Involvement of a AS3MT/c‐Fos/p53 signaling axis in arsenic‐induced tumor in human lung cells

Abstract

Arsenite methyltransferase (AS3MT) is an enzyme that catalyzes the dimethylation of arsenite (+3 oxidation state). At present, the studies on arsenic carcinogenicity mainly focus on studying the polymorphisms of AS3MT and measuring their catalytic activities.We recently showed that AS3MT was overexpressed in lung cancer patients who had not been exposed to arsenic. However, little is known about the molecular mechanisms of AS3MT in arsenite-induced tumorigenesis. In this study, we showed that AS3MT protein expression was higher in the arsenic-exposed population compared to the unexposed population. AS3MT was also overexpressed in human lung adenocarcinoma (A549) and human bronchial epithelial (16HBE) cells exposed to arsenic (A549: 20-60 μmol/L; 16HBE: 2-6 μmol/L) for 48 h. Furthermore, we investigated the effects of AS3MT on cell proliferation and apoptosis using siRNA. The downregulation of AS3MT inhibited the proliferation and promoted the apoptosis of cells. Mechanistically, AS3MT was found to specifically bind to c-Fos, thereby inhibiting the binding of c-Fos to c-Jun.Additionally, the siRNA-mediated knockdown of AS3MT enhanced the phosphorylation of Ser392 in p53 by upregulating p38 MAPK expression. This led to the activation of p53 signaling and the upregulated expression of downstream targets, such as p21, Fas, PUMA, and Bax. Together, these studies revealed that the inorganic arsenic-mediated upregulation of AS3MT expression directly affected the proliferation and apoptosis of cells, leading to arsenic-induced toxicity or carcinogenicity.

DCAF13 inhibits the p53 signaling pathway by promoting p53 ubiquitination modification in lung adenocarcinoma

“…Tumor protein p53 (p53) is the most important tumor suppressor and involved in cell signaling in a variety of processes [ 26 ], including cell cycle arrest, DNA repair, apoptosis, senescence, autophagy, immunity, ferroptosis, or metabolism [ 27 , 28 ]. The most important role of p53 as a transcription factor is considered to directly regulate the expression of ~ 500 target genes [ 29 – 31 ], such as CDKN1A (encoding cyclin-dependent kinase inhibitor 1, also known as p21 protein) [ 32 ], BBC3 (encoding Bcl-2-binding component 3) [ 33 ], BAX (encoding BCL2 associated X, apoptosis regulator) [ 34 ], FAS [ 35 ] and some other target genes so as to suppress tumor development. As a nuclear transcription factor, p53 does not possess typical drug target features and has therefore long been considered to be undruggable [ 36 ].…”