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

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.