Effects of endosulfan on hepatoma cell adhesion: Epithelial–mesenchymal transition and anoikis resistance

Abstract

Endosulfan is an organochlorine pesticide commonly used in agriculture yet classified by the Stockholm Convention in 2011 as a persistent organic pollutant (POP). Its potential toxicity makes its continued use a major public health concern. Despite studies in laboratory animals, the molecular mechanisms underlying the carcinogenic effects of endosulfan in human liver remain poorly understood. In this study, we investigated the phenotypical effects of endosulfan on HepG2 liver cells. First, we found that endosulfan disrupted the anoikis process. Indeed, cells exposed to endosulfan were initially sensitized to anoikis and thereafter recovered their resistance to this process. This phenomenon occurred in parallel to the induction of the epithelial to mesenchymal (EMT) process, as demonstrated by: (1) reorganization of the actin cytoskeleton together with activation of the FAK signaling pathway; (2) repression of E-cadherin expression; (3) induction of Snail and Slug; (4) activation of the WNT/β-catenin pathway; and (5) induction and reorganization of mesenchymal markers (S100a4, vimentin, fibronectin, MMP-7). Secondly, despite the acquisition of mesenchymal characteristics, HepG2 cells exposed to endosulfan failed to migrate. This incapacity to acquire a motile phenotype could be attributed to a disruption of the interaction between the ECM and the cells. Taken together, these results indicate that endosulfan profoundly alters the phenotype of liver cells by inducing cell detachment and partial EMT as well as disrupting the anoikis process. All these events account, at least in part, for the carcinogenic potential of endosulfan in liver.

Potential involvement of chemicals in liver cancer progression: An alternative toxicological approach combining biomarkers and innovative technologies

“…Yet, the increase in caspase-3 activity observed is normally consecutive to the induction of an apoptotic process. This phenomenon has already been described by our team (Peyre et al, 2012) and is linked to an anoïkis process. The number of modulations and near-identical behavior observed between dioxin and endosulfan, would indicate the same mechanism of action between the two pesticides.…”

Pesticide exposure and liver cancer: a review

“…Specific pesticides demonstrated statistically significant associations with liver cancer among studies included in this review, including the organochlorine insecticide DDT. Broader pesticide chemical classes associated with increased risk of liver cancer include organochlorines, organophosphates, and carbamates, each comprised of pesticides showing carcinogenic potential [60–62]. Organochlorines are mostly insecticides, were widely used in the 1940s to 60s, but have largely been banned in many countries due to adverse wildlife and human health effects and environmental persistence [18, 63].…”

Gene expression profiling to identify the toxicities and potentially relevant disease outcomes due to endosulfan exposure

“…43 The observed transcriptomic changes associated with alteration of actin cytoskeleton, cell death, and Wnt signaling support the carcinogenic morphological changes observed in HepG2 cells after endosulfan treatment. 22 The transcriptomic changes associated with perturbations of cell cycle, DNA repair, and p53 signaling correlate with genotoxicity, along with previously established phenotypes induced by endosulfan. 44,45…”

“…Liver cancer (score 87), prostate cancer (score 71), myeloid leukemia (score 70) and lymphoid leukemia (score 69) were listed as the top four cancers predicted to be associated with endosulfan exposure, consistent with previous reports. [22][23][24][25] Interestingly, several genes including Kcnma1, The changes in genes expression were indicated by up-regulated (↑) or down-regulated (↓). The changes in genes expression were indicated by up-regulated (↑) or down-regulated (↓) or no changes (-).…”