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.

Cholesterol metabolism and lipid droplet vacuoles; a potential target for the therapy of aggressive lymphoma

“…However, we have reported that in malignant lymphoma cells, downregulation of SREBP-2 and LDLR does not occur even under cholesterol-rich conditions, indicating that the negative feedback mechanism is disrupted. 10 ACAT1 is an enzyme belonging to the membrane-bound O-acyltransferase (MBOAT) family, which esterifies free cholesterol to produce cholesterol esters that are stored as lipid droplets. Overexpression of ACAT1 has been reported in some malignant tumors, including pancreatic cancer 12 and clear cell renal cell carcinoma (ccRCC).…”

“…13 We have reported that in malignant lymphomas, ACAT1 expression is increased in response to the uptake of large amounts of cholesterol and protects cells from cholesterol toxicity by esterifying excess cholesterol, thereby maintaining intracellular cholesterol homeostasis. 10 SR-BI is a high-density lipoprotein (HDL) receptor first identified by sequence homology to cluster determinant 36 (CD36) and is a member of the class B scavenger receptor family. 14,15 SR-BI expressed in hepatocytes mediates reverse cholesterol transport by uptake of HDL cholesterol for routing to bile.…”

“… 8 , 9 In our study using malignant lymphoma cell lines, LDL stimulation resulted in an increase in lipid droplet vacuoles and an increase in intracellular cholesterol content, indicating that the major component of these vacuoles is LDL-derived cholesterol. 10 In addition, the expression of cholesterol metabolism-related factors such as LDLR, acetyl-CoA acetyltransferase 1 (ACAT1), and scavenger receptor class B type I (SR-BI) is increased in malignant lymphoma cells and plays an important role in lymphoma lipid metabolism. 10 …”

Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy

“…Therefore, cholesterol is rapidly esterified and exported under the action of acetyl-coenzyme A:cholesterol acetyltransferase (ACAT) and scavenger receptor class B member I (SR-BI) to form vacuoles containing cholesterol ester derivatives ( Figure 1 ). A large number of vacuoles have been observed in highly aggressive lymphoma cells, which have been shown to contain lipids by Sudan black positive staining, and up-regulation of molecules related to cholesterol metabolism has also been detected ( 88 ).…”

“…Overactivation of ERK/MAPK signaling pathway using limonoid compounds A1542 and A1543 induces excessive cholesterol biosynthesis in leukemia cells, leading to cholesterol accumulation and programmed apoptosis in leukemia cells ( 97 ). In addition, blocking cholesterol efflux by SR-BI inhibitor, resulting in intracellular cholesterol accumulation, can also stimulate ER stress response and eventually lead to apoptosis ( 88 ).…”