Abstract

BackgroundThe hERG potassium channel can modulate the proliferation of the chronic myelogenous leukemic K562 cells, and its role in the erythroid differentiation of K562 cells still remains unclear.Principal FindingsThe hERG potassium channel blockage by a new 36-residue scorpion toxin BmKKx2, a potent hERG channel blocker with IC50 of 6.7±1.7 nM, enhanced the erythroid differentiation of K562 cells. The mean values of GPA (CD235a) fluorescence intensity in the group of K562 cells pretreated by the toxin for 24 h and followed by cytosine arabinoside (Ara-C) treatment for 72 h were about 2-fold stronger than those of K562 cells induced by Ara-C alone. Such unique role of hERG potassium channel was also supported by the evidence that the effect of the toxin BmKKx2 on cell differentiation was nullified in hERG-deficient cell lines. During the K562 cell differentiation, BmKKx2 could also suppress the expression of hERG channels at both mRNA and protein levels. Besides the function of differentiation enhancement, BmKKx2 was also found to promote the differentiation-dependent apoptosis during the differentiation process of K562 cells. In addition, the blockage of hERG potassium channel by toxin BmKKx2 was able to decrease the intracellular Ca2+ concentration during the K562 cell differentiation, providing an insight into the mechanism of hERG potassium channel regulating this cellular process. Conclusions/SignificanceOur results revealed scorpion toxin BmKKx2 could enhance the erythroid differentiation of leukemic K562 cells via inhibiting hERG potassium channel currents. These findings would not only accelerate the functional research of hERG channel in different leukemic cells, but also present the prospects of natural scorpion toxins as anti-leukemic drugs.

Highlights

  • Human erythropoiesis is a complex multi-step developmental process that begins at the level of hematopoietic stem cells (HSCs) at bone marrow microenvironment and terminates with the production of erythrocytes

  • Scorpion toxin BmKKx2 shares the similar structure to scorpion toxin BeKm-1, a known hERG channel-selective blocker with an IC50 value of 3.3 nM [11,19,22] (Figure 1A), which suggests that BmKKx2 may act as a hERG channel blocker

  • We investigated whether scorpion toxin BmKKx2 could inhibit the hERG channel currents in K562 cells, a chronic myelogenous leukemic cell line experessing hERG potassium channels [8,9,10]

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Summary

Introduction

Human erythropoiesis is a complex multi-step developmental process that begins at the level of hematopoietic stem cells (HSCs) at bone marrow microenvironment and terminates with the production of erythrocytes. The mean values of GPA (CD235a) fluorescence intensity in the group of K562 cells pretreated by the toxin for 24 h and followed by cytosine arabinoside (Ara-C) treatment for 72 h were about 2-fold stronger than those of K562 cells induced by Ara-C alone Such unique role of hERG potassium channel was supported by the evidence that the effect of the toxin BmKKx2 on cell differentiation was nullified in hERG-deficient cell lines. Conclusions/Significance: Our results revealed scorpion toxin BmKKx2 could enhance the erythroid differentiation of leukemic K562 cells via inhibiting hERG potassium channel currents. These findings would accelerate the functional research of hERG channel in different leukemic cells, and present the prospects of natural scorpion toxins as anti-leukemic drugs

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