Gene expression profile in a glioma cell line resistant to cell death induced by a the chimeric tumor suppressor-1 (CTS-1), a dominant-positive variant of p53-the role of NFB

The identification of genes involved in carcinogenesis and tumor progression is of great interest since these genes might be feasible as candidates for new tumor-targeted therapy strategies. Chimeric tumor suppressor-1 (CTS-1), an artificial synthetic variant of p53, resists common p53 inactivation and could therefore be defined as a dominant-positive p53 variant. Overexpression of CTS-1 induces caspase-independent cell death. We used whole-genome microarray expression analysis in a parental (229 super(P)) and a CTS-1-resistant glioma cell line (229 super(Res)) to analyze alterations in gene expression in Ad-CTS-1-infected and in uninfected parental and resistant cells. In total, 700 genes were differentially expressed in infected and 313 genes in uninfected 229 super(Res) versus 229 super(P) cells. Ingenuity Pathway Analysis determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of intracellular networks with central tumor-involved players such as nuclear factor-kappaB (NFB), protein kinase B/AKT or transforming growth factor-b. Here we focused on the function of NFB in Ad-CTS-1-mediated cell death in glioma. NFB was activated in Ad-CTS-1-infected 229 super(P) but not 229 super(Res) cells. NFB activation was accompanied by the induction of cell death in parental cells. Inhibition of NFB activity by expression of an IB super repressor or upregulation of the NFB-linked gene Bex protected parental cells to Ad-CTS-1-induced cell death, whereas knockdown of Bex sensitized both parental and resistant cells. Taken together, these data suggest that activation of the normally antiapoptotic protein NFB does not always necessarily protect cells from apoptosis but, in the glioma cell lines tested so far, and in an environment where p53 is constitutively active, also leads to the induction of cell death.