a Center of Retrovirus Research, Department of Veterinary Biosciences , The Ohio State University , Columbus , OH , USA.
b Center for Cardiovascular Research , Nationwide Children's Hospital Research Institute , Columbus , OH , USA.
Cell Cycle. 2018;17(9):1124-1137. doi: 10.1080/15384101.2018.1480218. Epub 2018 Jul 17.
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 α (TNF-α) in tumors, which may suggest that TNF-α-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.
sterile alpha motif and HD domain-containing protein 1 (SAMHD1) 是一种哺乳动物 dNTP 水解酶，作为胞嘧啶阿拉伯糖苷治疗急性髓细胞白血病 (AML) 疗效的负调节剂。然而，SAMHD1 在 AML 发展和进展中的作用尚不清楚。我们已经报道，AML 衍生的 THP-1 细胞中的 SAMHD1 敲除 (KO) 导致增殖增强和凋亡减少，但潜在机制尚不清楚。在这里，我们显示 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 活性的药理学抑制特异性地降低了 SAMHD1 KO 细胞的细胞增殖，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 抑制并未显著影响 SAMHD1 KO 减少的凋亡，暗示涉及其他机制。SAMHD1 KO 还导致 p27 在残基 T157 处的磷酸化增强及其错误定位到细胞质中。PI3K 活性的抑制逆转了这些效应，表明 SAMHD1 KO 诱导的 p27 磷酸化和定位变化是通过 PI3K-Akt 信号传导介导的。虽然 SAMHD1 KO 显著增强了 THP-1 细胞在体外的迁移能力，但 SAMHD1 KO 减弱了 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。这种效应与肿瘤中肿瘤坏死因子 α (TNF-α) 的表达显著增加相关，这可能表明 TNF-α 介导的炎症可能解释了体内肿瘤发生能力的降低。我们的研究结果表明，SAMHD1 可以通过调节 PI3K-Akt-p27 信号轴来调节 AML 细胞的增殖，并且 SAMHD1 可能通过下调炎症来影响肿瘤发生。
