Myosin IIa activation is crucial in breast cancer derived galectin-1 mediated tolerogenic dendritic cell differentiation |
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Authors: | Da-En Cheng Jen-Yu Hung Ming-Shyan Huang Ya-Ling Hsu Chi-Yu Lu Eing-Mei Tsai Ming-Feng Hou Po-Lin Kuo |
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Affiliation: | 1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;2. School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;3. Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan;4. Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan;5. Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;6. Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;g Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan |
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Abstract: |
BackgroundTolerogenic dendritic cells (tDCs) play important roles in immune tolerance, autoimmune disease, tissue transplantation, and the tumor micro-environment. Factors that induce tDCs have been reported, however the intracellular mechanisms involved are rarely discussed.MethodsCirculating CD14+CD16+ of breast cancer patients and induced CD14+CD16+ DCs were identified as tDCs by treating CD14+ monocytes with galectin-1 and cancer cell-derived medium combined with IL-4 and GM-CSF. In addition, the 4T1 breast cancer syngeneic xenograft model was used to investigate the effect of galectin-1 in vivo.ResultsThe CD14+CD16+ tDC population in the breast cancer patients was comparatively higher than that in the healthy donors, and both the MDA-MB-231 conditioned medium and galectin-1 could induce tDC differentiation. In a BALB/c animal model, the 4T1 breast cancer cell line enhanced IL-10 expression in CD11c+ DCs which was down-regulated after knocking down the galectin-1 expression of 4T1 cells. Analysis of galectin-1 interacting proteins showed that myosin IIa was a major target of galectin-1 after internalization through a caveolin-dependent endocytosis. Myosin IIa specific inhibitor could diminish the effects of galectin-1 on monocyte-derived tDCs and also block the 4T1 cell induced CD11c+/Ly6G+/IL-10+ in the BALB/c mice.ConclusionsGalectin-1 can induce tDCs after internalizing into CD14+ monocytes through the caveolae-dependent pathway and activating myosin IIa. For the breast cancer patients with a high galectin-1 expression, blebbistatin and genistein show potential in immune modulation and cancer immunotherapy.General significanceMyosin IIa activation and galectin-1 endocytosis are important in tumor associated tDC development. |
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Keywords: | Galectin-1 Breast cancer Myosin IIa Endocytosis Dendritic cell |
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