Arsenic-induced apoptosis in the p53-proficient and p53-deficient cells through differential modulation of NFkB pathway

Arsenic is a well-known environmental carcinogen and an effective chemotherapeutic agent. The underlying mechanism of this dual-effect, however, is not fully understood. In this study, we applied mouse p53(+ / +) and p53(- / -)cells to examine the NF kappa B pathway and proinflammatory cytokines after arsenic treatment. Arsenic reduced cell viability and increased more apoptosis in the p53 - / - cells as compared to p53 + / + cells, which was correlated with activation of SAPK/JNK, p38 MAPK, and AKT pathways. A transcriptional regulatory network analysis revealed that arsenic activated transcription regulatory elements E2F, Egr1, Trp53, Stat6, Bc16, Creb2 and ATF4 in the p53 + / + cells, while in the p53 - / - cells, arsenic treatment altered transcription factors NF kappa B, Pparg, Creb2, ATF4, and Egr1. We observed dynamic changes in phosphorylated NF kappa B p65 (p-NF kappa B p65) and phosphorylated IKK alpha beta(p-IKK alpha beta) in both genotypes from 4 h to 24 h after treatment, significant decreases of p-NF kappa B p65 and p-IKK alpha beta in the p53 - / - cells, whereas increases of p-NF kappa B p65 and p-IKK alpha beta were observed in the p53 + / + cells. Our study confirmed the differential modulation of NF kappa B pathway by arsenic in the p53 + / + or p53 - / - cells and this observation of the differential mechanism of cell death between the p53 + / + and p53 - / - cells might be linked to the unique ability of arsenic to act as both a carcinogen and a chemotherapeutic agent.