Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways

Oncogene volume 22, pages 7809–7818 (2003)Cite this article

Abstract

The production of interleukin-6 (IL-6) has been discovered in a variety of human tumors. Here we report the expression of IL-6, IL-6 receptor α (IL-6Rα), and gp130 in human esophageal carcinoma tissues. We further demonstrate that IL-6 protects an esophageal carcinoma cell line CE48T/VGH from apoptosis induced by staurosporine. IL-6 stimulation induced a rapid phosphorylation of gp130 and STAT3, and a dominant-negative STAT3 completely abolished the antiapoptotic effect. IL-6 also activated ERK 1/2 in CE48T/VGH cells. Inhibition of the ERK activation by PD98059 and transfection of a dominant-negative ERK2 completely blocked the protection of IL-6 against apoptosis. Thus, both STAT and MAP kinase pathways are responsible for the IL-6-delivered survival signal in human esophageal carcinoma cells. In contrast, PI3-K inhibitors only partially attenuated the effect of IL-6, suggesting that PI3-K does not play a major role in the antiapoptotic signal of IL-6 in our system. To investigate whether IL-6 could induce the production of antiapoptotic molecules, proteins of the Bcl-2 family were measured. While Bcl-2, Bcl-xL,, and Bax were not affected, Mcl-1 was induced by IL-6 in human esophageal carcinoma cells. Our results suggest that IL-6 may contribute to the progression of esophageal cancers in an autocrine or paracrine manner.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Abe K, Hirai M, Mizuno K, Higashi N, Sekimoto T, Miki T, Hirano T and Nakajima K . (2001). Oncogene, 20, 3464–3474.

  • Blot WJ . (1994). Semin. Onco., 21, 403–410.

  • Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albancese C and Darnell Jr JE . (1999). Cell, 98, 295–303.

  • Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto A, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS and Jove R . (1999). Immunity, 10, 105–115.

  • Chen RH, Chang MC, Su YH, Tsai YT and Kuo ML . (1998). J. Biol. Chem., 274, 23013–23019.

  • Chen T, Wang LH and Farrar WL . (2001). Cancer Res., 60, 2132–2135.

  • Chung J, Uchida E, Grammer TC and Blenis J . (1997). Mol. Cell. Biol., 17, 6508–6516.

  • Enzinger DC, Ilson DH and Kelsen DP . (1999). Semin. Oncol., 26, 12–20.

  • Epling-Burnette PK, Liu JH, Catlett-Falcone R, Turkson J, Oshiro M, Kothapalli R, Li Y, Wang JM, Yang-Yen HF, Karras J, Jove R and Loughran Jr TP . (2001). J. Clin. Invest., 107, 351–362.

  • Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaghichi T, Nakaajima K and Hirano T . (1996). Immunity, 5, 449–460.

  • Gallo RL, Dorschner RA, Takashima S, Klagsbrun M, Eriksson E and Bernfield M . (1997). J. Invest. Dermatol., 109, 597–603.

  • Halapi E . (1998). Med. Oncol., 15, 203–211.

  • Hirano T . (1998). Int. Rev. Immunol., 16, 249–284.

  • Hirano T, Ishihara K and Hibi M . (2000). Oncogene, 19, 2548–2556.

  • Hu C, Hsieh H, Chien K, Wang P, Wang C, Chen C, Lo SJ, Wuu K and Chang C . (1984). J. Natl. Cancer Inst., 72, 577–583.

  • Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto K, Okada N and Kishimoto T . (1988). Nature, 332, 83–85.

  • Kulik G, Klippel A and Weber MJ . (1997). Mol. Cell. Biol., 17, 1595–1606.

  • Kulik G and Weber MJ . (1998). Mol. Cell. Biol., 18, 6711–6718.

  • Kuo ML, Chuang SE, Lin MT and Yang SY . (2001). Oncogene, 20, 677–685.

  • Lauta VM . (2001). Cytokine, 16, 79–86.

  • Leu CM, Chang C and Hu C . (2000). Oncogene, 19, 1665–1675.

  • Lim CP and Cao X . (1999). J. Biol. Chem., 274, 31055–31061.

  • Ma Y, Xian M, Li J, Kawabata T and Okada S . (1999). APMIS, 107, 514–522.

  • Mateo RB, Reichner JS and Albina JE . (1994). Am. J. Physiol., 266, R1840–R1844.

  • Meir EV, Sawamura Y, Diserens A, Hamou M and Tribolet N . (1990). Cancer Res., 50, 6683–6688.

  • Minshall C, Arkins S, Freund GG and Kelly KW . (1996). J. Immunol., 156, 939–947.

  • Mocellin S, Wang E and Marincola FM . (2001). J. Immunother., 24, 392–407.

  • Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, Kitaoka T, Fukada T, Hibi M and Hirano T . (1996). EMBO J., 15, 3651–3658.

  • Nobori T, Milura K, Wu DJ, Lois A, Takabayashi K and Carson DA . (1994). Nature, 368, 753–756.

  • Oka M, Hirose K, Iizuka N, Aoyagi K, Yamamoto K, Abe T, Hazama S and Suzuki T . (1995). J. Interf. Cytok. Res., 15, 1005–1009.

  • Oka M, Yamamoto K, Takahashi M, Hakozaki M, Abe T, Iizuka N, Hazama S, Hirazawa K, Hayashi H, Tangoku A, Hirose K, Ishihara T and Suzuki T . (1996). Cancer Res., 56, 2776–2780.

  • Okamoto M, Lee C and Oyasu R . (1997). Cancer Res., 57, 141–146.

  • Park J, Tadlock L, Gores GJ and Patel T . (1999). Hepatology, 30, 1128–1133.

  • Puthier D, Bataille R and Amiot M . (1999). Eur. J. Immunol., 29, 3945–3950.

  • Qiu Y, Robinson D, Pretlow TG and Kung HJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 3644–3649.

  • Ribeiro Jr U, Posner MC, Safatle-Ribeiro AV and Reynolds JC . (1996). Br. J. Surg., 83, 1174–1185.

  • Robbins DJ, Zhen E, Owaki H, Vanderbilt CA, Ebert D, Geppert TD and Cobb MH . (1993). J. Biol. Chem., 268, 5097–5106.

  • Schuringa JJ, Jonk LJC, Dokter WHA, Vellenga E and Kruijer W . (2000). Biochem. J., 347, 89–96.

  • Singleton JR, Dixit VM and Feldman EL . (1996). J. Biol. Chem., 271, 31791–31794.

  • Smith PC, Hobisch A, Lin DL, Culig Z and Keller ET . (2001). Cytokine Growth Factor Rev., 12, 33–40.

  • Taga T . (1997). Annu. Rev. Immunol., 15, 797–819.

  • Takeda K, Kaisho Y, Yoshida N, Takeda J, Kishimoto T and Akira S . (1998). J. Immunol., 161, 4652–4660.

  • Wen Z, Zhong Z and Darnell Jr JE . (1995). Cell, 82, 241–250.

  • Wong F, Hu C, Chiu J, Huang B, Chang J, Lin P, Chien K and Chang C . (1994). Cancer Invest., 12, 121–131.

  • Yao R and Cooper GM . (1995). Science, 267, 2003–2006.

  • Zhang Y, Liu G and Dong Z . (2001). J. Biol. Chem., 276, 42534–42542.

Download references

Acknowledgements

We thank Dr Jen-Ping Chang, Dr Pyng-Jing Lin, Dr Biing-Shiun Huang, Dr Yi-Ming Chen, and Dr Yi-Jen Chen for providing the surgical specimens. We also thank Dr Ming-Ji Fann and Dr Ruey-Hwa Chen for their valuable suggestions. We appreciate Ms Shiang-Lien Lu for her excellent secretarial assistance. This work was supported in part by Grants NSC88-2314-B075-013 from the National Science Council and VTY89-P5-45 from VTY Joint Research Program, Tsou's Foundation, Taiwan, Republic of China.

Author information

Authors and Affiliations

  1. Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China

    Chuen-Miin Leu & Cheng-po Hu

  2. Institute of Microbiology & Immunology, National Yang-Ming University, Taipei, Taiwan, Republic of China

    Chuen-Miin Leu, Chungming Chang & Cheng-po Hu

  3. Institute of Public Health, National Yang-Ming University, Taipei, Taiwan, Republic of China

    Fen-Hwa Wong

  4. Department of Intramural Research Affairs, National Health Research Institute, Taipei, Taiwan, Republic of China

    Chungming Chang

  5. Division of Molecular and Genomic Medicine, National Health Research Institute, Taipei, Taiwan, Republic of China

    Shiu-Feng Huang

  6. Department of Pathology, Chang Gung Memorial Hospital, Taipei, Taiwan, Republic of China

    Shiu-Feng Huang

Authors
  1. Chuen-Miin Leu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fen-Hwa Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chungming Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shiu-Feng Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng-po Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cheng-po Hu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leu, CM., Wong, FH., Chang, C. et al. Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene 22, 7809–7818 (2003). https://doi.org/10.1038/sj.onc.1207084

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207084

Keywords

This article is cited by

Search

Advanced search

Quick links