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首页> 外文期刊>Cell cycle >SAMHD1 modulates in vitro proliferation of acute myeloid leukemia-derived THP-1 cells through the PI3K-Akt-p27 axis
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SAMHD1 modulates in vitro proliferation of acute myeloid leukemia-derived THP-1 cells through the PI3K-Akt-p27 axis

机译：Samhd1通过PI3K-AKT-P27轴调节急性髓性白血病衍生的THP-1细胞的体外增殖

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摘要

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase that acts as a negative regulator in the efficacy of cytarabine treatment against acute myeloid leukemia (AML). However, the role of SAMHD1 in AML development and progression remains unknown. We have reported that SAMHD1 knockout (KO) in the AML-derived THP-1 cells results in enhanced proliferation and reduced apoptosis, but the underlying mechanisms are unclear. Here we show that SAMHD1 KO in THP-1 cells increased PI3K activity and reduced expression of the tumor suppressor PTEN. Pharmacological inhibition of PI3K activity reduced cell proliferation specifically in SAMHD1 KO cells, suggesting that SAMHD1 KO-induced cell proliferation is mediated via enhanced PI3K signaling. However, PI3K inhibition did not significantly affect SAMHD1 KO-reduced apoptosis, implicating the involvement of additional mechanisms. SAMHD1 KO also led to enhanced phosphorylation of p27 at residue T157 and its mis-localization to the cytoplasm. Inhibition of PI3K activity reversed these effects, indicating that SAMHD1 KO-induced changes in p27 phosphorylation and localization is mediated via PI3K-Akt signaling. While SAMHD1 KO significantly enhanced THP-1 cell migration in vitro, SAMHD1 KO attenuated the ability of THP-1 cells to form subcutaneous tumors in xenografted immunodeficient mice. This effect correlated with significantly increased expression of tumor necrosis factor (TNF-alpha) in tumors, which may suggest that TNF-alpha-mediated inflammation could account for the decreased tumorigenicity in vivo. Our findings implicate that SAMHD1 can regulate AML cell proliferation via modulation of the PI3K-Akt-p27 signaling axis, and that SAMHD1 may affect tumorigenicity by downregulating inflammation.
机译：无菌α基序和含HD结构域的蛋白质1（SamHD1）是一种哺乳动物DNTP水解酶，其作用为阴性调节剂，其在对急性髓性白血病（AML）对急性髓鞘体（AML）的疗效作用。然而，Samhd1在AML发展和进展中的作用仍然未知。我们据报道，AML衍生的THP-1细胞中的Samhd1敲除（KO）导致增强和细胞凋亡降低，但下面的机制尚不清楚。在这里，我们显示SAMHD1 KO在THP-1细胞中增加了PI3K活性，并降低了肿瘤抑制PTEN的表达。 PI3K活性的药理抑制特异性在SamHD1 KO细胞中细胞增殖降低，表明SamHD1诱导的细胞增殖通过增强的PI3K信号传导介导。然而，PI3K抑制没有显着影响SamHD1降低的细胞凋亡，暗示额外机制的参与。 Samhd1 KO还导致残留物T157的P27的磷酸化，并在细胞质上的错误定位。抑制PI3K活性逆转了这些效果，表明SamHD1 KO诱导的P27磷酸化和定位的变化通过PI3K-AKT信号传导介导。虽然Samhd1 KO在体外显着增强了THP-1细胞迁移，但SamHD1 KO衰减了THP-1细胞在异种移植免疫缺陷小鼠中形成皮下肿瘤的能力。这种效果与肿瘤中的肿瘤坏死因子（TNF-α）的显着增加相关，这可能表明TNF-α-介导的炎症可以考虑体内致瘤性降低。我们的发现涉及SamHD1可以通过调节PI3K-AKT-P27信号轴来调节AML细胞增殖，并且SAMHD1可以通过下调炎症来影响肿瘤性。

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