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:

The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI 3-K/Akt pathway

Oncogene volume 20, pages 5799–5809 (2001)Cite this article

Abstract

Interleukin-6 (IL-6), a multifunctional cytokine, has recently been implicated in human cervical cancer, though the mechanism remains elusive. This study demonstrates that the anti-apoptotic protein Mcl-1 and IL-6 was concomitantly expressed in human cervical cancer tissues and cell lines, but not in normal cervix tissues. Upon IL-6 treatment, Mcl-1, but not other Bcl-2 family members, was rapidly up-regulated peaking at 4–8 h in human cervical cancer C33A cells. Supporting this observation, using anti-IL-6 or anti-IL-6 receptor antibody to interrupt the IL-6 autocrine loop in SiHa cells significantly reduced cellular level of Mcl-1. This study hypothesizes that the expression of Mcl-1 in cervical cancer cells is regulated by IL-6. The matter of which signaling pathways transduced by IL-6 is responsible for the Mcl-1 up-regulation is further investigated herein. Blocking the STAT3 or MAPK pathway with dominant-negative mutant STAT3F or the MEK inhibitor PD98059 failed to inhibit IL-6-mediated Mcl-1 expression. Meanwhile, the IL-6-induced Mcl-1 up-regulation was effectively abolished by treatment with PI 3-K inhibitors, LY294002. Additionally, overexpression of dominant-negative (dn) Akt in C33A cells could inhibit the IL-6-induced increase of Mcl-1. Finally, overexpression of IL-6 in C33A cells caused a markable resistance to apoptosis induced by doxorubicin or cisplatin. Transient transfection of IL-6-overexpressed cells with a mcl-1 antisense vector, leading to the attenuation of their apoptosis-resistant activity. In conclusion, the data herein suggest that IL-6 regulated the mcl-1 expression via a PI 3-K/Akt-dependent pathway that may facilitate the oncogenesis of human cervical cancer by modulating the apoptosis threshold.

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

  • Adams JM, Cory S . 1998 Science 281: 1322–1326

  • Castrilli G, Tatone D, Diodoro MG, Rosini S, Piantelli M, Musiani P . 1997 Br. J. Cancer 75: 855–859

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

  • Cervero C, Escribano L, San Miguel JF, Diaz-Agustin B, Bravo P, Villarrubia J, Garcia-Sanz R, Velasco JL, Herrera P, Vargas M, Gonzalez M, Navarro JL, Orfao A . 1999 Am. J. Hematol. 60: 191–195

  • Chao DT, Korsmeyer SJ . 1998 Annu. Rev. Immunol. 16: 395–419

  • Chao JR, Wang JM, Lee SF, Peng HW, Lin YH, Chou CH, Li JC, Huang HM, Chou CK, Kuo ML, Yen JJ, Yang-Yen HF . 1998 Mol. Cell. Biol. 18: 4883–4898

  • Chen RH, Chang MC, Su YH, Tsai YT, Kuo ML . 1999 J. Biol. Chem. 274: 23013–23019

  • Choi SS, Park IC, Yun JW, Sung YC, Hong SI, Shin HS . 1995 Oncogene 11: 1693–1698

  • Crawford RA, Caldwell C, Iles RK, Lowe D, Shepherd JH, Chard T . 1998 Br. J. Cancer 78: 210–214

  • Dole MG, Jasty R, Cooper MJ, Thompson CB, Nunez G, Castle VP . 1995 Cancer Res. 55: 2576–2582

  • Elder DJ, Hague A, Hicks DJ, Paraskeva C . 1996 Cancer Res. 56: 2273–2276

  • Eustace D, Han X, Gooding R, Rowbottom A, Riches P, Heyderman E . 1993 Gynecol. Oncol. 50: 15–19

  • Jee SH, Shen SC, Chiu HC, Tsai WL, Kuo ML . 2001 Oncogene 20: 198–208

  • Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, et al. 1988 Nature 332: 83–85

  • Kishimoto T . 1989 Blood 74: 1–10

  • Kishimoto T, Akira S, Narazaki M, Taga T . 1995 Blood 86: 1243–1254

  • Klippel A, Escobedo MA, Wachowicz MS, Apell G, Brown TW, Giedlin MA, Kavanaugh WM, Williams LT . 1998 Mol. Cell. Biol. 18: 5699–5711

  • Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW . 1993 Proc. Natl. Acad. Sci. USA 90: 3516–3520

  • Krajewski S, Bodrug S, Gascoyne R, Berean K, Krajewska M, Reed JC . 1994 Am. J. Pathol. 145: 515–525

  • Krajewski S, Bodrug S, Krajewska M, Shabaik A, Gascoyne R, Berean K, Reed JC . 1995 Am. J. Pathol. 146: 1309–1319

  • Krajewska M, Krajewski S, Epstein JI, Shabaik A, Sauvageot J, Song K, Kitada S, Reed JC . 1996 Am. J. Pathol. 148: 1567–1576

  • Kuo M, Shiah SG, Wang CJ, Chuang SE . 1999 Mol. Pharmacol. 55: 894–901

  • Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J, Liu JM, Yang DM, Yang WK, Shen CY . 2000 Oncogene 19: 2739–2744

  • Miki S, Iwano M, Miki Y, Yamamoto M, Tang B, Yokokawa K, Sonoda T, Hirano T, Kishimoto T . 1989 FEBS Lett. 250: 607–610

  • Moulding DA, Quayle JA, Hart CA, Edwards SW . 1998 Blood 92: 2495–2502

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

  • Nakashima K, Wiese S, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Yoshida K, Kishimoto T, Sendtner M, Taga T . 1999 J. Neurosci. 19: 5429–5434

  • Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL, Anderson KC . 1997 J. Immunol. 159: 2212–2221

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

  • Pinion SB, Kennedy JH, Miller RW, MacLean AB . 1991 Lancet 337: 819–820

  • Ponten J, Adami HO, Bergstrom R, Dillner J, Friberg LG, Gustafsson L, Miller AB, Parkin DM, Sparen P, Trichopoulos D . 1995 Int. J. Cancer 60: 1–26

  • Puthier D, Bataille R, Amiot M . 1999a Eur. J. Immunol. 29: 3945–3950

  • Puthier D, Derenne S, Barille S, Moreau P, Harousseau JL, Bataille R, Amiot M . 1999b Br. J. Haematol. 107: 392–395

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

  • Reynolds JE, Yang T, Qian L, Jenkinson JD, Zhou P, Eastman A, Craig RW . 1994 Cancer Res. 54: 6348–6352

  • Richter HE, Holley RL, Andrews WW, Owen J, Miller KB . 1999 Am. J. Obstet. Gynecol. 181: 940–944

  • Robert ME, Fu YS . 1990 Semin. Diagn. Pathol. 7: 173–189

  • Schlaifer D, March M, Krajewski S, Laurent G, Pris J, Delsol G, Reed JC, Brousset P . 1995 Blood 85: 2671–2674

  • Tartour E, Fossiez F, Joyeux I, Galinha A, Gey A, Claret E, Sastre-Garau X, Couturier J, Mosseri V, Vives V, Banchereau J, Fridman WH, Wijdenes J, Lebecque S, Sautes-Fridman C . 1999 Cancer Res. 59: 3698–3704

  • Tartour E, Gey A, Sastre-Garau X, Pannetier C, Mosseri V, Kourilsky P, Fridman WH . 1994 Cancer Res. 54: 6243–6248

  • Thompson CB . 1995 Science 267: 1456–1462

  • Tjiong MY, van der Vange N, ten Kate FJ, Tjong AHSP, ter Schegget J, Burger MP, Out TA . 1999 Gynecol. Oncol. 73: 285–291

  • Tlsty TD . 1999 Nat. Genet. 21: 64–65

  • Wei LH, Kuo ML, Chen CA, Cheng WF, Cheng SP, Hsieh FJ, Hsieh CY . 2001 Gynecol. Oncol. 82: 49–56

  • Wu S, Rodabaugh K, Martinez-Maza O, Watson JM, Silberstein DS, Boyer CM, Peters WP, Weinberg JB, Berek JS, Bast Jr RC . 1992 Am. J. Obstet. Gynecol. 166: 997–1007

  • Yang T, Kozopas KM, Craig RW . 1995 J. Cell Biol. 128: 1173–1184

  • Zhou P, Qian L, Kozopas KM, Craig RW . 1997 Blood 89: 630–643

Download references

Acknowledgements

The authors would like to thank the National Science Council of the Republic of China for financially supporting this research under Contract No. NSC89-2314-B-002-261.

Author information

Author notes

  1. Lin-Hung Wei and Min-Liang Kuo: L-H Wei and M-L Kuo contributed equally to the article

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei, Taiwan

    Lin-Hung Wei, Chi-An Chen, Wen-Fang Cheng & Chang-Yao Hsieh

  2. Laboratory of Molecular & Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Lin-Hung Wei, Min-Liang Kuo, Chia-Hung Chou, Ming-Cheng Chang & Jen-Liang Su

Authors
  1. Lin-Hung Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min-Liang Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chi-An Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chia-Hung Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-Fang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming-Cheng Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jen-Liang Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chang-Yao Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chang-Yao Hsieh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wei, LH., Kuo, ML., Chen, CA. et al. The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI 3-K/Akt pathway. Oncogene 20, 5799–5809 (2001). https://doi.org/10.1038/sj.onc.1204733

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204733

Keywords

This article is cited by

Search

Advanced search

Quick links