Dataset Information

PLSCR1/IP3R1/Ca²⁺ axis contributes to differentiation of primary AML cells induced by wogonoside.

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.

SUBMITTER: Li H

PROVIDER: S-EPMC5520700 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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PLSCR1/IP3R1/Ca<sup>2+</sup> axis contributes to differentiation of primary AML cells induced by wogonoside.

Li Hui H Xu Jingyan J Zhou Yuxin Y Liu Xiao X Shen L E LE Zhu Y U YU Li Zhiyu Z Wang Xiaotang X Guo Qinglong Q Hui Hui H

Cell death & disease 20170511 5

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 traf ...[more]

PMID: 28492556

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Project description:Background Arginase II activity contributes to reciprocal regulation of endothelial nitric oxide synthase ( eNOS ). We tested the hypotheses that arginase II activity participates in the regulation of Ca2+/Ca2+/calmodulin-dependent kinase II / eNOS activation, and this process is dependent on mitochondrial p32. Methods and Results Downregulation of arginase II increased the concentration of cytosolic Ca2+ ([Ca2+]c) and decreased mitochondrial Ca2+ ([Ca2+]m) in microscopic and fluorescence-activated cell sorting analyses, resulting in augmented eNOS Ser1177 phosphorylation and decreased eNOS Thr495 phosphorylation through Ca2+/Ca2+/calmodulin-dependent kinase II . These changes were observed in human umbilical vein endothelial cells treated with small interfering RNA against p32 (sip32). Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorescence immunoassay, and ion chromatography, inhibition of arginase II reduced the amount of spermine, a binding molecule, and the release of Ca2+ from p32. In addition, arginase II gene knockdown using small interfering RNA and knockout arginase II -null mice resulted in reduced p32 protein level. In the aortas of wild-type mice, small interfering RNA against p32 induced eNOS Ser1177 phosphorylation and enhanced NO -dependent vasorelaxation. Arginase activity, p32 protein expression, spermine amount, and [Ca2+]m were increased in the aortas from apolipoprotein E (ApoE-/-) mice fed a high-cholesterol diet, and intravenous administration of small interfering RNA against p32 restored Ca2+/Ca2+/calmodulin-dependent kinase II -dependent eNOS Ser1177 phosphorylation and improved endothelial dysfunction. The effects of arginase II downregulation were not associated with elevated NO production when tested in aortic endothelia from eNOS knockout mice. Conclusions These data demonstrate a novel function of arginase II in regulation of Ca2+-dependent eNOS phosphorylation. This novel mechanism drives arginase activation, mitochondrial dysfunction, endothelial dysfunction, and atherogenesis.

Dataset Information

PLSCR1/IP3R1/Ca²⁺ axis contributes to differentiation of primary AML cells induced by wogonoside.

Publications

PLSCR1/IP3R1/Ca<sup>2+</sup> axis contributes to differentiation of primary AML cells induced by wogonoside.

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Dataset Information

PLSCR1/IP3R1/Ca2+ axis contributes to differentiation of primary AML cells induced by wogonoside.

Publications

PLSCR1/IP3R1/Ca<sup>2+</sup> axis contributes to differentiation of primary AML cells induced by wogonoside.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

PLSCR1/IP3R1/Ca²⁺ axis contributes to differentiation of primary AML cells induced by wogonoside.