Skip to main content

Advertisement

SpringerLink
Log in

Knockdown of RON Inhibits AP-1 Activity and Induces Apoptosis and Cell Cycle Arrest Through the Modulation of Akt/FoxO Signaling in Human Colorectal Cancer Cells

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background/Aims

Altered Recepteur d’Origine nantais (RON) expression transduces signals inducting invasive growth phenotype that includes cell proliferation, migration, matrix invasion, and protection of apoptosis in human cancer cells. The aims of the current study were to evaluate whether RON affects tumor cell behavior and cellular signaling pathways including activator protein-1 (AP-1) and Akt/forkhead box O (FoxO) in human colorectal cancer cells.

Methods

To study the biological role of RON on tumor cell behavior and cellular signaling pathways in human colorectal cancer, we used small interfering RNA (siRNA) to knockdown RON gene expression in human colorectal cancer cell line, DKO-1.

Results

Knockdown of RON diminished migration, invasion, and proliferation of human colorectal cancer cells. Knockdown of RON decreased AP-1 transcriptional activity and expression of AP-1 target genes. Knockdown of RON activated cleaved caspase-3, -7, -9, and PARP, and down-regulated the expression of Mcl-1, survivin and XIAP, leading to induction of apoptosis. Knockdown of RON induced cell cycle arrest in the G2/M phase of cancer cells by an increase of p27 and a decrease of cyclin D3. Knockdown of RON inhibited the phosphorylation of Akt/FoxO signaling proteins such as Ser473 and Thr308 of Akt and FoxO1/3a.

Conclusions

These results indicate that knockdown of RON inhibits AP-1 activity and induces apoptosis and cell cycle arrest through the modulation of Akt/FoxO signaling in human colorectal cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Lu Y, Yao HP, Wang MH. Multiple variants of the RON receptor tyrosine kinase: biochemical properties, tumorigenic activities, and potential drug targets. Cancer Lett. 2007;257:157–164.

    Article  PubMed  CAS  Google Scholar 

  2. Leonis MA, Thobe MN, Waltz SE. Ron-receptor tyrosine kinase in tumorigenesis and metastasis. Future Oncol. 2007;3:441–448.

    Article  PubMed  CAS  Google Scholar 

  3. Camp ER, Liu W, Fan F, Yang A, Somcio R, Ellis LM. RON, a tyrosine kinase receptor involved in tumor progression and metastasis. Ann Surg Oncol. 2005;12:273–281.

    Article  PubMed  Google Scholar 

  4. Wang MH, Yao HP, Zhou YQ. Oncogenesis of RON receptor tyrosine kinase: a molecular target for malignant epithelial cancers. Acta Pharmacol Sin. 2006;27:641–650.

    Article  PubMed  CAS  Google Scholar 

  5. Wang MH, Wang D, Chen YQ. Oncogenic and invasive potentials of human macrophage-stimulating protein receptor, the RON receptor tyrosine kinase. Carcinogenesis. 2003;24:1291–1300.

    Article  PubMed  CAS  Google Scholar 

  6. Wagh PK, Peace BE, Waltz SE. Met-related receptor tyrosine kinase Ron in tumor growth and metastasis. Adv Cancer Res. 2008;100:1–33.

    Article  PubMed  CAS  Google Scholar 

  7. Danilkovitch-Miagkova A. Oncogenic signaling pathways activated by RON receptor tyrosine kinase. Curr Cancer Drug Targets. 2003;3:31–40.

    Article  PubMed  CAS  Google Scholar 

  8. Lee CT, Chow NH, Su PF, Lin SC, Lin PC, Lee JC. The prognostic significance of RON and MET coexpression in patients with colorectal cancer. Dis Colon Rectum. 2008;5:1268–1274.

    Article  Google Scholar 

  9. Maggiora P, Marchio S, Stella MC, et al. Overexpression of the RON gene in human breast carcinoma. Oncogene. 1998;16:2927–2933.

    Article  PubMed  CAS  Google Scholar 

  10. Willett CG, Wang MH, Emanuel RL, et al. Macrophage-stimulating protein and its receptor in non-small cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration. Am J Respir Cell Mol Biol. 1998;18:489–496.

    PubMed  CAS  Google Scholar 

  11. Maggiora P, Lorenzato A, Fracchioli S, et al. The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness. Exp Cell Res. 2003;288:382–389.

    Article  PubMed  CAS  Google Scholar 

  12. Cheng HL, Liu HS, Lin YJ, et al. Coexpression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br J Cancer. 2005;92:1906–1914.

    Article  PubMed  CAS  Google Scholar 

  13. Matthews CP, Colburn NH, Young MR. AP-1 a target for cancer prevention. Curr Cancer Drug Targets. 2007;7:317–324.

    Article  PubMed  CAS  Google Scholar 

  14. Shaulian E. AP-1-The Jun proteins: oncogenes or tumor suppressors in disguise? Cell Signal. 2010;22:894–899.

    Article  PubMed  CAS  Google Scholar 

  15. Ozanne BW, Spence HJ, McGarry LC, Hennigan RF. Transcription factors control invasion: AP-1 the first among equals. Oncogene. 2007;26:1–10.

    Article  PubMed  CAS  Google Scholar 

  16. Dong Z, Birrer MJ, Watts RG, Matrisian LM, Colburn NH. Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells. Proc Natl Acad Sci USA. 1994;91:609–613.

    Article  PubMed  CAS  Google Scholar 

  17. Young MR, Li JJ, Rincón M, et al. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA. 1999;96:9827–9832.

    Article  PubMed  CAS  Google Scholar 

  18. Yang JY, Hung MC. A new fork for clinical application: targeting forkhead transcription factors in cancer. Clin Cancer Res. 2009;15:752–757.

    Article  PubMed  CAS  Google Scholar 

  19. Finlay D, Cantrell D. Phosphoinositide 3-kinase and the mammalian target of rapamycin pathways control T cell migration. Ann N Y Acad Sci. 2010;1183:149–157.

    Article  PubMed  CAS  Google Scholar 

  20. Reagan-Shaw S, Ahmad N. The role of Forkhead-box Class O (FoxO) transcription factors in cancer: a target for the management of cancer. Toxicol Appl Pharmacol. 2007;224:360–368.

    Article  PubMed  CAS  Google Scholar 

  21. Lam EW, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cell fate. Biochem Soc Trans. 2006;34:722–726.

    Article  PubMed  CAS  Google Scholar 

  22. Ito K, Bernardi R, Pandolfi PP. A novel signaling network as a critical rheostat for the biology and maintenance of the normal stem cell and the cancer-initiating cell. Curr Opin Genet Dev. 2009;19:51–59.

    Article  PubMed  CAS  Google Scholar 

  23. Vaiopoulos AG, Papachroni KK, Papavassiliou AG. Colon carcinogenesis: learning from NF-kappaB and AP-1. Int J Biochem Cell Biol. 2010;42:1061–1065.

    Article  PubMed  CAS  Google Scholar 

  24. Raff MC. Social controls on cell survival and cell death. Nature. 1992;356:397–400.

    Article  PubMed  CAS  Google Scholar 

  25. Mason EF, Rathmell JC. Cell metabolism: an essential link between cell growth and apoptosis. Biochim Biophys Acta. 2011;1813:645–654.

    Article  PubMed  CAS  Google Scholar 

  26. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20.

    Article  PubMed  CAS  Google Scholar 

  27. Morgan DO. Principles of CDK regulation. Nature. 1995;374:131–134.

    Article  PubMed  CAS  Google Scholar 

  28. Grana X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene. 1995;11:211–219.

    PubMed  CAS  Google Scholar 

  29. Johnson N, Shapiro GI. Cyclin-dependent kinases (cdks) and the DNA damage response: rationale for cdk inhibitor-chemotherapy combinations as an anticancer strategy for solid tumors. Expert Opin Ther Targets. 2010;14:1199–1212.

    Article  PubMed  CAS  Google Scholar 

  30. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9:59–71.

    Article  PubMed  CAS  Google Scholar 

  31. Li Z, Yao H, Guin S, Padhye SS, Zhou YQ, Wang MH. Monoclonal antibody (mAb)-induced down-regulation of RON receptor tyrosine kinase diminishes tumorigenic activities of colon cancer cells. Int J Oncol. 2010;37:473–482.

    PubMed  Google Scholar 

  32. Wang MH, Lao WF, Wang D, Luo YL, Yao HP. Blocking tumorigenic activities of colorectal cancer cells by a splicing RON receptor variant defective in the tyrosine kinase domain. Cancer Biol Ther. 2007;6:1121–1129.

    Article  PubMed  CAS  Google Scholar 

  33. Baba Y, Nosho K, Shima K, et al. Phosphorylated AKT expression is associated with PIK3CA mutation, low stage, and favorable outcome in 717 colorectal cancers. Cancer. 2011;117:1399–1408.

    Article  PubMed  CAS  Google Scholar 

  34. McNamara CR, Degterev A. Small-molecule inhibitors of the PI3K signaling network. Future Med Chem. 2011;3:549–565.

    Article  PubMed  CAS  Google Scholar 

  35. Kousteni S. FoxO1: a molecule for all seasons. J Bone Miner Res. 2011;26:912–917.

    Article  PubMed  CAS  Google Scholar 

  36. Myatt SS, Brosens JJ, Lam EW. Sense and sensitivity: FOXO and ROS in cancer development and treatment. Antioxid Redox Signal. 2011;14:675–687.

    Article  PubMed  CAS  Google Scholar 

  37. Zanella F, Carnero A. Adding more content to screening: reactivation of FOXO as a therapeutic strategy. Clin Transl Oncol. 2009;11:651–658.

    Article  PubMed  Google Scholar 

  38. Maiese K, Chong ZZ, Hou J, Shang YC. The “O” class: crafting clinical care with FoxO transcription factors. Adv Exp Med Biol. 2009;665:242–260.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the Korea Science & Engineering Foundation through the Medical Research Center for Gene Regulation (R13-2002-013-06002-0) at Chonnam National University, Republic of Korea, and partly by a grant (0720570) from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Chonnam National University Medical School, 8 Hak-Dong, Dong-ku, Gwangju, 501-757, Korea

    Cho-Yun Chung, Young-Lan Park, Young-A Song, Eun Myung, Kyu-Yeol Kim, Gi-Hoon Lee, Ho-Seok Ki, Kang-Jin Park, Sung-Bum Cho, Wan-Sik Lee & Young-Eun Joo

  2. Department of Biochemistry, Chonnam National University Medical School, Gwangju, Korea

    Young-Do Jung

  3. Department of Pharmacology, Chonnam National University Medical School, Gwangju, Korea

    Kyung-Keun Kim

Authors
  1. Cho-Yun Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young-Lan Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Young-A Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eun Myung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyu-Yeol Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gi-Hoon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ho-Seok Ki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kang-Jin Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sung-Bum Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wan-Sik Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Young-Do Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kyung-Keun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Young-Eun Joo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young-Eun Joo.

Additional information

Cho-Yun Chung and Young-Lan Park contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chung, CY., Park, YL., Song, YA. et al. Knockdown of RON Inhibits AP-1 Activity and Induces Apoptosis and Cell Cycle Arrest Through the Modulation of Akt/FoxO Signaling in Human Colorectal Cancer Cells. Dig Dis Sci 57, 371–380 (2012). https://doi.org/10.1007/s10620-011-1892-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-011-1892-7

Keywords

Search

Navigation