Molecular features in arsenic-induced lung tumors

Abstract

Arsenic is a well-known human carcinogen, which potentially affects ~160 million people worldwide via exposure to unsafe levels in drinking water. Lungs are one of the main target organs for arsenic-related carcinogenesis. These tumors exhibit particular features, such as squamous cell-type specificity and high incidence among never smokers. Arsenic-induced malignant transformation is mainly related to the biotransformation process intended for the metabolic clearing of the carcinogen, which results in specific genetic and epigenetic alterations that ultimately affect key pathways in lung carcinogenesis. Based on this, lung tumors induced by arsenic exposure could be considered an additional subtype of lung cancer, especially in the case of never-smokers, where arsenic is a known etiological agent. In this article, we review the current knowledge on the various mechanisms of arsenic carcinogenicity and the specific roles of this metalloid in signaling pathways leading to lung cancer.

Figure 1

Arsenic occurrence in North America and documented relationship with different cancer types. A) Light red circles on the map represent Canada provinces and US States affected by arsenic concentrations over 10μg/L. Estimations were made on the basis of data obtained from Health Canada [10] and the US Geological Service [11]. Please note that circled areas are approximations only; for detailed information, see references. States in red indicate evidence of arsenic exposure and higher cancer incidence, based on published literature. B) Histogram representing maximum concentrations detected in countries with evidence of arsenic exposure and cancer relationship (blue) [12] and in provinces/states of Canada and United States (light red) [10,11].

Figure 2

Mechanisms of arsenic-induced carcinogenesis. Carcinogenic effects induced by arsenic exposure are mostly generated due to its biotransformation process, having effects at genetic and epigenetic levels. Arsenic biotransformation occurs through a series of cycles of reduction, oxidation, and methylation reactions. Pentavalent arsenic (As^V) is reduced to arsenite (As^III), using glutathione (GSH) and thioredoxin (TRX) as electron donors. In the excretion process, As^III is methylated using S-Adenosyl methionine (SAM) as a source of methyl groups resulting in generation of arsenic species with higher carcinogenic potential. Genetic alterations are largely due to generation of reactive oxygen and/or nitrogen species, partially derived from arsenic-induced mitochondrial dysfunction. Epigenetic effects, such as changes in DNA methylation patterns have been linked to deprivation of SAM.

Figure 3

Arsenic-mediated activation of EGFR signaling pathway. EGFR and several components of this pathway can be activated by arsenic exposure in human lung cells. This activation can be inhibited by EGFR-TKI, revealing a potential role for TKIs in the management of arsenic associated lung tumors, regardless of the mutational status of EGFR. As^III can also induce STAT3 inhibition by targeting JAK, while it can activate STAT3 trough JNK, contributing to AKT activation.

Figure 4

Arsenic-mediated disruption of PI3K/AKT signaling pathway. Depending on the receptor, different proteins can bind to the phosphorylated tyrosine residue of the RTK to recruit PI3K to the plasma membrane. There, the activated PI3K can interact with phosphatidylinositol 4,5-bisphosphate (PIP2) on the inner side of the membrane, and catalyze its phosphorylation to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 activates the kinase AKT, which is capable of phosphorylating a number of target proteins in the cytoplasm and nucleus. Some of the direct targets of PI3K (light blue) and AKT (grey), and their consequences on cell fate are depicted. Arsenic targets sulfhydryl groups of PI3K kinases such as c-Src, also resulting in activation of the PI3K/AKT pathway. As^III can also activate AKT independently of PI3K, both through STAT3 and/or induction of miR-190. PTEN is an inhibitor of the pathway that has been shown to be a target of arsenic in stem cells. Among other mechanisms, methylation patterns at the promoter region of the p53 gene have been shown to be modified by arsenic, resulting in silencing of this tumor suppressor.

Figure 5

Arsenic affects NRF2 signaling pathway. The transcription factor nuclear factor erythroid-derived factor 2–related factor 2 (NRF2) has classically been associated with a cancer preventive function through the induction of cytoprotective proteins that inactivate reactive carcinogenic species and their intermediates. Arsenic can stimulate the activity of the NFR2 pathway mainly through generation of ROS. These events can protect the cell during acute/short-term exposure to low doses of arsenic. However, chronic arsenic-mediated activation of the NRF2 pathway may result in detrimental cellular effects associated with arsenic-induced pathogenesis.