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

ABSTRACT: 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?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, Bcl6, Creb2 and ATF4 in the p53+/+ cells, while in the p53-/- cells, arsenic treatment altered transcription factors NF?B, Pparg, Creb2, ATF4, and Egr1. We observed dynamic changes in phosphorylated NF?B p65 (p-NF?B p65) and phosphorylated IKK?? (p-IKK??) in both genotypes from 4 h to 24 h after treatment, significant decreases of p-NF?B p65 and p-IKK?? in the p53-/- cells, whereas increases of p-NF?B p65 and p-IKK?? were observed in the p53+/+ cells. Our study confirmed the differential modulation of NF?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.

SUBMITTER: Yin L 

PROVIDER: S-EPMC6689409 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature