Influence of human tumor suppressor PTEN on sensitivity of malignant cells to anticancer drugs

  • E. A. Shcherbakova
  • T. P. Stromskaya
  • E. Yu. Rybalkina
  • A. A. Stavrovskaya


The influence of the human tumor suppressor PTEN on sensitivity of tumor cells to cytostatic drugs was studied. Rat ras-transformed (N-ras Asp12 ) fibroblasts were stably transfected with a full-size PTEN gene. Transfected clone was characterized by an enhanced expression of PTEN and a more normal phenotype in comparison with the parental cells. The effect of transient transfection with PTEN on the sensitivity of several malignant cell lines to the cytostatic drugs colchicine and adriablastine was studied. These drugs differ from each other in action mechanisms and intracellular targets. The tumor cell lines tested in this study included parental cell lines and stable sublines possessing drug resistance due to overexpression of P-glycoprotein. In all cell lines, introduction of exogenous PTEN caused a decrease in proliferation rates. This indicated that transgene was active. The chemosensitivity of some drug-resistant sublines was changed after PTEN transfection, but the drug sensitivity of parental cell lines remained unaffected. The effect of PTEN overexpression on chemosensitivity of malignant cells to cytostatic drugs was found to depend both on their mechanisms of action and on the origin of transfected cells. Our data suggest that PTEN is involved into the molecular mechanisms of drug resistance in cells studied.


Colchicine Supplement Series PTEN Expression Parental Cell Line PTEN Gene 
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  1. 1.
    Hanahan, D. and Weinberg, R.A., The hallmarks of cancer, Cell, 2000, vol. 100, pp. 57–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Kanamori, Y., Kigawa, J., Itamochi, H., et al., Correlation between loss of PTEN expression and Aktphosphorylation in endometrial carcinoma, Clin. Cancer Res., 2001, vol. 7, pp. 892–895.PubMedGoogle Scholar
  3. 3.
    Uegaki, K., Kanamori, Y., Kigawa, J., et al., PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma, Oncol. Rep., 2005, vol. 14, pp. 389–392.PubMedGoogle Scholar
  4. 4.
    Tsutsui., S., Inoue, H., Yasuda, K., et al., Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast, Oncology, 2005, vol. 68, pp. 398–404.PubMedCrossRefGoogle Scholar
  5. 5.
    Eng, C., PTEN: One gene, many syndromes, Hum Mutat., 2003, vol. 22, no. 3, pp. 183–198.PubMedCrossRefGoogle Scholar
  6. 6.
    Stambolic, V., Suzuki, A., de la Pompa, J.L., et al., Negative regulation of PKB/Akt-dependent cell survival by tumor suppressor PTEN, Cell, 1998, vol. 95, pp. 29–39.PubMedCrossRefGoogle Scholar
  7. 7.
    Khramtsova, S., Stromskaya, T., Potapova, G., et al., Human p53, mutated at codon 273, causes distinct effects on nucleotide biosynthesis salvage pathway key enzymes in Rat-1 cells and in their derivatives activated ras Oncogene, Biochem. Biophys. Res. Comm., 1993, vol. 194, no. 1, pp. 383–390.PubMedCrossRefGoogle Scholar
  8. 8.
    Deichman, G.I., Kluchareva, T.E., Matveeva, V.A., et al., Clustering of discrete cell properties essential for tumorigenicity and metastasis. III. Dissociation of the properties in N-ras-transfected RSV-SR-transformed cells, Int. J. Cancer, 1992, vol. 51, pp. 903–908.PubMedCrossRefGoogle Scholar
  9. 9.
    Akiyama, S.-I., Fojo, A., Hanover, J.A., et al., Isolation and genetic characterization of human KB cell lines resistant to multiple drugs, Somatic Cell Molec. Genet., 1985, vol. 11, pp. 117–126.CrossRefGoogle Scholar
  10. 10.
    Chen, Y.N., Mickley, L.A., Schwartz, A.M., et al., Characterization of adriamicyn-resistant human breast cancer cells which display overexpression of a novel resistance-related membrane protein, J. Biol. Chem., 1990, vol. 265, no. 17, pp. 10073–10083.PubMedGoogle Scholar
  11. 11.
    Chaudhary, P.M. and Roninson, I.B., Activation of MDR1 (P-glycoprotein) gene expression in human cells by protein kinase-C agonists, Oncol. Res., 1992, vol. 4, pp. 281–290.PubMedGoogle Scholar
  12. 12.
    Vaiman, L.V., Stromskaya, T.P., Rybalkina, E.Yu., et al., Intracellular localization and content of YB-1 protein in multidrug resistant tumor cells, Biochemistry (Mosc)., 2006, vol. 71, pp. 190–200.Google Scholar
  13. 13.
    Tolkacheva, T. and Chan, A.M., Inhibition of H-Ras transformation by the PTEN/MMAC1/TEP1 tumor suppressor gene, Oncogene, 2000, vol. 19, no. 5, pp. 680–689.PubMedCrossRefGoogle Scholar
  14. 14.
    Tsao, H., Zhang, X., Fowlkes, K., and Haluska, F.G., Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines, Cancer Research, 2000, vol. 60, no. 7, pp. 1800–1804.PubMedGoogle Scholar
  15. 15.
    Lee, J.T.Jr., Steelman, L.S., and McCubrey, J.A., Phosphatidylinositol 3′-kinase activation leads to multidrug resistance protein-1 expression and subsequent chemoresistance in advanced prostate cancer cells, Cancer Research, 2004, vol. 64, pp. 8397–8404.PubMedCrossRefGoogle Scholar
  16. 16.
    Tanaka, M., Koul, D., Davies, M.A., et al., MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells, Oncogene, 2000, vol. 19, pp. 5406–5412.PubMedCrossRefGoogle Scholar
  17. 17.
    Huang, H., Cheville, J.C., Pan, Y., et al., PTEN induces chemosensitivity in PTEN-mutated prostate cancer cells by suppression of Bcl-2 expression., J. Biol. Chem., 2001, vol. 276, pp. 38830–38836.PubMedCrossRefGoogle Scholar
  18. 18.
    Goswami, A., Ranganathan, P., and Rangnekar, V.M., The phosphoinositide 3-kinase/Akt1/Par-4 axis: A cancer-selective therapeutic target, Cancer Research, 2006, vol. 66, no. 6, pp. 2889–2892.PubMedCrossRefGoogle Scholar
  19. 19.
    Huiling, Y., Yu-Ye, W., Lin, Y.L., Fournier, K., et al., DNA damage-induced protein 14-3-3 S inhibits protein kinase B/Akt activation and suppresses Akt-activated cancer, Cancer Research, 2006, vol. 66, no. 6, pp. 3096–3105.CrossRefGoogle Scholar
  20. 20.
    Furnari, F.B., Huang, H.J., and Cavenee, W.K., The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells, Cancer Research, 1998, vol. 58, no. 22, pp. 5002–5008.PubMedGoogle Scholar
  21. 21.
    Zhu, X., Kwon, C.H., Schlosshauer, P.W., et al., PTEN induces G1 cell cycle arrest and decreases cyclin D3 levels in endometrial carcinoma cells, Cancer Research, 2001, vol. 61, pp. 4569–4575.PubMedGoogle Scholar
  22. 22.
    Saga, Y., Mizukami, H., Suzuki, M., et al., Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells, Clinical Cancer Research, 2002, vol. 8, pp. 1248–1252.PubMedGoogle Scholar
  23. 23.
    Yan X., Fraser M., Qiu Q., and Tsang, B.K., Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner, Gynecol. Oncol., 2006, vol. 102, no. 2, pp. 348–355.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2007

Authors and Affiliations

  • E. A. Shcherbakova
    • 1
  • T. P. Stromskaya
    • 1
  • E. Yu. Rybalkina
    • 1
  • A. A. Stavrovskaya
    • 1
  1. 1.Institute of CarcinogenesisBlokhin Cancer Research CenterMoscowRussia

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