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

The development and progression of bladder cancer is associated with multip le alterations in the genome, including loss of chromosome 10. Recently, MM AC1/ PTEN, a phosphatidylinositol phosphatase, has been mapped to chromosom e 10q23. We previously demonstrated that MMAC1/PTEN has tumor suppressive p roperties in glioblastoma and prostate cancer. To investigate the efficacy of gene therapy with MMAC1/ PTEN, we examined whether the exogenous introdu ction of MMAC1/PTEN via an adenoviral vector (Ad-MMAC) can inhibit tumor gr owth and reverse drug resistance to doxorubicin in human bladder cancer cel ls. Human bladder cancer cell lines UM-UC-3 and T24 were infected with Ad-M MAC to induce exogenous expression of MMAC1/PTEN. The cells were then analy sed for cell growth and expression of phosphorylated protein kinase B (Akt/ PKB) and MMAC1/PTEN. UM-UC-6dox, a doxorubicin resistant subline, was infec ted with Ad-MMAC to evaluate its role in reversing drug resistance to doxor ubicin. We found that MMAC1/ PTEN suppressed tumor growth in UM-UC-3 and T2 4 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 suppre ssion and increase sensitivity to doxorubicin in bladder cancer cells and s uggest that the MMAC1/ PTEN gene and its pathways can be therapeutic target s for bladder cancer.