p53 Gene Expression and 2-Methoxyestradiol Treatment Differentially Induce Nuclear Factor Kappa B Activation in Human Lung Cancer Cells with Different p53 Phenotypes

Abstract

The p53 tumor suppressor gene is frequently mutated in multiple human cancers, leading to loss of wild-type p53 (wt-p53)–dependent functions and tumorigenesis. p53 gene therapy is used to induce apoptosis in human cancer cells and tumors. Activation of nuclear factor kappa B (NF-κB) causes resistance to both chemotherapy and apoptosis in tumor cells. We show that expression of wt-p53 from a recombinant adenovirus-p53 followed by treatment with 2-methoxyestradiol (2-ME), an endogenous, nontoxic, estrogenic metabolite, resulted in differential NF-κB activation and inhibitor kappaB α (IκB-α) degradation in three different human lung cancer cell lines with different p53 phenotypes. The H322J cells, with mutant (Arg248Gln) p53, showed NF-κB activation and IκB-α degradation after adeno-p53 expression + 2-ME treatment; however, these conditions separately did not activate NF-κB, rather caused accumulation of IκB-α. In contrast, either adeno-p53 expression or 2-ME treatment induced NF-κB activation in the p53-deleted H1299 cells, but H460 cells, containing wt-p53, did not show NF-κB activation under any of these conditions. This shows p53-dependent differential signaling to NF-κB by 2-ME. Since NF-κB activation inhibits apoptosis and causes resistance to chemotherapy, our study suggests the need to distinguish p53 phenotypes of tumors for p53 gene and 2-ME therapy.