Reduced Reactive Oxygen Species–Generating Capacity Contributes to the Enhanced Cell Growth of Arsenic-Transformed Epithelial Cells

Abstract

Reactive oxygen species (ROS) have been implicated in the activation of protein kinases, DNA damage responses, and cell apoptosis. The details of how ROS regulate these intracellular biochemical and genetic processes remain to be fully understood. By establishing transformed bronchial epithelial cells through chronic low-dose arsenic treatment, we showed that the capacity of ROS generation induced by arsenic is substantially reduced in the transformed cells relative to the nontransformed cells. Such a reduction in ROS generation endows cells with premalignant features, including rapid growth, resistance to arsenic toxicity, and increased colony formation of the transformed cells. To validate these observations, the capability of ROS generation was restored in the transformed cells by treatment with inhibitors or siRNAs to silence the function of superoxide dismutase (SOD) or catalase and cell growth was determined following these treatments. Enhancement in ROS generation suppressed cell growth and colony formation of the transformed cells significantly. Despite the fact that the transformed cells showed a decreased expression of NF-κB signaling proteins IKKβ and IKKγ, the proteolytic processing p105 and p100 and NF-κB DNA binding activity were elevated in these cells. Increasing ROS generation by silencing SOD and catalase reduced the DNA binding activity of NF-κB in the transformed cells. Taken together, the transformed cells induced by arsenic exhibited a decrease in ROS generation, which is responsible for the enhanced cell growth and colony formation of the transformed cells, most likely through a sustained alternative activation of the NF-κB transcription factor.

Antioncogenic and Oncogenic Properties of Nrf2 in Arsenic-induced Carcinogenesis

“…Cigarette smoke, As 3ϩ -contaminated food, and As 3ϩ -contaminated water are non-occupational sources of human exposure to As 3ϩ (22). Our previous study has shown that chronic exposure of human bronchial epithelial cells to As 3ϩ generates ROS and that ROS are responsible for As 3ϩ -induced transformation of these cells (16). In our present study, we have shown that As 3ϩ -transformed cells have a low level of ROS along with highly expressed antiapoptotic proteins (Bcl-2 and Bcl-xL) and antioxidant enzymes (catalase and SOD2) as well as Nrf2 and p62.…”

“…7G). As 3ϩ -induced ROS have been shown to have oncogenic properties in the premalignant stage; exposure of human lung bronchial epithelial cells to As 3ϩ generates ROS, which are responsible for malignant transformation of these cells (16). In this stage, the Nrf2 is inducible and is regulated by Keap1.…”

“…As 3ϩ -transformed cells were generated as described previously (16). The transformation ability and tumorigenicity of the transformed cells were confirmed by soft agar assay and xenograft assay, respectively.…”

Arsenic, cadmium, mercury and nickel stimulate cell growth via NADPH oxidase activation

“…In accordance, proliferation of HaCaT cells were shown to be stimulated at low H 2 O 2 concentrations [35]. Our results correlate with other studies showing an association between low-concentrations of metals and stimulation of cell proliferation [36][37][38] and generation of ROS through NOX activation [39,40].…”

Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

“…One mechanism involves the iAs-induced production of reactive oxygen species (ROS) which has been reported in multiple cell models including human lung bronchial epithelial BEAS-2B cells, human vascular smooth muscle cells, vascular endothelial cells, U937 cells, NB4 cells, human-hamster hybrid cells, CHO-K1 cells, and HEL30 cells (10)(11)(12)(13)(14)(15)(16). The impact of iAs on ROS production is hypothesized to occur in two steps.…”