Translational Oncology (Aug 2021)

Luteolin promotes macrophage-mediated phagocytosis by inhibiting CD47 pyroglutamation

  • Zhiqiang Li,
  • Xuemei Gu,
  • Danni Rao,
  • Meiling Lu,
  • Jing Wen,
  • Xinyan Chen,
  • Hongbing Wang,
  • Xianghuan Cui,
  • Wenwen Tang,
  • Shilin Xu,
  • Ping Wang,
  • Lei Yu,
  • Xin Ge

Journal volume & issue
Vol. 14, no. 8
p. 101129

Abstract

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‘Don't eat me’ signal of CD47 is activated via its interaction with SIRPα protein on myeloid cells, especially phagocytic cells, and prevents malignant cells from anti-tumor immunity in which pyroglutamate modification of CD47 by glutaminyl-peptide cyclotransferase-like protein (isoQC) takes an important part evidenced by our previous report that isoQC is an essential regulator for CD47-SIRPα axis with a strong inhibition on macrophage-mediated phagoctyosis. Therefore, we screened for potential isoQC inhibitors by fluorescence-activated cell sorting assay and identified luteolin as a potent compound that blocked the pyroglutamation of CD47 by isoQC. We further demonstrated that luteolin directly bound to isoQC using pull-down assay and isothermal calorimetric (ITC) assay. In consistency, we showed that luteolin markedly abrogated the cell-surface interaction between CD47 and SIRPα in multiple myeloma H929 cells and consequently promoted the macrophage-mediated phagocytosis. Collectively, our study discovered a promising lead compound targeting isoQC, luteolin, which functions distinctly from current CD47 antibody-based drugs and therefore may potentially overcome the clinical side effects associated with CD47 antibody treatment-induced anemia.

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