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:

MAD2-induced sensitization to vincristine is associated with mitotic arrest and Raf/Bcl-2 phosphorylation in nasopharyngeal carcinoma cells

Oncogene volume 22, pages 109–116 (2003)Cite this article

Abstract

Mitotic arrest deficient 2 (MAD2) is thought to be a key component of the mitotic checkpoint, which ensures accurate chromosome segregation. Reduced expression of MAD2 protein is associated with mitotic checkpoint abrogation and chromosomal instability in certain types of human cancers. To explore the possibility of developing a novel strategy for the treatment of cancer based on selective killing of mitotic checkpoint-defective or -competent cells, here we have investigated the effect of MAD2 expression on cellular sensitivity to checkpoint-targeting anticancer drugs. We reintroduced MAD2 protein in a mitotic checkpoint-defective nasopharyngeal carcinoma cell line, CNE2, using an inducible expression vector. We found that overexpression of MAD2 led to an increased sensitivity to vincristine, which was accompanied by increased mitotic index and G2/M cell cycle arrest. In addition, increased phosphorylation of Raf, MEK1/2 and Bcl-2 was observed in MAD2-overexpressing cells in response to vincristine. Furthermore, inhibition of phosphorylation of MEK1/2 by its inhibitor PD098059 led to reduced sensitivity to vincristine, which was associated with decreased Bcl-2 phosphorylation. Our data suggest a role for MAD2 in the sensitization of cancer cells to certain mitotic checkpoint-targeting anticancer drugs.

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

Similar content being viewed by others

References

  • Amon A . (1999). Curr. Opin. Genet. Dev., 9, 69–75.

  • Blagosklonny MV, Giannakakou P, el Deiry WS, Kingston DG, Higgs PI, Neckers L, Fojo T . (1997). Cancer Res., 57, 130–135.

  • Brichese L, Barboule N, Heliez C, Valette A . (2002). Exp. Cell. Res., 278, 101–111.

  • Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B . (1998). Nature, 392, 300.

  • Dimmeler S, Breitschopf K, Haendeler J, Zeiher AM . (1999). J Exp Med, 189, 1815–1818

  • Dobles M, Liberal V, Scott ML, Benezra R, Sorger PK . (2000). Cell, 101, 635–645.

  • Fan M, Du L, Stone AA, Gilbert KM, Chambers TC . (2000). Cancer Res., 60, 6403–6407.

  • Haldar S, Jena N, Croce CM . (1995). Proc. Natt. Acad. Sci. USA, 92, 4507–4611.

  • Hayne C, Tzivion G, Luo Z . (2000). J. Biol. Chem., 275, 31876–31882.

  • Huang ST, Cidlowski JA . (2002). FASEB J., 16, 825–832.

  • Huang Y, Sheikh MS, Fomace AJ, Holbrook NJ . (1999). Oncogene, 18, 3431–3439.

  • Jin DY, Spencer F, Jeang KT . (1998). Cell, 93, 81–91.

  • Jordan MA, Wendell K, Gardiner S, Deny WB, Copp H, Wilson L . (1996). Cancer Res., 56, 816–825.

  • Kallio M, Weinstein J, Daum JR, Burke DJ, Gorbsky, GJ . (1998). J. Cell Biol., 141, 1393–1406.

  • Kasai T, Iwanaga Y, Iha H, Jeang KT . (2002). J. Biol. Chem., 277, 5187–5193.

  • Laird AD, Taylor SJ, Oberst M, Shalloway D . (1995). J. Biol. Chem., 270, 26742–26745.

  • Lengauer C, Kinzler KW, Vogelstein B . (1998). Nature, 396, 643–649.

  • Li Y, Benezra R . (1996). Science, 274, 246–248.

  • Lovric J, Moelling K . (1996). Oncogene, 12, 1109–1116.

  • Minn AJ, Boise LH, Thompson CB . (1996). Genes Dev., 10, 2621–2631.

  • Minshull J, Sun H, Tonks NK, Murray AW . (1994). Cell, 79, 475–486.

  • Pennisi E . (1998). Science, 279, 477–478.

  • Sherwood SW, Sheridan JP, Schimke RT . (1994). Exp. Cell Res., 215, 373–379.

  • Srivastava RK, Srivastava AR, Korsmeyer SJ, Nesterova M, Cho-Chung YS, Longo DL . (1998). Mol Cell. Bio., 18, 3509–3617.

  • Stadheim TA, Xiao H, Eastman A . (2001). Cancer Res., 61, 1533–1540.

  • Takahashi T, Haruki N, Nomoto S, Masuda A, Saji S, Osada H, Takahashi T . (1999). Oncogene, 18, 4295.

  • Takenaka K, Gotoh Y, Nishida E . (1997). J. Cell Biol., 136, 1091–1097.

  • Takenaka K, Moriguchi T, Nishida E . (1998). Science, 280, 599–602.

  • Wahl AF, Donaldson KL, Fairchild C, Lee FY, Foster SA, Demers GW, Galloway DA . (1996). Nat. Med., 2, 72–79.

  • Wang TH, Popp DM, Wang HS, Saitoh M, Mural JG, Henley DC, Ichijo H, Wimalasena JJ . (1999). Biol Chem., 274, 8208–8216.

  • Wang X, Jin DY, Ng RW, Feng H, Wong YC, Cheung AL, Tsao SW . (2002). Cancer Res., 62, 1662–1668.

  • Wang X, Jin DY, Wong YC, Cheung AL, Chun AC, Lo AK, Liu Y, Tsao SW . (2000). Carcinogenesis, 21, 2293–2297.

  • Wang X, Liu Y, Chow LS, Wong SC, Tsao SW, Kwong DL, Wang J, Sham JS, Nicholls JM . (1999). Int. J. Oncol., 15, 1097–1102.

  • Wang X, Wong SC, Pan J, Tsao SW, Fung KH, Kwong DL, Sham JS, Nicholls JM . (1998). Cancer Res., 58, 5019–5022.

  • Wang X, Zhai Y, Ferrell Jr JE (1997). J. Cell Biol., 137, 433–443.

  • Wassmann K, Benezra R . (2001). Curr. Opin. Genet. Dev., 11, 83–90.

  • Yamamoto K, Ichijo H, Korsmeyer SJ . (1999). Mol. Cell Biol., 19, 8469–8478

  • Yeung K, Seitz T Li S, Janosch P, McFerran B, Kaiser C, Fee F, Katsanakis KD, Rose DW, Mischak H, SedivyJM, Kolch W (1999). Nature, 401, 173–177.

  • Zhang Y, Lees E . (2001). Mol. Cell. Biol., 21, 5190–5199.

Download references

Author information

Author notes

  1. Dong-Yan Jin: D-Y Jin is a Leukemia and Lymphoma Society Scholar.

Authors and Affiliations

  1. Department of Anatomy 21 Sassoon Road, 1st Floor, Laboratory Block, Faculty of Medicine Building, Hong Kong

    Xianghong Wang, Hing Lok Wong, Huichen Feng, Yong-Chuan Wong & Sai Wah Tsao

  2. Department of Biochemistry 21 Sassoon Road, 1st Floor, Laboratory Block, Faculty of Medicine Building, Hong Kong

    Dong-Yan Jin

Authors
  1. Xianghong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dong-Yan Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hing Lok Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huichen Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong-Chuan Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sai Wah Tsao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sai Wah Tsao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, X., Jin, DY., Wong, H. et al. MAD2-induced sensitization to vincristine is associated with mitotic arrest and Raf/Bcl-2 phosphorylation in nasopharyngeal carcinoma cells. Oncogene 22, 109–116 (2003). https://doi.org/10.1038/sj.onc.1206069

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206069

Keywords

This article is cited by

Search

Advanced search

Quick links