Blocking cholesterol efflux mechanism is a potential target for antilymphoma therapy

Cancer Sci. 2022 Jun;113(6):2129-2143. doi: 10.1111/cas.15349. Epub 2022 Apr 8.


Cholesterol is an essential plasma membrane lipid for the maintenance of cellular homeostasis and cancer cell proliferation. Free cholesterol is harmful to cells; therefore, excessive free cholesterol must be quickly esterified by acetyl-coenzyme A:cholesterol acetyltransferase (ACAT) and exported by scavenger receptor class B member I (SR-BI) or ATP-binding cassette protein A1 from specific cells such as macrophage foam cells, which contain cholesteryl ester-derived vacuoles. Many vacuoles are present in the cytoplasm of Burkitt lymphoma cells. In this study, we observed that these vacuoles are often seen in high-grade lymphomas. Cell culture study using lymphoma cell lines found that esterified cholesterol is the main component of these vacuoles and the expression of cholesterol metabolism-related molecules was significantly upregulated in lymphoma cell lines, with SR-BI and ACAT inhibitors (BLT-1 and CI-976, respectively) impeding lymphoma cell proliferation. Cytoplasmic free cholesterol was increased by ACAT and SR-BI inhibitors, and the accumulation of free cholesterol induced lymphoma cell apoptosis by inducing endoplasmic reticulum stress. Furthermore, synergistic effects of SR-BI and ACAT inhibitors were observed in a preclinical study. Treatment with SR-BI inhibitor suppressed lymphoma progression in a tumor-bearing mouse model, whereas ACAT inhibitor did not. Therefore, SR-BI inhibitors are potential new antilymphoma therapeutics that target cholesterol metabolism.

Keywords: ACAT; ER stress; SR-BI; cholesterol; lymphoma.

MeSH terms

  • ATP-Binding Cassette Transporters* / metabolism
  • Animals
  • Cholesterol / metabolism
  • Cholesterol Esters / metabolism
  • Foam Cells* / metabolism
  • Foam Cells* / pathology
  • Humans
  • Mice
  • Scavenger Receptors, Class B / metabolism


  • ATP-Binding Cassette Transporters
  • Cholesterol Esters
  • Scavenger Receptors, Class B
  • Cholesterol