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    • Apoptosis is one of critical toxic mechanisms of benzene met

    2021-11-29

    Apoptosis is one of critical toxic mechanisms of benzene metabolites. In this work, overexpression of HIF-1a could significantly reduce the increase in cell apoptosis caused by 40 μM BQ. At the meanwhile, anti-apoptotic protein Bcl-2 level was significantly elevated in HIF-1a overexpression cells than in HIF-1a control cells. Bcl-2 proteins block apoptosis initiation via binding Bcl-2 homology 3 (BH3)-only proteins or inhibiting the activated effectors (Zheng et al., 2016). MiR-34a was reported to be involved in 1,4-BQ-induced apoptosis by regulating Bcl-2 (Chen et al., 2017). Zheng et al. found that the HIF-1a/ROS signaling pathway was involved in promoting erythroid apoptosis in MDS patients with iron overload (Zheng et al., 2017). Another study showed that HIF-1a was able to protect cervical carcinoma cells from apoptosis through modulation of VEGF and p53 (Fu et al., 2015). In addition, Tang et al. found Nox4 regulates apoptosis through the generation of ROS and its downstream signaling in gastric cancer cells (Tang et al., 2018). Furthermore, accumulation of Pfkfb3, one target gene of HIF-1a, was reported to protect cells from cisplatin-induced apoptosis by promoting glycolysis (Li et al., 2018). Thus, HIF-1a overexpression could protect K562 cells from apoptosis caused by 1,4-BQ through regulating ROS level, specific apoptosis gene and its target genes. Glycolysis is an oxygen-independent metabolic pathway, which leads to production of lactic 4-Hydroxytamoxifen (Tang et al., 2017). In tumor cells, glycolysis is ten times faster than their noncancerous tissue counterparts to meet energy demands (Santos et al., 2018; Xiao and Wang, 2018). Numerous evidence indicates the enhanced glycolysis is a normal protective mode of the body and that malignant change could be primarily caused by energy metabolism (Cairns et al., 2011). The data revealed that 1,4-BQ exposure induced significantly decreased in ratio of LD/PA in both HIF-1a overexpression and control cells. While the LD/PA ratio was significantly increased in HIF-1a overexpression groups than that in control cells at the same dose of 1,4-BQ. These findings indicated that overexpression of HIF-1a could enhance glycolysis which was inhibited in 1,4-BQ treated K562 cells. In addition to being an end product of glycolysis, lactic acid is also a signaling molecular in multiple cellular processes, including energy modulation, immune regulation and cancer growth and metastasis (Sun et al., 2017). Further investigations are required to study the specific role of glycolysis in 1,4-BQ-caused cytotoxicity. We further investigated the specific mechanism by which overexpression of HIF-1a affected glycolysis. Activation of HIF-1a leads to a switch from oxidative to glycolysis (Wheaton and Chandel, 2011), which has been reported to decrease pyruvate conversion to acetyl-coA via its major targets, including Glut1, Ldha and Pdk1 (Kim et al., 2006; Luo et al., 2011). Glut1 regulates glucose transport across the cell membrane which is the first and the rate-limiting step of glycolysis (Deng et al., 2014). By utilizing the NADH, Ldha diverts pyruvate from fueling the mitochondria to generation of lactate (Vander Heiden et al., 2009). The increased level in Pdk1 inactivates the catalytic subunit of PDH to shift pyruvate conversion to lactate (Wheaton and Chandel, 2011). Pkm2, a key enzyme that determines glycolytic activity, is also activated by HIF-1a (Luo et al., 2011). Luo et al. demonstrated that Pkm2 acts as a coactivator that stimulates HIF-1 transactivation of target genes in cancer cells (Luo et al., 2011). In human lung cancer cells, the increased ROS level induced inhibition of Pkm2 by oxidation of Cys358 (Anastasiou et al., 2011). Zhu et al. found that accumulated ROS was involved in the Pkm2 protein degradation in yolk sac hematopoietic stem cells response to 1,4-BQ (Zhu et al., 2014). This present study found that the proteins levels of Glut1, Ldha, Pdk1 and Pkm2 at 1,4-BQ treatments were significantly elevated in HIF-1a overexpression group than in HIF-1a control groups. What's more, overexpression of HIF-1a also caused significant increases in expression of other glycolytic enzymes, Pgk1, Pfkfb3 and Pfk1. Our results suggested that HIF-1a overexpression could enhance glycolysis by regulating its target genes.