p53 gene expression and 2-methoxyestradiol treatment differentially induce nuclear factor kappa B activation in human lung cancer cells with different p53 phenotypes.
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-kappaB) 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-kappaB activation and inhibitor kappaB alpha (IkappaB-alpha) degradation in three different human lung cancer cell lines with different p53 phenotypes. The H322J cells, with mutant (Arg248Gln) p53, showed NF-kappaB activation and IkappaB-alpha degradation after adeno-p53 expression + 2-ME treatment; however, these conditions separately did not activate NF-kappaB, rather caused accumulation of IkappaB-alpha. In contrast, either adeno-p53 expression or 2-ME treatment induced NF-kappaB activation in the p53-deleted H1299 cells, but H460 cells, containing wt-p53, did not show NF-kappaB activation under any of these conditions. This shows p53-dependent differential signaling to NF-kappaB by 2-ME. Since NF-kappaB 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.
Rath
Pramod C
PC
Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India. pcrath@mail.jnu.ac.in
Mukhopadhyay
Tapas
T
D000077584:2-Methoxyestradiol; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D000077584:2-Methoxyestradiol; D004247:DNA; D051550:I-kappa B Kinase