Influence of arsenate and arsenite on signal transduction pathways: an update

Abstract

Arsenic has been a recognized contaminant and toxicant, as well as a medicinal compound throughout human history. Populations throughout the world are exposed to arsenic and these exposures have been associated with a number of human cancers. Not much is known about the role of arsenic as a human carcinogen and more recently its role in non-cancerous diseases, such as cardiovascular disease, hypertension and diabetes mellitus have been uncovered. The health effects associated with arsenic are numerous and the association between arsenic exposure and human disease has intensified the search for molecular mechanisms that describe the biological activity of arsenic in humans and leads to the aforementioned disease states. Arsenic poses a human health risk due in part to the regulation of cellular signal transduction pathways and over the last few decades, some cellular mechanisms that account for arsenic toxicity, as well as, signal transduction pathways have been discovered. However, given the ubiquitous nature of arsenic in the environment, making sense of all the data remains a challenge. This review will focus on our knowledge of signal transduction pathways that are regulated by arsenic.

Fig. 1

Arsenic signaling. Arsenate [As(V)] may enter the cell through phosphate anti-transporters located at the cell membrane, which normally transport phosphate into the cell and hydroxide out of the cell. Arsenite [As(III)] may enter the cell via cell diffusion or through aquaporin transporters (AQP9) located the cell membrane. There is evidence that AQP9 may transport arsenite out of the cell. At physiological pH arsenate is reduced to arsenite, which may undergo a Fenton reaction and produce reactive oxygen species (ROS). ROS may interact with NF-E2 related factor 2 (Nrf2) which would then cause Nrf2 to disassociate from the Keap1-Cul3 complex and translocate to the nucleus. In the nucleus, Nrf2 binds to a small MAF protein and to the antioxidant response element (ARE) located at the promoter region of phase II and antioxidant genes, resulting in the transcription of anti-oxidant enzymes such as NQO1, GST, and HO-1. Arsenite activates the G-protein-coupled receptor, S1P1. Activation of the S1P1 receptor has been shown to activate the Ras-Raf pathway leading to cell proliferation and survival

Fig. 2

Mechanisms of arsenic-induced insulin resistance. Under normal conditions insulin binds to the insulin receptor located at the cell membrane. Activated insulin receptor autophosphorylates and trans-phosphorylates the β subunits of the receptor located at the innermembrane. This is followed by phosphorylation of the insulin receptor substrate (IRS) causing activation of the phosphatidylinositol 3-kinase (PI3K) pathway leading to phosphorylation of AKT at serine 473 by mTOR. This phosphorylation allows for phosphorylation of AKT at threonine 308 by PDK-1. These phosphorylations of AKT at serine 473 and threonine 308 allow for the stimulation of GLUT4 from cellular vesicles to translocate to the cell membrane and allows for glucose to enter the cell. It is postulated that arsenite and its metabolite MMA(III) directly inhibit the phosphorylation of AKT at serine 473 by mTOR (continuous red line) and indirectly inhibit phosphorylation of threonine 308 by PDK-1 (broken red line) thereby preventing the translocation of the GLUT4 transporter to the cell membrane and leading to insulin resistance