Skip to main content
SpringerLink
Log in

Requirement for pre-existing of p21 to prevent doxorubicin-induced apoptosis through inhibition of caspase-3 activation

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Doxorubicin (DOX)-induced apoptosis is suppressed by p21 (waf1/cip1/sdi1), a cyclin dependent kinase (CDK) inhibitor. Here we show that exogenous expression of p21 before, but not after, the DOX-treatment protected p21-deficient human colorectal cancer cell line DLD1 from DOX-induced apoptosis. In previous work, we demonstrated that p21 inhibits DOX-induced apoptosis via its CDK-binding and CDK-inhibitory activity. Here we report that pre-existing p21 can associate with pro-caspase-3 and inhibit caspase-3 activation in the cells, which was at least in part responsible for enhancing survival of DOX-treated cells. Furthermore, the N-terminal domain of p21 was found to interact with pro-caspase-3 in DLD1 cells. Thus, we propose that pre-existing p21 is required to prevent DOX-induced apoptosis.

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

Similar content being viewed by others

References

  1. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan JY: Human ICE/CED-3 protease nomenclature. Cell 87: 171–177, 1996

    Article  PubMed  CAS  Google Scholar 

  2. Cao W, Ma SL, Tang JJ, Shi JQ, Lu YJ: A combined treatment TNF-αDoxorubicin alleviates the resistance of MCF-7/Adr cells to cytotoxic treatment. Biochimica et Biophysica Acta (Elsevier). In press, 2006

  3. Cao W, Chi WH, Wang J, Tang JJ, Lu YJ: TNF-a promotes Doxorubicin-induced cell apoptosis and anti-cancer e.ect through downregulation of p21 in p53-deficient tumor cells. Biochem Bioph Res Co 330: 1034–1040, 2005

    Article  CAS  Google Scholar 

  4. Chen J, Jackson PK, Kirschner MW, Dutta A: Procaspase 3/p21 complex formation to resist Fas-mediated cell death is initiated as a result of the phosphorylation of p21 by protein kinase A. Nature 374: 386–388, 1995

    Article  PubMed  CAS  Google Scholar 

  5. Chen J, Peters R, Saha P, Lee P, Theodoras A, Pagano M, Wagner G, Dutta A: Procaspase 3/p21 complex formation to resist Fas-mediated cell death is initiated as a result of the phosphorylation of p21 by protein kinase A. Nucleic Acids Res 24: 1727–1733, 1996

    Article  PubMed  CAS  Google Scholar 

  6. el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Wiman KG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW, Vogelstein B: WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis: Cancer Res 54: 1169–1174, 1994

    PubMed  CAS  Google Scholar 

  7. Gervais JLM, Seth P, Zhang H: Cleavage of CDK inhibitor p21Cip1 Waf1 by Caspases is an early event during DNA damage-induced apoptosis. J Biol Chem 273: 19207–19212, 1998

    Article  PubMed  CAS  Google Scholar 

  8. Gil-Gomez G, Berns A, Brady HJ: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. EMBO J 17: 7209–7218, 1998

    Article  PubMed  CAS  Google Scholar 

  9. Lin J, Reichner C, Wu X, Levine AJ: Analysis of wild-type and mutant p21Waf -1 gene activities. Mol Cell Biol 16: 1786–1793, 1996

    PubMed  CAS  Google Scholar 

  10. Li R, Hannon GJ, Beach D, Stillman B: Subcellular distribution of p21 and PCNA in normal and repair-deficient cells following DNA damage. Curr Biol 6: 189–199, 1996

    Article  PubMed  CAS  Google Scholar 

  11. Li R, Waga S, Hannon GJ, Beach D, Stillma B: Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Nature 37: 1534–1537, 1994

    Google Scholar 

  12. Luo Y, Hurwitz J, Massague J: Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1a. Nature (Lond.) 375: 159–161, 1995

    Article  CAS  Google Scholar 

  13. Lu YJ, Tatsuka M, Takebe H, Yagi T: Involvement of cyclin-dependent kinases in doxorubicin-induced apoptosis in human tumor cells. Mol Carcinog 29: 1–7, 2000

    Article  PubMed  Google Scholar 

  14. Lu YJ, Yamagishi N, Yagi T, Takebe H: Mutated p21WAF1/CIP1/SDI1 lacking CDK-inhibitory activity fails to prevent apoptosis in human colorectal carcinoma cells. Oncogene 16: 705–712, 1998

    Article  PubMed  CAS  Google Scholar 

  15. Noda A, Ning Y, Venable SF, Pereire-Smith OM, Smith JR: Cloning of senescent cell derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211: 90–98, 1994

    Article  PubMed  CAS  Google Scholar 

  16. Park JS, Carter S, Reardon DB, Schmidt-Ullrich R, Dent P, Fisher PB: Roles for Basal and Stimulated p21Cip-1/WAF1/MDA6 Expression and Mitogen-activated protein kinase signaling in radiation-induced cell cycle checkpoint control in carcinoma cells. Mol Biol Cell 10 (12): 4231–4246, 1999

    PubMed  CAS  Google Scholar 

  17. Steller H: Mechanisms and genes of cellular suicide. Science 267: 1445–1449, 1995

    PubMed  CAS  Google Scholar 

  18. Suzuki A, Kawano H, Hayashida M, Hayasaki Y, Tsutomi Y, Akahane K: Procaspase 3/p21 complex formation to resist fas-mediated cell death is initiated as a result of the phosphorylation of p21 by protein kinase A. Cell death Differ 7: 721–728, 2000

    Article  PubMed  CAS  Google Scholar 

  19. Suzuki A, Tsutomi Y, Miura M, Akahane K: Caspase 3 inactivation to suppress Fas-mediated apoptosis identification of binding domain with p21 and inactivation machinery by p21. Oncogene 18: 1239–1244, 1998

    Article  Google Scholar 

  20. Waldman T, Lengauer C, Kinzler KW, Vogelstein B: Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381: 713–716, 1996

    Article  PubMed  CAS  Google Scholar 

  21. Zakut R, Givol D: The tumor suppression function of p21Waf is contained in its N-terminal half (‘half-WAF’). Oncogene 11: 393–395, 1995

    PubMed  CAS  Google Scholar 

  22. Yu DH, Jing T, Liu B, Yao J, Tan M, McDonnell TJ, Hung MC: Overexpression of ErbB2 blocks taxol-induced apoptosis by upregulation of p21p21Cip1, which inhibits p34Cdc2 kinase. Mol. Cell 2: 581–591, 1998

    Article  PubMed  CAS  Google Scholar 

  23. Zhang H, Hannon G, Beach D: p21-containing cyclin kinases exist in both active and inactive states. Genes Dev 8: 1750–1758, 1994

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Research Center, Celstar Bio-Pharmaceutical Co. Ltd., Shanghai, P.R. China

    J. J. Tang & Y. J. Lu

  2. Pulmonary Department, Sixth People‘s Hospital, Jiao Tong University, Shanghai, P.R. China

    C. Shen

Authors
  1. J. J. Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. J. Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y. J. Lu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tang, J.J., Shen, C. & Lu, Y.J. Requirement for pre-existing of p21 to prevent doxorubicin-induced apoptosis through inhibition of caspase-3 activation. Mol Cell Biochem 291, 139–144 (2006). https://doi.org/10.1007/s11010-006-9206-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-006-9206-7

Keywords

Search

Navigation