PBK/TOPK mediates promyelocyte proliferation via Nrf2-regulated cell cycle progression and apoptosis

Abstract

Acute myeloid leukemia (AML) is a disorder involving hematopoietic stem cells, characterized by blockage of hematopoietic cell differentiation and an increase in clonal neoplastic proliferation. AML is associated with poor patient outcome. PBK/TOPK is a protein kinase derived from PDZ-binding kinase (PBK)/T-lymphokine-activated killer (T-LAK) cell-originated protein kinase (TOPK). Previous studies have shown that PBK/TOPK is expressed in hematologic tumors. In the present study, we aimed to investigate the role of PBK/TOPK in promyelocyte proliferation and to clarify the molecular mechanism. PBK/TOPK knockdown (KD) significantly decreased cell proliferation and viability in the NB4 and HL-60 promyelocytes. PBK/TOPK KD resulted in G2/M cell cycle arrest that attributed to a decrease in cdc2 and cyclin B expression. In addition, PBK/TOPK KD caused apoptosis, as evidenced by activation of the mitochondrial apoptotic pathway and an increase in TUNEL-positive cells. PBK/TOPK KD induced mitochondrial dysfunction and ROS generation, and inhibition of mitochondrial dysfunction and ROS production suppressed PBK/TOPK KD-induced cell cycle arrest and apoptosis. Moreover, PBK/TOPK KD decreased Nrf2 expression and ARE-binding activity. Overexpression of Nrf2 inhibited the PBK/TOPK KD-induced decrease in cdc2 and cyclin B expression and cell cycle arrest, and blocked ROS production and apoptosis. Based on literature and our results, it was demonstrated that Nrf2 may be a crucial regulator that mediates PBK/TOPK-exerted promotion of cell proliferation. PBK/TOPK stabilizes Nrf2, strictly regulates the ROS level, promotes cell cycle progression and inhibits apoptosis, contributing to the proliferation of promyelocytes. Our results provide new insights into the molecular mechanism of PBK/TOPK-mediated promyelocyte proliferation and shed light on the pathogenesis of AML.

Dose-dependent phorbol 12-myristate-13-acetate-mediated monocyte-to-macrophage differentiation induces unique proteomic signatures in THP-1 cells

“…GM-CSF-mediated differentiation of primary human monocytes to macrophages upregulates the macrophage-specific surface markers/receptors, antigen-presenting function, phagocytosis, anti-microbial activity, lipid metabolism and production of growth factors and pro-inflammatory cytokines as evidenced by the global transcriptome analysis of GM-CSF-induced macrophages (46). We too observed a similar trend with treatment condition B showing a better representation of proteins involved in innate immune signaling while cathepsins-proteases involved in innate immune responses and protein kinases involved in the processes of cell proliferation and differentiation (47, 48) were found to be significantly induced in condition A. The increased expression of IL1B upon PMA differentiation has been reported earlier at the transcriptome level (11).…”

The toxic effects and possible mechanisms of Brusatol on mouse oocytes

“…Of note, recent findings suggest that Nrf2 regulated cell cycle progression by adjusting a series of cyclin[6, 7, 15–17]. Cyclin B1 play an important role on G2/M cell cycle progression.…”

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“…PBK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun [35] . PBK mediates promyelocyte proliferation via Nrf2-regulated cell cycle progression and apoptosis [36] . TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer [37] .…”