E3 ligase FBXW7 restricts M2-like tumor-associated macrophage polarization by targeting c-Myc

Aging (Albany NY). 2020 Dec 1;12(23):24394-24423. doi: 10.18632/aging.202293. Epub 2020 Dec 1.

Abstract

FBXW7 functions as an E3 ubiquitin ligase to mediate oncoprotein degradation via the ubiquitin-proteasome system in cancer cells, effectively inhibiting the growth and survival of tumor cells. However, little is known about the functions of FBXW7 in macrophages and the tumor immune microenvironment. In this study, we find that FBXW7 suppresses M2-like tumor-associated macrophage (TAM) polarization to limit tumor progression. We identified a significant increase in the proportion of M2-like TAMs and aggravated tumor growth in mice with myeloid FBXW7 deficiency by subcutaneous inoculation with Lewis lung carcinoma cells (LLCs). When stimulated with LLCs supernatant in vitro, FBXW7-knockout macrophages displayed increased M2 macrophage polarization and enhanced ability of supporting cancer cells growth. In mechanism, we confirmed that FBXW7 inhibited M2-like TAM polarization by mediating c-Myc degradation via the ubiquitin-proteasome system. These findings highlight the role of FBXW7 in M2-like TAM polarization and provide new insights into the potential targets for cancer immunotherapies.

Keywords: FBXW7; c-Myc; macrophage polarization; tumor-associated macrophages; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Lewis Lung / enzymology*
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / pathology
  • Cell Proliferation
  • Cells, Cultured
  • F-Box-WD Repeat-Containing Protein 7 / deficiency
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • F-Box-WD Repeat-Containing Protein 7 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction
  • Tumor Burden
  • Tumor Microenvironment
  • Tumor-Associated Macrophages / enzymology*
  • Tumor-Associated Macrophages / pathology
  • Ubiquitination

Substances

  • F-Box-WD Repeat-Containing Protein 7
  • Fbxw7 protein, mouse
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Proteasome Endopeptidase Complex