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:

MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells

Oncogene volume 19, pages 5406–5412 (2000)Cite this article

Abstract

The development and progression of bladder cancer is associated with multiple alterations in the genome, including loss of chromosome 10. Recently, MMAC1/PTEN, a phosphatidylinositol phosphatase, has been mapped to chromosome 10q23. We previously demonstrated that MMAC1/PTEN has tumor suppressive properties in glioblastoma and prostate cancer. To investigate the efficacy of gene therapy with MMAC1/PTEN, we examined whether the exogenous introduction of MMAC1/PTEN via an adenoviral vector (Ad-MMAC) can inhibit tumor growth and reverse drug resistance to doxorubicin in human bladder cancer cells. Human bladder cancer cell lines UM-UC-3 and T24 were infected with Ad-MMAC to induce exogenous expression of MMAC1/PTEN. The cells were then analysed for cell growth and expression of phosphorylated protein kinase B (Akt/PKB) and MMAC1/PTEN. UM-UC-6dox, a doxorubicin resistant subline, was infected with Ad-MMAC to evaluate its role in reversing drug resistance to doxorubicin. We found that MMAC1/PTEN suppressed tumor growth in UM-UC-3 and T24 cells with arrest in the G1 phase of the cell cycle. We also showed that gene therapy with MMAC1/PTEN abrogated phosphorylated Akt/PKB expression in UM-UC-3, T24 and UMUC-6dox cells, and restored doxorubicin sensitivity in UM-UC-6dox. These data demonstrate that MMAC1/PTEN can induce growth suppression and increase sensitivity to doxorubicin in bladder cancer cells and suggest that the MMAC1/PTEN gene and its pathways can be therapeutic targets for bladder cancer.

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

Similar content being viewed by others

References

  • Ahn H, Lee E, Kim K and Lee C. . 1994 J. Urol. 151: 263–267.

  • Alessi DR and Cohen P. . 1998 Curr. Opin. Genet. Dev. 8: 55–62.

  • Aveyard JS, Skilleter A, Habuchi T and Knowles MA. . 1999 Br. J. Cancer 80: 904–908.

  • Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG, Jen J, Isaacs WB, Bova GS and Sidransky D. . 1997 Cancer Res. 57: 4997–5000.

  • Cairns P, Evron E, Okami K, Halachmi N, Esteller M, Herman JG, Bose S, Wang SI, Parsons R and Sidransky D. . 1998 Oncogene 16: 3215–3218.

  • Cappellen D, Gil Diez de Medina S, Chopin D, Thiery JP and Radvanyi F. . 1997 Oncogene 14: 3059–3066.

  • Cookson MS, Herr HW, Zhang ZF, Soloway S, Sogani PC and Fair WR. . 1997 J. Urol. 158: 62–67.

  • Corral DA and Logothetis CJ. . 1997 World J. Urol. 15: 139–143.

  • Dahia PL, Marsh DJ, Zheng Z, Zedenius J, Komminoth P, Frisk T, Wallin G, Parsons R, Longy M, Larsson C and Eng C. . 1997 Cancer Res. 57: 4710–4713.

  • Davies MA, Lu Y, Sano T, Fang X, Tang P, LaPushin R, Koul D, Bookstein R, Stokoe D, Yung WK, Mills GB and Steck PA. . 1999a Cancer Res. 58: 5285–5290.

  • Davies MA, Koul D, Dhesi H, Berman R, McDonnell TJ, McConkey D, Yung WK and Steck PA. . 1999b Cancer Res. 59: 2551–2556.

  • Fujiwara T, Grimm EA, Mukhopadhyay T, Zhang WW, Owen-Schaub LB and Roth JA. . 1994 Cancer Res. 54: 2287–2291.

  • Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF and Zeuthen J. . (1997). Cancer Res. 57: 3660–3663.

  • Gurnani M, Lipari P, Dell J, Shi B and Nielsen LL. . 1999 Cancer Chemother. Pharmacol. 44: 143–151.

  • Herr HW. . 1997 World J. Urol. 15: 84–88.

  • Kanamaru H and Yoshida O. . 1989 Urol. Res. 17: 259–264.

  • Kim WJ, Kakehi Y, Hirai M, Arao S, Hiai H, Fukumoto M and Yoshida O. . 1995 Jpn. J. Cancer Res. 86: 969–977.

  • Kim SK, Su LK, Oh Y, Kemp BL, Hong WK and Mao L. . 1998 Oncogene 16: 89–93.

  • Kozlowski J. . 1999 J. Urol. 162: 1581.

  • Kroft SH and Oyasu R. . 1994 Lab. Invest. 71: 158–174.

  • Levine RL, Cargile CB, Blazes MS, van Rees B, Kurman RJ and Ellenson LH. . 1998 Cancer Res. 58: 3254–3258.

  • Li DM and Sun HI. . 1997 Cancer Res. 57: 2130–2136.

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH and Parsons R. . 1997 Science 275: 1943–1947.

  • Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zhang Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C and Parsons R. . 1997 Nat. Genet. 16: 64–67.

  • Liu J, Liebert M, Steck PA and Kagan J. . 2000 Mol. Carcinog. in press.

  • Maehama T and Dixon JE. . 1998 J. Biol. Chem. 273: 13375–13378.

  • Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ and Eng C. . 1997 Nat. Genet. 16: 333–334.

  • Maxwell GL, Risinger JI, Gumbs C, Shaw H, Bentley RC, Barrett JC, Berchuck A and Futreal PA. . 1998 Cancer Res. 58: 2500–2503.

  • Naito S, Hasegawa S, Yokomizo A, Koga H, Kotoh S, Kuwano M and Kumazawa J. . 1995 Jpn. J. Cancer Res. 86: 1112–1118.

  • Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, Padberg GW and Kremer H. . 1997 Hum. Mol. Genet. 6: 1383–1387.

  • Ogawa N, Fujiwara T, Kagawa S, Nishizaki M, Morimoto Y, Tanida T, Hizuta A, Yasuda T, Roth JA and Tanaka N. . 1997 Int. J. Cancer 73: 367–370.

  • Pu YS, Tsai TC, Cheng AL, Tsai CY, Tseng NF, Su IJ, Hsieh CY and Lai MK. . 1996 J. Urol. 156: 271–275.

  • Rhei E, Kang L, Bogomolniy F, Federici MG, Borgen PI and Boyd J. . 1997 Cancer Res. 57: 3657–3659.

  • Sandberg AA and Berger CS. . 1994 J. Urol. 151: 545–560.

  • Sano T, Lin H, Chen X, Langford LA, Koul D, Bondy ML, Hess KR, Myers JN, Hong YK, Yung WK and Steck PA. . 1999 Cancer Res. 59: 1820–1824.

  • Shinohara H, Liebert M, Wedemeyer G, Chang JH and Grossman HB. . 1993 J. Urol. 150: 505–509.

  • Starink TM, van der Veen JP, Arwert F, de Waal LP, de Lange GG, Gille JJ and Eriksson AW. . 1986 Clin. Genet. 29: 222–233.

  • Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH and Tavtigian SV. . 1997 Nat. Genet. 15: 356–362.

  • Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D, Isaacs WB and Bova GS. . 1998 Cancer Res. 58: 204–209.

  • Tanaka M, Müllauer L, Ogiso Y, Fujita H, Moriya S, Furuuchi K, Harabayashi T, Shinohara N, Koyanagi T and Kuzumaki N. . 1995 Cancer Res. 55: 3228–3232.

  • Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, Li J, Parsons R and Ellenson LH. . 1997 Cancer Res. 57: 3935–3940.

  • Thakar M, Gutkind S, Eskenazi A and Toretsky JA. . 1999 Proc. Am. Assoc. Cancer Res. 40: 633 (abstract).

  • Usansky JI, Liebert M, Wendemeyer G, Grossman HB and Wagner JG. . 1991 Sel. Cancer Ther. 7: 139–150.

  • Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D and Parsons R. . 1997 Cancer Res. 57: 4183–4186.

  • Warde P and Gospodarowicz MK. . 1997 World J. Urol. 15: 125–133.

  • Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL, Said JW, Isaacs WB and Sawyers CL. . 1998 Proc. Natl. Acad. Sci. USA 95: 5246–5250.

Download references

Acknowledgements

This work was supported in part by the American Foundation for Urologic Disease and grants CA56973 and CA16672 from the National Cancer Institute.

Author information

Author notes

  1. Monica Liebert

    Present address: NIDDK and Urologic Oncology Branch, NCI, NIH, Bethesda, 20892, MD, USA

Authors and Affiliations

  1. Department of Urology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, TX, USA

    Motoyoshi Tanaka, Monica Liebert & H Barton Grossman

  2. Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, TX, USA

    Dimpy Koul, Michael A Davies & Peter A Steck

Authors
  1. Motoyoshi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dimpy Koul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael A Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Monica Liebert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter A Steck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Barton Grossman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanaka, M., Koul, D., Davies, M. et al. MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells. Oncogene 19, 5406–5412 (2000). https://doi.org/10.1038/sj.onc.1203918

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203918

Keywords

This article is cited by

Search

Advanced search

Quick links