Vacuolin-1 enhances RA-induced differentiation of human myeloblastic leukemia cells: evidence for involvement of a CD11b/FAK/LYN/SLP-76 axis subject to endosomal regulation that drives late differentiation steps

Cell & Bioscience

Research

Andrew Yen¹  Noor Kazim¹  Kaiyuan Zhu²  Jianbo Yue³ 

[1] Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA;Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA;Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China;City University of Hong Kong Shenzhen Research Institute, ShenZhen, China;Division of Natural and Applied Sciences, Synear Molecular Biology Lab, Duke Kunshan University, Kunshan, China;City University of Hong Kong Shenzhen Research Institute, ShenZhen, China;

关键词: Vacuolin-1;    Retinoic acid;    HL-60 cells;    CD11b/FAK/LYN/SLP-76 axis;    NUMB;    Differentiation therapy;    Leukemia.;   

DOI  :  10.1186/s13578-022-00911-6

 received in 2022-03-19, accepted in 2022-10-07,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundRetinoic acid(RA), an embryonic morphogen, regulates cell differentiation. Endocytosis regulates receptor signaling that governs such RA-directed cellular processes. Vacuolin-1 is a small molecule that disrupts endocytosis, motivating interest in its effect on RA-induced differentiation/arrest. In HL-60 myeloblastic-leukemia cells, RA causes differentiation evidenced by a progression of cell-surface and functional markers, CD38, CD11b, and finally reactive oxygen species(ROS) production and G1/0 cell cycle arrest in mature cells.ResultsWe found that Vacuolin-1 enhanced RA-induced CD11b, ROS and G1/0 arrest, albeit not CD38. Enhanced CD11b expression was associated with enhanced activation of Focal Adhesion Kinase(FAK). Adding vacuolin-1 enhanced RA-induced tyrosine phosphorylation of FAK, Src Family Kinases(SFKs), and the adaptor protein, SLP-76, expression of which is known to drive RA-induced differentiation. Depleting CD11b cripples late stages of progressive myeloid differentiation, namely G1/0 arrest and inducible ROS production, but not expression of CD38. Loss of NUMB, a protein that supports early endosome maturation, affected RA-induced ROS and G1/0 arrest, but not CD38 expression.ConclusionHence there appears to be a novel CD11b/FAK/LYN/SLP-76 axis subject to endosome regulation which contributes to later stages of RA-induced differentiation. The effects of vacuolin-1 thus suggest a model where RA-induced differentiation consists of progressive stages driven by expression of sequentially-induced receptors.

【 授权许可】

CC BY   
© The Author(s) 2022. corrected publication 2023

【 图 表 】

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