MEK1/2. The prevention of MEK by the pharmacologic inhibitors PD98059 and U0126, resulted in decreased UDCA-induced apoptosis as shown by the reduction of apoptotic body formation, caspase-8 activity, and caspase-3, -6 and PARP cleavage, indicating that ERK exerts pro-apoptotic activity upon exposure to UDCA. In addition, U0126 reduced UDCA-triggered TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) expression. In gene silencing studies, we observed that RNA interference of ERK2 decreased apoptosis and reduced DR5 overexpression. Lipid raft disrupting agent, methyl-β-cyclodextrin, blunted the phosphorylation of ERK1/2, indicating that ERK activation is regulated in a lipid raft-dependent manner. On the other hand, tumor-promoting bile acid, deoxycholic acid (DCA), also phosphorylated ERK in SNU601 cells. However, the DCA-triggered ERK pathway exerted anti-apoptotic function in the cells. Suppression of the ERK pathway enhanced DCA-induced apoptosis, and ERK activation was observed to be lipid raft-independently controlled. These results indicated that UDCA and DCA may cause differential responses in gastric cancer cells through the ERK signaling molecule. Thus, ERK activation may be a possible mechanism by which UDCA and DCA represent differential activities in gastrointestinal cancer.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Greim H, Trulzsch D, Czygan P, Rudick J, Hutterer F, Schaffner F and Popper H: Mechanism of cholestasis. 6. Bile acids in human livers with or without biliary obstruction. Gastroenterology. 63:846–850. 1972.PubMed/NCBI

2 

Qiao L, Studer E, Leach K, McKinstry R, Gupta S, Decker R, Kukreja R, Valerie K, Nagarkatti P, El Deiry W, et al: Deoxycholic acid (DCA) causes ligand-independent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: inhibition of EGFR/mitogen-activated protein kinase-signaling module enhances DCA-induced apoptosis. Mol Biol Cell. 12:2629–2645. 2001. View Article : Google Scholar

3 

Loddenkemper C, Keller S, Hanski ML, Cao M, Jahreis G, Stein H, Zeitz M and Hanski C: Prevention of colitis-associated carcinogenesis in a mouse model by diet supplementation with ursodeoxycholic acid. Int J Cancer. 118:2750–2757. 2006. View Article : Google Scholar

4 

Alberts DS, Martinez ME, Hess LM, Einspahr JG, Green SB, Bhattacharyya AK, Guillen J, Krutzsch M, Batta AK, Salen G, et al: Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. J Natl Cancer Inst. 97:846–853. 2005. View Article : Google Scholar : PubMed/NCBI

5 

Qiao D, Stratagouleas ED and Martinez JD: Activation and role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis. Carcinogenesis. 22:35–41. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Rust C, Karnitz LM, Paya CV, Moscat J, Simari RD and Gores GJ: The bile acid taurochenodeoxycholate activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J Biol Chem. 275:20210–20216. 2000. View Article : Google Scholar : PubMed/NCBI

7 

Higuchi H and Gores GJ: Bile acid regulation of hepatic physiology: IV. Bile acids and death receptors. Am J Physiol Gastrointest Liver Physiol. 284:G734–G738. 2003. View Article : Google Scholar : PubMed/NCBI

8 

Higuchi H, Grambihler A, Canbay A, Bronk SF and Gores GJ: Bile acids up-regulate death receptor 5/TRAIL-receptor 2 expression via a c-Jun N-terminal kinase-dependent pathway involving Sp1. J Biol Chem. 279:51–60. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Higuchi H, Bronk SF, Taniai M, Canbay A and Gores GJ: Cholestasis increases tumor necrosis factor-related apoptotis-inducing ligand (TRAIL)-R2/DR5 expression and sensitizes the liver to TRAIL-mediated cytotoxicity. J Pharmacol Exp Ther. 303:461–467. 2002. View Article : Google Scholar

10 

Higuchi H, Bronk SF, Takikawa Y, Werneburg N, Takimoto R, El-Deiry W and Gores GJ: The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis. J Biol Chem. 276:38610–38618. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 270:1326–1331. 1995. View Article : Google Scholar : PubMed/NCBI

12 

Qiao L, Han SI, Fang Y, Park JS, Gupta S, Gilfor D, Amorino G, Valerie K, Sealy L, Engelhardt JF, et al: Bile acid regulation of C/EBPbeta, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Mol Cell Biol. 23:3052–3066. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Looby E, Abdel-Latif MM, Athie-Morales V, Duggan S, Long A and Kelleher D: Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells. BMC Cancer. 9:1902009. View Article : Google Scholar : PubMed/NCBI

14 

Baek MK, Park JS, Park JH, Kim MH, Kim HD, Bae WK, Chung IJ, Shin BA and Jung YD: Lithocholic acid upregulates uPAR and cell invasiveness via MAPK and AP-1 signaling in colon cancer cells. Cancer Lett. 290:123–128. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Liao M, Zhao J, Wang T, Duan J, Zhang Y and Deng X: Role of bile salt in regulating Mcl-1 phosphorylation and chemoresistance in hepatocellular carcinoma cells. Mol Cancer. 10:442011. View Article : Google Scholar : PubMed/NCBI

16 

Oka H, Chatani Y, Hoshino R, Ogawa O, Kakehi Y, Terachi T, Okada Y, Kawaichi M, Kohno M and Yoshida O: Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res. 55:4182–4187. 1995.PubMed/NCBI

17 

Sivaraman VS, Wang H, Nuovo GJ and Malbon CC: Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest. 99:1478–1483. 1997. View Article : Google Scholar : PubMed/NCBI

18 

Lim SC, Duong HQ, Choi JE, Lee TB, Kang JH, Oh SH and Han SI: Lipid raft-dependent death receptor 5 (DR5) expression and activation are critical for ursodeoxycholic acid-induced apoptosis in gastric cancer cells. Carcinogenesis. 32:723–731. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Lim SC, Choi JE, Kang HS and Si H: Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53-caspase 8 pathway in HepG2 hepatocellular carcinoma. Int J Cancer. 126:1582–1595. 2010.

20 

Zhao Y, Zhao X, Yang B, Neuzil J and Wu K: alpha-Tocopheryl succinate-induced apoptosis in human gastric cancer cells is modulated by ERK1/2 and c-Jun N-terminal kinase in a biphasic manner. Cancer Lett. 247:345–352. 2007. View Article : Google Scholar

21 

Schweyer S, Soruri A, Meschter O, Heintze A, Zschunke F, Miosge N, Thelen P, Schlott T, Radzun HJ and Fayyazi A: Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation. Br J Cancer. 91:589–598. 2004. View Article : Google Scholar : PubMed/NCBI

22 

Singh S, Upadhyay AK, Ajay AK and Bhat MK: p53 regulates ERK activation in carboplatin induced apoptosis in cervical carcinoma: a novel target of p53 in apoptosis. FEBS Lett. 581:289–295. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Wang X, Martindale JL and Holbrook NJ: Requirement for ERK activation in cisplatin-induced apoptosis. J Biol Chem. 275:39435–39443. 2000. View Article : Google Scholar

24 

Woessmann W, Chen X and Borkhardt A: Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines. Cancer Chemother Pharmacol. 50:397–404. 2002. View Article : Google Scholar : PubMed/NCBI

25 

Amran D, Sancho P, Fernandez C, Esteban D, Ramos AM, de Blas E, Gomez M, Palacios MA and Aller P: Pharmacological inhibitors of extracellular signal-regulated protein kinases attenuate the apoptotic action of cisplatin in human myeloid leukemia cells via glutathione-independent reduction in intracellular drug accumulation. Biochim Biophys Acta. 1743:269–279. 2005. View Article : Google Scholar

26 

Im E and Martinez JD: Ursodeoxycholic acid (UDCA) can inhibit deoxycholic acid (DCA)-induced apoptosis via modulation of EGFR/Raf-1/ERK signaling in human colon cancer cells. J Nutr. 134:483–486. 2004.PubMed/NCBI

27 

Lee HY, Crawley S, Hokari R, Kwon S and Kim YS: Bile acid regulates MUC2 transcription in colon cancer cells via positive EGFR/PKC/Ras/ERK/CREB, PI3K/Akt/IkappaB/NF-kappaB and p38/MSK1/CREB pathways and negative JNK/c-Jun/AP-1 pathway. Int J Oncol. 36:941–953. 2010.PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Lim S, Duong H, Parajuli KR and Han SI: Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells. Oncol Rep 28: 1429-1434, 2012.
APA
Lim, S., Duong, H., Parajuli, K.R., & Han, S.I. (2012). Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells. Oncology Reports, 28, 1429-1434. https://doi.org/10.3892/or.2012.1918
MLA
Lim, S., Duong, H., Parajuli, K. R., Han, S. I."Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells". Oncology Reports 28.4 (2012): 1429-1434.
Chicago
Lim, S., Duong, H., Parajuli, K. R., Han, S. I."Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells". Oncology Reports 28, no. 4 (2012): 1429-1434. https://doi.org/10.3892/or.2012.1918
Copy and paste a formatted citation
x
Spandidos Publications style
Lim S, Duong H, Parajuli KR and Han SI: Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells. Oncol Rep 28: 1429-1434, 2012.
APA
Lim, S., Duong, H., Parajuli, K.R., & Han, S.I. (2012). Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells. Oncology Reports, 28, 1429-1434. https://doi.org/10.3892/or.2012.1918
MLA
Lim, S., Duong, H., Parajuli, K. R., Han, S. I."Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells". Oncology Reports 28.4 (2012): 1429-1434.
Chicago
Lim, S., Duong, H., Parajuli, K. R., Han, S. I."Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells". Oncology Reports 28, no. 4 (2012): 1429-1434. https://doi.org/10.3892/or.2012.1918
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team