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Modification of sialylation is associated with multidrug resistance in human acute myeloid leukemia

Oncogene volume 34, pages 726–740 (2015)Cite this article

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Abstract

Aberrant cell surface sialylation patterns have been shown to correlate with tumor progression and metastasis. However, the role of sialylation regulation of cancer multidrug resistance (MDR) remains poorly understood. This study investigated sialylation in modification on MDR in acute myeloid leukemia (AML). Using mass spectrometry (MS) analysis, the composition profiling of sialylated N-glycans differed in three pairs of AML cell lines. Real-time PCR showed the differential expressional profiles of 20 sialyltransferase (ST) genes in the both AML cell lines and bone marrow mononuclear cells (BMMCs) of AML patients. The expression levels of ST3GAL5 and ST8SIA4 were detected, which were overexpressed in HL60 and HL60/adriamycin-resistant (ADR) cells. The altered levels of ST3GAL5 and ST8SIA4 were found in close association with the MDR phenotype changing of HL60 and HL60/ADR cells both in vitro and in vivo. Further data demonstrated that manipulation of these two genes’ expression modulated the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway and its downstream target thus regulated the proportionally mutative expression of P-glycoprotein (P-gp) and MDR-related protein 1 (MRP1), both of which are known to be involved in MDR. Blocking the PI3K/Akt pathway by its specific inhibitor LY294002 or by Akt small interfering RNA resulted in the reduced chemosensitivity of HL60/ADR cells. Therefore, this study indicated that sialylation involved in the development of MDR of AML cells probably through ST3GAL5 or ST8SIA4 regulating the activity of PI3K/Akt signaling and the expression of P-gp and MRP1.

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Acknowledgements

This work was supported by grants from National Key Basic Research and Development Program (973 program) of China (no. 2012CB822100), from National Natural Science Foundation of China (81271910), and supported by Project for Liaoning BaiQianWan Talents Program (2012921014).

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Authors and Affiliations

  1. Department of Medical Basic Laboratory, College of Laboratory Medicine, Dalian Medical University, Dalian, China

    H Ma, S Shi & L Jia

  2. Department of Microbiology, Dalian Medical University, Dalian, China

    H Zhou

  3. Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway

    X Song

  4. Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, Dalian, China

    J Zhang

  5. Department of Biochemistry, School of Life Science and Medicine, Dalian University of Technology, Panjin, China

    J Zhang

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Correspondence to L Jia.

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Ma, H., Zhou, H., Song, X. et al. Modification of sialylation is associated with multidrug resistance in human acute myeloid leukemia. Oncogene 34, 726–740 (2015). https://doi.org/10.1038/onc.2014.7

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