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Phosphatase and Tensin Analog Gene Overexpression Engenders Cellular Death in Human Malignant Mesothelioma Cells via Inhibition of AKT Phosphorylation

From the Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Correspondence: Address correspondence and reprint requests to: W. Roy Smythe, MD, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 109, Houston, TX 77030; Fax: 713-794-4669; E-mail: rsmythe{at}mdanderson.org

Background: Abnormal phosphatase and tensin analog (PTEN) gene expression has been noted in neoplasms. The PTEN protein cleaves phosphate groups from cellular growth kinases, inhibiting tumor propagation. A downstream target of PTEN is AKT, a serine-threonine kinase that when activated inhibits apoptosis. We sought to determine whether PTEN overexpression in mesothelioma cells would engender hypophosphorylation of AKT and apoptosis.

Methods: Human malignant mesothelioma cell lines REN and I-45 were transfected with adenoviral vectors AdPTEN and AdBgal (marker gene) at various multiplicities of infection (MOI). Cell viability was measured using a colorimetric assay, and apoptosis was assessed by morphology and subG1 fluorescence-activated cell sorter (FACS) analysis. PTEN protein and AKT phophorylation were evaluated by Western blot, and AKT kinase activity was evaluated by functional assay.

Results: Increased cellular killing was noted with AdPTEN gene transfer. The ratio of cell killing with AdPTEN to AdBgal widened with increasing MOI and was statistically significant at all MOI. Cells demonstrated apoptosis by morphologic and subG1 FACS analyses. Cells overexpressing PTEN demonstrated decreased phosphorylated (active) AKT and AKT kinase activity compared with controls.

Conclusions: Overexpression of PTEN engenders apoptosis in mesothelioma by AKT hypophosphorylation. The forced overexpression of PTEN may prove useful clinically in this treatment-resistant neoplasm.

Key Words: Mesothelioma • PTEN • AKT • Apoptosis

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