The Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway has been shown to play an important role in hematopoiesis, and hematopoietic cells are sensitive targets for benzene-induced hematotoxicity. We therefore hypothesized that dysregulation of the Akt/GSK-3β/β-catenin signaling was associated with benzene-induced hematotoxicity. Here, we showed that hydroquinone (HQ), a major metabolite of benzene in humans, significantly inhibited cell viability and colony formation while inducing apoptosis of human bone marrow mononuclear cells in vitro. Interestingly, we found that HQ inhibited the Akt affected β-catenin signaling by activation of GSK-3β, resulting in downregulation of β-catenin and its targets Cyclin D1 and Survivin. HQ blocked nuclear translocation of β-catenin and lymphoid enhancer-binding factor 1 (LEF-1), and importantly, HQ also reduced the interaction of β-catenin and LEF-1 in the nucleus. As expected, blockage of GSK-3β activity with a GSK-3β inhibitor lithium chloride (LiCl) or activation of Akt signaling with an Akt agonist insulin-like growth factor-1 (IGF-1) could inhibit HQ-induced activation of GSK-3β as well as hematotoxicity. Taken together, our results suggest that HQ-induced hematotoxicity in bone marrow mononuclear cells is associated with dysregulation of Akt/GSK-3β/β-catenin signaling due to the dissociation of β-catenin/LEF-1 complex, and LiCl and IGF-1 may be two potential agents to ameliorate HQ-induced hematotoxicity.

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http://dx.doi.org/10.1016/j.tiv.2017.08.018DOI Listing

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