Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells.
Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells.
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DOI：
10.1016/j.celrep.2023.112794
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发表时间：
2023-07-25
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
急性髓性白血病（AML）的复发仍然是一个重要的问题，因为持续的白血病起始干细胞（lic）通常不是大多数现有治疗的靶点。通过小鼠AML模型、人类AML细胞系和患者样本，我们发现AML lic对内源性和外源性环戊烯酮前列腺素- j （CyPG）、Δ12-PGJ2和15d-PGJ2敏感，这些物质通过环氧化酶-造血PGD合成酶途径在膳食硒补充后增加。CyPGs是过氧化物酶体增殖物激活受体γ和GPR44 （CRTH2; PTGDR2）的内源性配体。在AML小鼠模型中，GPR44的缺失加重了疾病，这表明GPR44的激活介导了硒介导的lic细胞凋亡。GPR44−/−lic的转录组学分析表明，CyPGs激活GPR44可抑制kras介导的MAPK和PI3K/AKT/mTOR信号通路，从而促进细胞凋亡。我们的研究表明GPR44的作用，为硒和CyPGs在AML中的化学预防和化学治疗特性提供了机制基础。Qian等人描述了膳食硒增强H-PGDS表达的重要机制，这种表达有利于产生环戊酮前列腺素（cyclopentenone prostaglandin, CyPG）。除了激活PPARγ外，CyPGs激活GPR44抑制rtk激活的kras介导的MAPK和PI3K/AKT/mTORC1通路，导致p53介导的AML细胞凋亡。
Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive to endogenous and exogenous cyclopentenone prostaglandin-J (CyPG), Δ12-PGJ2, and 15d-PGJ2, which are increased upon dietary selenium supplementation via the cyclooxygenase-hematopoietic PGD synthase pathway. CyPGs are endogenous ligands for peroxisome proliferator-activated receptor gamma and GPR44 (CRTH2; PTGDR2). Deletion of GPR44 in a mouse model of AML exacerbated the disease suggesting that GPR44 activation mediates selenium-mediated apoptosis of LICs. Transcriptomic analysis of GPR44−/− LICs indicated that GPR44 activation by CyPGs suppressed KRAS-mediated MAPK and PI3K/AKT/mTOR signaling pathways, to enhance apoptosis. Our studies show the role of GPR44, providing mechanistic underpinnings of the chemopreventive and chemotherapeutic properties of selenium and CyPGs in AML. Qian et al. describe an important mechanism by which dietary selenium enhances H-PGDS expression that favors production of cyclopentenone prostaglandin (CyPG) production. In addition to activating PPARγ, CyPGs activate GPR44 to suppress RTK-activated KRAS-mediated MAPK and PI3K/AKT/mTORC1 pathways, leading to the P53-mediated apoptosis in AML.
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DOI：
10.1084/jem.193.2.255
发表时间：
2001-01-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hirai H;Tanaka K;Yoshie O;Ogawa K;Kenmotsu K;Takamori Y;Ichimasa M;Sugamura K;Nakamura M;Takano S;Nagata K
通讯作者：
Nagata K
影响因子：
11.2
作者：
Gandhi UH;Kaushal N;Hegde S;Finch ER;Kudva AK;Kennett MJ;Jordan CT;Paulson RF;Prabhu KS
通讯作者：
Prabhu KS
影响因子：
12.8
作者：
De Kouchkovsky I;Abdul-Hay M
通讯作者：
Abdul-Hay M
影响因子：
4.8
作者：
Kasaikina, Marina V.;Kravtsova, Marina A.;Gladyshev, Vadim N.
通讯作者：
Gladyshev, Vadim N.
影响因子：
2.9
作者：
Jandl K;Heinemann A
通讯作者：
Heinemann A