Background: E1A gene therapy was tested in multiple clinical trials in breast, ovarian, and head and neck cancers. E1A can sensitize paclitaxel-induced cell death and combined paclitaxel chemotherapy and E1A gene therapy is currently tested in a clinical trial for ovarian cancer patients. It has been shown that resistance to paclitaxel occurs in cells expressing low level of FOXO3a. We found that Forkhead box O-class (FOXO) transcription factor FOXO3a is critical for E1A-mediated chemosensitization to paclitaxel. Knocked down FOXO3a expression dramatically abolished E1A-induced chemosensitization of paclitaxel. E1A stabilized FOXO3a by preventing ubiquitin-dependent proteolysis. The E3 ligase involved in stabilizing FOXO3a is β-transducin repeat-containing proteins (ßTrCP); ßTrCP binding to FOXO3a requires phosphorylation of FOXO3a at Ser644 by IKKβ. E1A reduces βTrCP-mediated ubiquitination of FOXO3a by inhibiting IKKβ activity. Further, inhibited IKKß activity is due to E1A-induced expression of PP2A, which binds to transforming growth factor β-activated kinase 1 (TAK1), thus inhibiting TAK1's activation of IKKβ. In this study, we found that E1A stabilizes FOXO3a which is required to sensitize paclitaxel-induced apoptosis. The stabilization is achieved by E1A-induced expression of PP2A/C, which inhibits the binding of TAK1 to IKKβ, therefore abolishing IKKß's function in phosphorylating FOXO3a and FOXO3a degradation. This result provides a rationale for the combination of E1A gene therapy and paclitaxel chemotherapy and may also shed light on design of targeted therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-10.

2010