Abstract
Multiple lines of evidence have demonstrated that increased expression of phospholipid scramblase 1 (PLSCR1) is involved in the differentiation of acute myeloid leukemia (AML) cells by several differentiation-inducing agents including ATRA and phorbol 12-myristate 13-acetate. However, none of these agents can achieve nonhomogenous subcellular distribution of PLSCR1. We have demonstrated that wogonoside possesses differentiation and anti-leukemic effects in AML cell lines by promoting PLSCR1 trafficking into nucleus. Here we report that wogonoside promotes the expression of PLSCR1 and enhances its nuclear translocation and binding to the 1, 4, 5-trisphosphate receptor 1 (IP3R1) promoter in AML patient-derived primary cells. Wogonoside activates IP3R1, in turn, promotes release of Ca2+ from endoplasmic reticulum, and eventually leads to cell differentiation. Our in vivo study further confirms that wogonoside can promote PLSCR1 and IP3R1 expression in primary AML cells and reduce the AML cell counts in engrafted nonobese diabetic/severe combined immunodeficient mice. Taken together, our findings provide new insight into the mechanism of wogonoside-induced differentiation and anti-leukemic effect on primary AML cells, suggesting the therapeutic potential of wogonoside for AML, especially for non-APL AML.
Highlights
Mutations of hematopoietic genes in progenitors result in acquisition of leukemia conferring deregulated proliferation, impaired differentiation and advantageous survival.[1]
To verify the effects of wogonoside on phospholipid scramblase 1 (PLSCR1) expression in primary Acute myeloid leukemia (AML) cells, we evaluated the PLSCR1 expression level in primary cells from 23 clinical AML patients after wogonoside (150 μM) treatment (Figures 1a, b and Table 1)
We speculate that the Asterisks denote statistically significant (*Po0.05 and **Po0.01) differences compared with controls by one-way analysis of variance (ANOVA). (c) #2 Primary AML cells were transfected with nonspecific small interfering RNA (siRNA) and PLSCR1 siRNA #1 treated with or without 150 μM wogonoside for 0, 12, 24, 48, 72 and 96 h
Summary
Mutations of hematopoietic genes in progenitors result in acquisition of leukemia conferring deregulated proliferation, impaired differentiation and advantageous survival.[1]. Wogonoside, a flavonoid extracted from Scutellaria baicalensis Georgi (huangqin), is a metabolite of wogonin with antitumor effect,[8] and considered as a natural, slow-release prodrug of wogonin.[9] Our previous studies have demonstrated the anti-leukemic properties of wogonoside, both in vivo and in vitro, and highlighted the importance of phospholipid scramblase 1 (PLSCR1) in wogonoside-induced differentiation of AML cell lines.[7] the mechanism underlying wogonoside-induced differentiation of AML cells remains poorly understood to date and is not authenticated in primary patient-derived AML cells. Primary AML cells maintain the basic nature and biological activity of AML samples and are more close to clinical practice compare with AML cell lines. These cells exhibit several similarities in terms of morphological structure and functional activity with the organism, and provide a good experimental subject for screening anti-leukemia drugs.
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