5‑aza‑2'‑deoxycytidine promotes migration of acute monocytic leukemia cells via activation of CCL2‑CCR2‑ERK signaling pathway

Xiao,Xia; Xu,Qian; Sun,Yan; Lu,Ziwei; Li,Rui; Wang,Xinxin; Jiang,Xin; Zhang,Guirong; Xiao,Yechen

doi:10.3892/mmr.2017.6737

5‑aza‑2'‑deoxycytidine promotes migration of acute monocytic leukemia cells via activation of CCL2‑CCR2‑ERK signaling pathway

Authors:
- Xia Xiao
- Qian Xu
- Yan Sun
- Ziwei Lu
- Rui Li
- Xinxin Wang
- Xin Jiang
- Guirong Zhang
- Yechen Xiao
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Affiliations: 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, School of Clinical Medicine, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Radiology, School of Public Health, Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: June 9, 2017 https://doi.org/10.3892/mmr.2017.6737
Pages: 1417-1424

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Abstract

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.

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