p53 stabilization is decreased upon NFκB activation: A role for NFκB in acquisition of resistance to chemotherapy

Chemotherapeutic agents simultaneously induce transcription factors p53 and NFκB. p53 induction can activate an apoptotic program, and resistance to chemotherapy correlates with the loss of a functional p53 pathway. By contrast, NFκB prevents apoptosis in response to chemotherapeutic agents. We have analyzed the p53 response in IKK1/2−/− MEFs, which lack detectable NFκB activity. Compared to WT fibroblasts, IKK1/2−/− fibroblasts showed increased cell death and p53 induction in response to the chemotherapeutic agent, doxorubicin. Reconstitution of IKK2, but not IKK1, increased Mdm2 levels and decreased doxorubicin-induced p53 stabilization and cell death. IKK2-mediated effects required its kinase function and were abrogated by coexpression of the dominant negative IκBαM, implying a role for NFκB in blocking chemotherapy-induced p53 and cell death.