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  • It has been indicated that chemicals induced mammalian cell

    2021-12-01

    It has been indicated that chemicals-induced mammalian cell death is mediated by GSK-3 activation (by downregulated of GSK-3 phosphorylation) leading to apoptosis (Huang et al., 2014, Li et al., 2014, Tanabe et al., 2011, Yun et al., 2009). In contrast, accumulating evidences have reported that the inhibition of GSK-3 activity (by increased in GSK-3 phosphorylation) triggers the apoptotic responses (Spokoini et al., 2010, Sun et al., 2014, Watcharasit et al., 2008). Furthermore, the important role of GSK-3 in β-cells is more related to regulation of cell survival and apoptosis than to its effects on carbohydrate metabolism seen in other tissues (Beurel and Jope, 2006). Inhibition of GSK-3 kinase protects β-cells from glucolipotoxicity-induced apoptosis, which associated with the increase in β-cell proliferation, has been reported (Mussmann et al., 5,8,11-Eicosatriynoic Acid 2007). In pancreatic β-cell-specific Gsk-3β knockout mice (β-Gsk-3β−/−), it was exhibited improved glucose intolerance and expanded β-cell mass with increased proliferation and decreased apoptosis relative to that in control mice under the high-fat diet-induced (Liu et al., 2010). Although some studies have shown that apoptotic stimuli, such as DNA damage induced by etoposide, have been revealed to cause the decrease in GSK-3 activation downstream-regulated signals (Jin et al., 2005, Watcharasit et al., 2008), the molecular mechanisms involved in the cytotoxic effects of etoposide in β-cells remain to be clarified. In the current study, the Western blot analysis showed that RIN-m5f 5,8,11-Eicosatriynoic Acid exposed to etoposide had significantly increased the phosphorylation level of GSK-3α/β. Pretreatment of cells with the pharmacological inhibitor of the GSK-3 (LiCl) effectively prevented the phosphorylated level of GSK-3 protein, as well as attenuated etoposide-induced the reduction of viable cells, apoptotic events (prevented caspase-3 activity and the expressions of cleaved form of caspase-3 and -7), and MMP depolarization. These results indicate that GSK-3 signal is involved in the apoptotic mechanism in etoposide-induced β-cell death. MAPKs comprise a family of serine/threonine protein kinases (including JNK, ERK, and p38-MAPK) that play the major role in the regulation of the sequential transduction of biological signals from cell surface to the nucleus such as differentiation, proliferation, transformation, and survival and death, and response to environmental and toxic stimuli (Boutros et al., 2008, Chang and Karin, 2001). For example, active JNK and/or p38-MAPK inhibits the anti-apoptotic function of Bcl-2 and induces the translocation of Bax and Bak (pro-apoptotic proteins) to mitochondria causes the loss of MMP and the release of apoptogenic proteins downstream-activated caspase cascades leading to apoptosis (Lei et al., 2002, Ravindran et al., 2011, Tournier et al., 2000). The activation of JNK pathway is involved in the progression of pancreatic β-cell apoptosis in the development of DM (Weston and Davis, 2007). Furthermore, ERK has been clear to mediate proliferative and survival responses, whereas it is also be directly linked to cell death signaling including β-cells (Martin and Pognonec, 2010, Pavlovic et al., 2000). A number of studies have indicated that activation of JNK- and/or ERK-mediated apoptotic pathways involves in toxic insults-induced pancreatic β-cell apoptosis (Chang et al., 2013, Maedler et al., 2004, Wu et al., 2012). It has also been shown that the exposure of cells to etoposide can induce JNK/ERK activation signals contributing to apoptosis (Brantley-Finley et al., 2003, Shimada et al., 2003, Stefanelli et al., 2002, Qu et al., 2010); however, the crucial role of JNK/ERK activation and the relationship between JNK/ERK and GSK-3 in etoposide-induced β-cell death which causes mitochondrial dysfunction leading to apoptosis are unknown. The results of the present work revealed that etoposide significantly increased phosphorylation levels of JNK and ERK, but not p38-MAPK, in RIN-m5F cells. Pretreatment with of cells with the specific JNK inhibitor (SP600125) and ERK inhibitor (PD98059) effectively blocked JNK and ERK activation as well as suppressed etoposide-induced cytotoxicity, the increase in caspase-3 activity and protein activation of caspase-3 and -7, and the depolarization of MMP. Moreover, the phosphorylated expression of GSK-3α/β protein was effectively abrogated by pretreatment with JNK and ERK inhibitor in etoposide-exposed cells, respectively; however, pretreated with GSK-3 inhibitor LiCl prior to etoposide exposure was not prevented both of JNK and ERK protein activation. These results indicate the activation of JNK/ERK pathways-mediated GSK-3 signaling is the critical for downstream triggered mitochondria-dependent apoptosis in etoposide-induced pancreatic β-cell death.