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  • Recent studies have shown arsenic could cause autophagic cel

    2021-04-21

    Recent studies have shown arsenic could cause autophagic cell death in malignant cells, including leukemia and malignant glioma Prednisone [16], [17]. However, at present, little is known about the consequences of arsenic-treated urothelial cells in autophagy and expression of its related proteins. This prompted us to investigate the possible significances of arsenic-induced autophagy. Therefore, the aim of the present study was to determine the role of ERK1/2 in arsenite-induced autophagy and the contribution of arsenite-induced DAPK decreased in human uroepithelial cells.
    Materials and methods
    Results
    Discussion Arsenite is a well-known oxidative stress-inducing agent that activates a variety of kinases such as tyrosine kinases, MAPK family, including ERK, JNK and p38. By using Comet assay, we shown that the arsenite caused oxidative DNA damage in arsenite-treated SV-HUC-1 [20]. Arsenic activates MAPK in mouse epidermal cell lines (JB6), as evidenced by ERK phosphorylation and increased ERK activity at concentration ranging from 0.8 to 200μM, but activating JNK only at higher concentration (>50μM) [21]. Furthermore, arsenite-induced cell transformation of this cell line is blocked by overexpression of a dominant-negative ERK, indicating a direct role of ERK in arsenic cell transformation. Activation of different members of MAPK has been related to specific stimuli. For example, ERK is strongly activated by mitogenic stimuli, but only moderately activated by stress. Most reports indicate that ERK, JNK and p38 are differentially activated by arsenic. The arsenic-induced activation of ERK seems to consistently lead to proliferative responses whereas activation of JNK appears to be associated with induction of apoptosis and inhibition of cell transformation. Ludwig et al. showed that ERK was activated by sodium arsenite in the human embryonic kidney cell line HEK293 [22]. It has also been shown that the effects of arsenic may be mediated through tyrosine kinases receptors and in particular the EGFR, c-Src, Shc, FAK [23], [24], and activation of the Ras-dependent pathway [25]. The summary of this evidence continues to accumulate, suggesting that MAPK are important in mediating the effects of arsenic. Additional studies report that arsenic may differentially affect transcription factors in a manner that is dependent upon the arsenic dose, length of exposure, the nature of the specific transcription factor, or cell type [26]. Our results show that p-ERK1/2 proteins were induced by arsenite in a dose-dependent manner, but high concentrations (10μM) caused p-ERK1/2 protein levels to decrease compared with 4μM arsenite and cell death (Fig. 1, Fig. 2A). In the present U0126 for 24h, that resulted in complete inhibition of ERK1/2 phosphorylation caused by arsenite. It indicates that ERK1/2 activation by arsenite may require the activation of MEK1/2. Little is known about signaling pathways that regulate arsenic-mediated autophagy. However, Pattingre et al. have demonstrated that TNF induces autophagy in MCF-7 cells via the ERK1/2 pathway [27]. Moreover, the ERK is also involved in promoting autophagy elicited by amino acid deprivation [19]. Some studies show the Ras-Raf-MAPK pathway, has emerged as a key regulator of autophagy. Sustained activation of ERK1/2 was associated with autophagy induction in H29 colon cancer cells [28] and by the carcinogen lindane [29]. A recent study showed that the natural product triterpenoid B-group saponins induced autophagy by inhibiting Akt signaling and enhanced ERK activity [30]. One study showed that MEK inhibitors prevented curcumin-induced autophagy in glioma cells, suggesting that the activation of ERK is associated with the induction of autophagy [31]. Thus, Akt inhibition and ERK activation are probably common mechanisms of autophagy induced by anticancer agents. These findings indicate the possibility that high constitutive ERK activity found in all cancers may provide a malignant advantage by impeding the tumor suppressive function of autophagy. It strongly supports a novel model by which the ERK pathway tightly controls autophagy at the maturation stage. Arsenic is widely found in the earth's crust, and it is a proven toxic and carcinogenic agent, which is associated with various human malignancies, including bladder cancer [32]. Some studies have shown arsenite may also induce autophagic cell death (programmed cell death type II) in malignant cells, including leukemic and malignant glioma cells [33], [34]. However, our ICC and Western blotting results revealed increased expression of LC3B and Beclin-1 in arsenic-treated SV-HUC-1 cells. This result is indeed associated with increased numbers of autophagosomes in the arsenic-treated SV-HUC-1 cells as demonstrated by TEM. It suggests that LC3B and Beclin-1 are closely related to arsenic-induced autophagy. And the results shown in Fig. 4, Fig. 5 indicate decreased autophagosomes and LC3B and Beclin-1 proteins levels in cells pretreated with 5-aza-CdR or U0126, followed by treatment with arsenite (Fig. 4, Fig. 5) compared with those treated with 4μM arsenite alone (Fig. 4, Fig. 5). Therefore, we suggest that arsenic induces cell death not only via apoptosis but via autophagy in certain cell lines as well, and possibly also through Prednisone activation of ERK signaling pathway.