Guangdong Pharmaceutical University, Guangzhou, China.
Department of Experimental Hematology and Biochemistry, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
Int J Hematol. 2021 Feb;113(2):254-262. doi: 10.1007/s12185-020-03026-1. Epub 2020 Oct 19.
Differentiation therapies with all-trans retinoic acid (ATRA) have been successful in treating acute promyelocytic leukemia, a rare subtype of acute myeloid leukemia (AML). However, their efficacy is limited in the case of other AML subtypes. Here, we show that the combination of ATRA with salt-inducible kinase (SIK) inhibition significantly enhances ATRA-mediated AML differentiation. SIK inhibition augmented the ability of ATRA to induce growth inhibition and G1 cell cycle arrest of AML cells. Moreover, combining ATRA and SIK inhibition synergistically activated the Akt signaling pathway but not the MAPK pathway. Pharmacological blockade of Akt activity suppressed the combination-induced differentiation, indicating an essential role for Akt in the action of the combination treatment. Taken together, our study reveals a novel role for SIK in the regulation of ATRA-mediated AML differentiation, implicating the combination of ATRA and SIK inhibition as a promising approach for future differentiation therapy.
全反式维甲酸（ATRA）的分化疗法已成功应用于治疗急性早幼粒细胞白血病，这是一种罕见的急性髓细胞白血病（AML）亚型。然而，在其他 AML 亚型的情况下，它们的疗效有限。在这里，我们表明 ATRA 与盐诱导激酶（SIK）抑制的联合应用显著增强了 ATRA 介导的 AML 分化。SIK 抑制增强了 ATRA 诱导 AML 细胞生长抑制和 G1 细胞周期阻滞的能力。此外，ATRA 和 SIK 抑制联合使用协同激活 Akt 信号通路，但不激活 MAPK 通路。Akt 活性的药理学阻断抑制了组合诱导的分化，表明 Akt 在联合治疗中的作用至关重要。总之，我们的研究揭示了 SIK 在调节 ATRA 介导的 AML 分化中的新作用，提示 ATRA 和 SIK 抑制的联合应用是未来分化治疗的一种有前途的方法。
