Blocking cholesterol efflux mechanism is a potential target for antilymphoma therapy.

Abstract

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.

• Authors: Hiromu Yano, Yukio Fujiwara, Hasita Horlad, Chang Pan, Keitaro Kai, Daisuke Niino, Kumiko Ohsawa, Morihiro Higashi, Kisato Nosaka, Yutaka Okuno, Jun-Ichi Tamaru, Akitake Mukasa, Masao Matsuoka, Yoshihiro Komohara
• Journal: Cancer science (Cancer Sci) Vol. 113 Issue 6 Pg. 2129-2143 (Jun 2022) ISSN: 1349-7006 [Electronic] England
• PMID: 35343027 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

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

Topics

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