Blocking cholesterol efflux mechanism is a potential target for antilymphoma therapy

• Published in: Cancer science Vol. 113; no. 6; pp. 2129 - 2143
• Main Authors: Yano, Hiromu, Fujiwara, Yukio, Horlad, Hasita, Pan, Chang, Kai, Keitaro, Niino, Daisuke, Ohsawa, Kumiko, Higashi, Morihiro, Nosaka, Kisato, Okuno, Yutaka, Tamaru, Jun‐ichi, Mukasa, Akitake, Matsuoka, Masao, Komohara, Yoshihiro
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2022; John Wiley and Sons Inc
• Subjects: ACAT; Acetyltransferase; Apoptosis; B cells; Brain cancer; Burkitt's lymphoma; Cancer therapies; Cell culture; Cell growth; Cell proliferation; Cellular biology; Cholesterol; Coenzyme A; Cytoplasm; Endoplasmic reticulum; Enzymes; Epstein-Barr virus; ER stress; High density lipoprotein; Homeostasis; Leukemia; Lipid metabolism; Lipoproteins; Lymphoma; Macrophages; Medical prognosis; Metabolism; Non-Hodgkin's lymphomas; Original; ORIGINAL ARTICLES; Protein binding; Proteins; Review boards; Scavenger receptors; SR‐BI; Tumor cell lines; Tumors; Vacuoles; Japan; ER stress; cholesterol; SR-BI; ACAT; lymphoma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15349

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. This study revealed that the main component of vacuoles seen in high‐grade lymphomas is esterified cholesterol. The expression of cholesterol metabolism‐related molecules such as scavenger receptor class B member I and acetyl‐coenzyme A:cholesterol acetyltransferase is significantly upregulated in lymphoma cells. Scavenger receptor class B member I inhibitor has potential as a new therapy for targeting the cholesterol metabolism pathway in lymphomas.