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Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53

Oncogene volume 26, pages 1003–1012 (2007)Cite this article

Abstract

Cancers harboring dominant-negative p53 mutations are often aggressive and difficult to treat. Direct attempts to restore wild-type p53 function have produced little clinical benefit. We investigated whether targeting a p53-target gene could induce certain tumor-suppressor characteristics. We found that inhibition of stathmin, a microtubule regulator that can be transcriptionally repressed by wild-type p53, restored certain wild-type functions to cancer cells with mutant p53. Silencing of stathmin by small interfering RNA (siRNA) in mutant p53 cell lines lowered expression to that observed following activation of wild-type p53 by DNA damage in wild-type p53 cell lines. siRNA-induced repression of stathmin decreased cell proliferation, viability and clonogenicity in mutant p53 cell lines. Furthermore, knockdown of stathmin partially restored cell-cycle regulation and activation of apoptosis. Therefore, targeting stathmin, a gene product that is overexpressed in the presence of mutant p53, may represent a novel approach to treating cancers with aberrant p53 function.

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References

  • Ahn J, Murphy M, Kratowicz S, Wang A, Levine AJ, George DL . (1999). Down-regulation of the stathmin/Op18 and FKBP25 genes following p53 induction. Oncogene 18: 5954–5958.

    Article  CAS  Google Scholar 

  • Alaiya AA, Franzen B, Fujioka K, Moberger B, Schedvins K, Silfversvard C et al. (1997). Phenotypic analysis of ovarian carcinoma: polypeptide expression in benign, borderline and malignant tumors. Int J Cancer 73: 678–683.

    Article  CAS  Google Scholar 

  • Alli E, Bash-Babula J, Yang JM, Hait WN . (2002). Effect of stathmin on the sensitivity to antimicrotubule drugs in human breast cancer. Cancer Res 62: 6864–6869.

    CAS  PubMed  Google Scholar 

  • Bieche I, Lachkar S, Becette V, Cifuentes-Diaz C, Sobel A, Lidereau R et al. (1998). Overexpression of the stathmin gene in a subset of human breast cancer. Br J Cancer 78: 701–709.

    Article  CAS  Google Scholar 

  • Bieche I, Manceau V, Curmi PA, Laurendeau I, Lachkar S, Leroy K et al. (2003). Quantitative RT–PCR reveals a ubiquitous but preferentially neural expression of the KIS gene in rat and human. Brain Res Mol Brain Res 114: 55–64.

    Article  CAS  Google Scholar 

  • Bossi G, Mazzaro G, Porrello A, Crescenzi M, Soddu S, Sacchi A . (2004). Wild-type p53 gene transfer is not detrimental to normal cells in vivo: implications for tumor gene therapy. Oncogene 23: 418–425.

    Article  CAS  Google Scholar 

  • Brattsand G . (2000). Correlation of oncoprotein 18/stathmin expression in human breast cancer with established prognostic factors. Br J Cancer 83: 311–318.

    Article  CAS  Google Scholar 

  • Bullock AN, Fersht AR . (2001). Rescuing the function of mutant p53. Nat Rev Cancer 1: 68–76.

    Article  CAS  Google Scholar 

  • Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P et al. (2002). Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8: 282–288.

    Article  CAS  Google Scholar 

  • Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G . (2004). Cell death by mitotic catastrophe: a molecular definition. Oncogene 23: 2825–2837.

    Article  CAS  Google Scholar 

  • Chang CL, Hora N, Huberman N, Hinderer R, Kukuruga M, Hanash SM . (2001). Oncoprotein 18 levels and phosphorylation mediate megakaryocyte polyploidization in human erythroleukemia cells. Proteomics 1: 1415–1423.

    Article  CAS  Google Scholar 

  • Curmi PA, Nogues C, Lachkar S, Carelle N, Gonthier MP, Sobel A et al. (2000). Overexpression of stathmin in breast carcinomas points out to highly proliferative tumours. Br J Cancer 82: 142–150.

    Article  CAS  Google Scholar 

  • Faille A, De Cremoux P, Extra JM, Linares G, Espie M, Bourstyn E et al. (1994). p53 mutations and overexpression in locally advanced breast cancers. Br J Cancer 69: 1145–1150.

    Article  CAS  Google Scholar 

  • Fei P, El-Deiry WS . (2003). P53 and radiation responses. Oncogene 22: 5774–5783.

    Article  CAS  Google Scholar 

  • Foster BA, Coffey HA, Morin MJ, Rastinejad F . (1999). Pharmacological rescue of mutant p53 conformation and function. Science 286: 2507–2510.

    Article  CAS  Google Scholar 

  • Friedrich B, Gronberg H, Landstrom M, Gullberg M, Bergh A . (1995). Differentiation-stage specific expression of oncoprotein 18 in human and rat prostatic adenocarcinoma. Prostate 27: 102–109.

    Article  CAS  Google Scholar 

  • Fujiwara T, Cai DW, Georges RN, Mukhopadhyay T, Grimm EA, Roth JA . (1994). Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. J Natl Cancer Inst 86: 1458–1462.

    Article  CAS  Google Scholar 

  • Hanash SM, Strahler JR, Kuick R, Chu EH, Nichols D . (1988). Identification of a polypeptide associated with the malignant phenotype in acute leukemia. J Biol Chem 263: 12813–12815.

    CAS  PubMed  Google Scholar 

  • Harris SL, Levine AJ . (2005). The p53 pathway: positive and negative feedback loops. Oncogene 24: 2899–2908.

    Article  CAS  Google Scholar 

  • Haupt S, Berger M, Goldberg Z, Haupt Y . (2003). Apoptosis – the p53 network. J Cell Sci 116: 4077–4085.

    Article  CAS  Google Scholar 

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC . (1991). p53 mutations in human cancers. Science 253: 49–53.

    Article  CAS  Google Scholar 

  • Hupp TR, Lane DP . (1994). Allosteric activation of latent p53 tetramers. Curr Biol 4: 865–875.

    Article  CAS  Google Scholar 

  • Johnsen JI, Aurelio ON, Kwaja Z, Jorgensen GE, Pellegata NS, Plattner R et al. (2000). p53-mediated negative regulation of stathmin/Op18 expression is associated with G(2)/M cell-cycle arrest. Int J Cancer 88: 685–691.

    Article  CAS  Google Scholar 

  • Levine AJ . (1997). p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.

    Article  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD . (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408.

    Article  CAS  Google Scholar 

  • Margolis RL, Lohez OD, Andreassen PR . (2003). G1 tetraploidy checkpoint and the suppression of tumorigenesis. J Cell Biochem 88: 673–683.

    Article  CAS  Google Scholar 

  • Meek DW . (2000). The role of p53 in the response to mitotic spindle damage. Pathol Biol (Paris) 48: 246–254.

    CAS  Google Scholar 

  • Murphy M, Ahn J, Walker KK, Hoffman WH, Evans RM, Levine AJ et al. (1999). Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev 13: 2490–2501.

    Article  CAS  Google Scholar 

  • Oesterreich S, Fuqua SA . (1999). Tumor suppressor genes in breast cancer. Endocr Relat Cancer 6: 405–419.

    Article  CAS  Google Scholar 

  • Pietenpol JA, Stewart ZA . (2002). Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology 181–182: 475–481.

    Article  Google Scholar 

  • Polager S, Ginsberg D . (2003). E2F mediates sustained G2 arrest and down-regulation of Stathmin and AIM-1 expression in response to genotoxic stress. J Biol Chem 278: 1443–1449.

    Article  CAS  Google Scholar 

  • Price DK, Ball JR, Bahrani-Mostafavi Z, Vachris JC, Kaufman JS, Naumann RW et al. (2000). The phosphoprotein Op18/stathmin is differentially expressed in ovarian cancer. Cancer Invest 18: 722–730.

    Article  CAS  Google Scholar 

  • Sionov RV, Haupt Y . (1999). The cellular response to p53: the decision between life and death. Oncogene 18: 6145–6157.

    Article  CAS  Google Scholar 

  • Sobel A, Tashjian Jr AH . (1983). Distinct patterns of cytoplasmic protein phosphorylation related to regulation of synthesis and release of prolactin by GH cells. J Biol Chem 258: 10312–10324.

    CAS  PubMed  Google Scholar 

  • Taylor WR, Agarwal ML, Agarwal A, Stacey DW, Stark GR . (1999). p53 inhibits entry into mitosis when DNA synthesis is blocked. Oncogene 18: 283–295.

    Article  CAS  Google Scholar 

  • Taylor WR, Stark GR . (2001). Regulation of the G2/M transition by p53. Oncogene 20: 1803–1815.

    Article  CAS  Google Scholar 

  • Thompson DA, Belinsky G, Chang TH, Jones DL, Schlegel R, Munger K . (1997). The human papillomavirus-16 E6 oncoprotein decreases the vigilance of mitotic checkpoints. Oncogene 15: 3025–3035.

    Article  CAS  Google Scholar 

  • Vecil GG, Lang FF . (2003). Clinical trials of adenoviruses in brain tumors: a review of Ad-p53 and oncolytic adenoviruses. J Neurooncol 65: 237–246.

    Article  Google Scholar 

  • Vogel C, Kienitz A, Hofmann I, Muller R, Bastians H . (2004). Crosstalk of the mitotic spindle assembly checkpoint with p53 to prevent polyploidy. Oncogene 23: 6845–6853.

    Article  CAS  Google Scholar 

  • Vogelstein B, Kinzler KW . (2004). Cancer genes and the pathways they control. Nat Med 10: 789–799.

    Article  CAS  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ . (2000). Surfing the p53 network. Nature 408: 307–310.

    Article  CAS  Google Scholar 

  • Wallace-Brodeur RR, Lowe SW . (1999). Clinical implications of p53 mutations. Cell Mol Life Sci 55: 64–75.

    Article  CAS  Google Scholar 

  • Zhou J, Giannakakou P . (2005). Targeting microtubules for cancer chemotherapy. Curr Med Chem Anti-Canc Agents 5: 65–71.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by US Public Health Service NCI CA 78695 and CA 72720.

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Authors and Affiliations

  1. Department of Pharmacology, The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    E Alli, J-M Yang & W N Hait

  2. Department of Medicine, The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    W N Hait

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  1. E Alli
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  2. J-M Yang
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  3. W N Hait
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Correspondence to J-M Yang or W N Hait.

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Alli, E., Yang, JM. & Hait, W. Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53. Oncogene 26, 1003–1012 (2007). https://doi.org/10.1038/sj.onc.1209864

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