Abstract
We demonstrated that glyphosate possesses tumor promoting potential in mouse skin carcinogenesis and SOD 1, calcyclin (S100A6), and calgranulin B (S100A9) have been associated with this potential, although the mechanism is unclear. We aimed to clarify whether imbalance in between [Ca2+]i levels and oxidative stress is associated with glyphosate-induced proliferation in human keratinocytes HaCaT cells. The [Ca2+]i levels, ROS generation, and expressions of G1/S cyclins, IP3R1, S100A6, S100A9, and SOD 1, and apoptosis-related proteins were investigated upon glyphosate exposure in HaCaT cells. Glyphosate (0.1 mM) significantly induced proliferation, decreases [Ca2+]i, and increases ROS generation in HaCaT cells, whereas antioxidant N-acetyl-L-cysteine (NAC) pretreatment reverts these effects which directly indicated that glyphosate induced cell proliferation by lowering [Ca2+]i levels via ROS generation. Glyphosate also enhanced the expression of G1/S cyclins associated with a sharp decrease in G0/G1 and a corresponding increase in S-phases. Additionally, glyphosate also triggers S100A6/S100A9 expression and decreases IP3R1 and SOD 1 expressions in HaCaT cells. Notably, Ca2+ suppression also prevented apoptotic related events including Bax/Bcl-2 ratio and caspases activation. This study highlights that glyphosate promotes proliferation in HaCaT cells probably by disrupting the balance in between [Ca2+]i levels and oxidative stress which in turn facilitated the downregulation of mitochondrial apoptotic signaling pathways.
Highlights
Glyphosate, “an organophosphate herbicide,” is the active component of Roundup and considered being innocuous whether alone or in combination with its formulation products such as surfactants under regular usage or chronic exposure in earlier testing approach in humans [1, 2]
Proliferation induced by glyphosate in the presence of antioxidant NAC was significantly inhibited compared to glyphosate alone and was not significantly different from control incubated with NAC alone, suggesting that reactive oxygen species (ROS) may be involved in glyphosate proliferation effect (Figure 1(b))
We have previously reported that glyphosate potentially causes tumor promotion in two-stage mouse skin carcinogenesis model, and S100A6, S100A9 (Ca2+-regulating proteins), superoxide dismutase (SOD) 1 are associated with this tumor promotion [30]
Summary
Glyphosate, “an organophosphate herbicide,” is the active component of Roundup and considered being innocuous whether alone or in combination with its formulation products such as surfactants under regular usage or chronic exposure in earlier testing approach in humans [1, 2]. Intracellular Ca2+ signaling is vital in the regulation of multiple cellular processes, including development, proliferation, secretion, gene activation, and cell death [6,7,8]. Calcyclin (S100A6) and calgranulin B (S100A9) containing 2 EF-hand Ca2+-binding motifs are presently enticing ample attention for their extensive variety of potential intracellular along with extracellular functions [12] Both proteins have been proposed to be involved in the regulation of cell proliferation, apoptosis, ISRN Dermatology and motility through Ca2+-dependent signaling pathways [13]. Likewise, both of them have been defined to play a part in the pathogenesis of epidermal disease involving melanoma or epithelial skin cancer and inflammation [14]. The expression pattern of S100A6 and S100A9 expressions was found to be considerably enhanced in some tumor tissues like hepatocellular carcinoma [15], lung cancer [16], colorectal cancer [17], and melanoma [18]
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