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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HD结构域包含蛋白1（SAMHD1）是一种哺乳动物dNTP水解酶，在阿糖胞苷治疗急性髓系白血病（AML）的疗效中起负性调节作用。然而，SAMHD1在AML发展和进展中的作用仍然未知。我们已经报道，AML来源的THP-1细胞中的SAMHD1敲除（KO）导致增殖增强和凋亡减少，但其潜在机制尚不清楚。我们发现THP-1细胞中的SAMHD1-KO增加了PI3K活性，并降低了肿瘤抑制因子PTEN的表达。PI3K活性的药理学抑制降低了SAMHD1-KO细胞的增殖，表明SAMHD1-KO诱导的细胞增殖是通过增强的PI3K信号传导介导的。然而，PI3K抑制并没有显著影响SAMHD1-KO减少的细胞凋亡，这意味着参与了其他机制。SAMHD1-KO还导致p27在T157残基处的磷酸化增强及其在细胞质中的错误定位。PI3K活性的抑制逆转了这些效应，表明SAMHD1-KO诱导的p27磷酸化和定位的变化是通过PI3K-Akt信号传导介导的。虽然SAMHD1-KO在体外显著增强THP-1细胞的迁移，但在异种移植免疫缺陷小鼠中，SAMHD1-KO减弱THP-1细胞形成皮下肿瘤的能力。这种效应与肿瘤中肿瘤坏死因子（TNF-α）的表达显著增加相关，这可能表明TNF-α介导的炎症可能是体内致瘤性降低的原因。我们的发现暗示SAMHD1可以通过调节PI3K-Akt-p27信号轴来调节AML细胞增殖，并且SAMHD1可能通过下调炎症来影响致瘤性。

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