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Article

Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line

  • Authors:
    • Xianfu Sheng
    • Hua Zhong
    • Haixia Wan
    • Jihua Zhong
    • Fangyuan Chen
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
  • Pages: 396-404
    |
    Published online on: April 20, 2016
       https://doi.org/10.3892/etm.2016.3268
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Abstract

Combining cytarabine, aclarubicin and granulocyte colony-stimulating factor (G‑CSF) has demonstrated marked efficacy in the treatment of elderly and relapsed/refractory patients with acute myeloid leukemia (AML); however, the role of G‑CSF remains poorly understood. The present study aimed to investigate the ability of G‑CSF to overcome stromal‑mediated drug resistance and the underlying molecular mechanism. Two types of co‑culture models were established in the HS‑5 human bone marrow/stromal and HL‑60 human promyelocytic leukemia cell lines, in order to imitate the interactions between stromal and leukemia cells in vitro, which is mediated by the stromal cell‑derived factor (SDF)‑1α signaling axis. In the present study, HL‑60 cells were attracted and adhered to HS‑5 cells using migration assay and flow cytometry, respectively; however, these interactions were inhibited by treatment with G‑CSF and/or the C‑X‑C chemokine receptor type 4 (CXCR4) antagonist, AMD3100. Co‑culture with HS‑5 cells, including direct and indirect contact, protected HL‑60 cells against spontaneous apoptosis or drug‑induced apoptosis; however, these protective effects were disrupted by treatment with G‑CSF and/or AMD3100. Notably, G‑CSF and/or AMD3100 did not alter cell viability or apoptosis when HL‑60 cells were cultured with medium alone. In addition, G‑CSF significantly reduced the expression levels of surface CXCR4 protein, total CXCR4 protein and CXCR4 mRNA, and significantly upregulated the expression of microRNA (miR)‑146a. Conversely, AMD3100 significantly reduced surface CXCR4 expression levels, but not the total CXCR4, CXCR4 mRNA or miR‑146a expression levels. The results of the present study suggested that interfering with the CXCR4/SDF‑1α signaling axis via G‑CSF inhibited the migration and adhesion of HL‑60 cells to HS‑5 cells and eliminated HS5 cell‑mediated protective effects. Furthermore, G‑CSF administration reduced CXCR4 expression levels by upregulating the expression of miR‑146a, whereas AMD3100 appeared to be predominantly dependent on receptor internalization. Therefore, a G‑CSF/miR‑146a/CXCR4 pathway may explain how G-CSF inhibits CXCR4/SDF‑1α signaling and overcomes stromal cell-mediated drug resistance in acute myeloid leukemia.
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Copy and paste a formatted citation
Spandidos Publications style
Sheng X, Zhong H, Wan H, Zhong J and Chen F: Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line. Exp Ther Med 12: 396-404, 2016.
APA
Sheng, X., Zhong, H., Wan, H., Zhong, J., & Chen, F. (2016). Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line. Experimental and Therapeutic Medicine, 12, 396-404. https://doi.org/10.3892/etm.2016.3268
MLA
Sheng, X., Zhong, H., Wan, H., Zhong, J., Chen, F."Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line". Experimental and Therapeutic Medicine 12.1 (2016): 396-404.
Chicago
Sheng, X., Zhong, H., Wan, H., Zhong, J., Chen, F."Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line". Experimental and Therapeutic Medicine 12, no. 1 (2016): 396-404. https://doi.org/10.3892/etm.2016.3268
Copy and paste a formatted citation
x
Spandidos Publications style
Sheng X, Zhong H, Wan H, Zhong J and Chen F: Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line. Exp Ther Med 12: 396-404, 2016.
APA
Sheng, X., Zhong, H., Wan, H., Zhong, J., & Chen, F. (2016). Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line. Experimental and Therapeutic Medicine, 12, 396-404. https://doi.org/10.3892/etm.2016.3268
MLA
Sheng, X., Zhong, H., Wan, H., Zhong, J., Chen, F."Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line". Experimental and Therapeutic Medicine 12.1 (2016): 396-404.
Chicago
Sheng, X., Zhong, H., Wan, H., Zhong, J., Chen, F."Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line". Experimental and Therapeutic Medicine 12, no. 1 (2016): 396-404. https://doi.org/10.3892/etm.2016.3268
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