Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, Jilin 130021, P.R. China.
Department of Oncology and Hematology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China.
Mol Med Rep. 2017 Aug;16(2):1417-1424. doi: 10.3892/mmr.2017.6737. Epub 2017 Jun 9.
5-aza‑2'-deoxycytidine (5-Aza) has been approved for clinical use in the treatment of myelodysplastic syndrome and acute myeloid leukemia (AML). It inhibits cell proliferation and induces cell differentiation by demethylating various genes, including tumor suppressor genes, transcription factors, and genes encoding cell cycle inhibitors. Although it has demonstrated efficacy in the clinic, drug resistance following 5‑Aza treatment occurs. Cell migration and invasion following 5‑Aza treatment are considered to be the key factors underlying drug resistance; however, there is currently limited information regarding the detailed mechanisms involved. In the present study, the THP‑1 monocytic leukemia cell line was employed. The anti‑leukemic functions of 5‑Aza in THP‑1 cells were first investigated. The results demonstrated that 5‑Aza induced differentiation and inhibited THP‑1 cell growth. Notably, 5‑Aza significantly promoted THP‑1 cell migration. Using reverse transcription‑polymerase chain reaction, Western blot and enzyme‑linked immunosorbent assay analyses, 5‑Aza treatment was observed to upregulate the expression of chemokine (C‑C motif) ligand 2 (CCL2) and C‑C chemokine receptor type 2 (CCR2) in THP‑1 cells. In addition, the results demonstrated that CCL2 induced extracellular signal‑regulated kinase (ERK) phosphorylation by CCR2 in 5‑Aza‑treated THP‑1 cells. Treatment with a CCR2 or ERK inhibitor inhibited the 5‑Aza‑induced increase in THP‑1 cell migration. In conclusion, the results of the present study provide an insight into the molecular mechanism underlying the 5‑Aza‑induced increase in THP‑1 cell migration, as well as a potential strategy to overcome drug resistance in AML therapy.
5-氮杂-2'-脱氧胞苷（5-Aza）已被批准用于治疗骨髓增生异常综合征和急性髓系白血病（AML）的临床应用。它通过去甲基化各种基因，包括肿瘤抑制基因、转录因子和细胞周期抑制剂，来抑制细胞增殖并诱导细胞分化。尽管它在临床上已显示出疗效，但在 5-Aza 治疗后会产生耐药性。5-Aza 治疗后细胞迁移和侵袭被认为是耐药的关键因素，但目前关于涉及的详细机制的信息有限。本研究采用 THP-1 单核白血病细胞系。首先研究了 5-Aza 在 THP-1 细胞中的抗白血病功能。结果表明，5-Aza 诱导分化并抑制 THP-1 细胞生长。值得注意的是，5-Aza 显著促进 THP-1 细胞迁移。通过逆转录-聚合酶链反应、Western blot 和酶联免疫吸附试验分析，观察到 5-Aza 处理上调了 THP-1 细胞中趋化因子（C-C 基序）配体 2（CCL2）和 C-C 趋化因子受体 2（CCR2）的表达。此外，结果表明，CCL2 通过 CCR2 诱导 5-Aza 处理的 THP-1 细胞中细胞外信号调节激酶（ERK）磷酸化。用 CCR2 或 ERK 抑制剂处理可抑制 5-Aza 诱导的 THP-1 细胞迁移增加。总之，本研究结果提供了对 5-Aza 诱导 THP-1 细胞迁移增加的分子机制的深入了解，并为克服 AML 治疗中的耐药性提供了一种潜在策略。
