Cholesterol esters as growth regulators of lymphocytic leukaemia cells

Abstract

Decreased levels of HDL-C were observed in plasma of leukaemic patients, levels of total cholesterol, LDL-C, triglycerides and phospholipids were unchanged or only slightly increased. As compared to normal lymphocytes, freshly isolated leukaemic cells showed increased levels of cholesterol esters and reduction in free cholesterol. Growth stimulation of ALL and CLL cells with phytohemagglutinin led to further increase in levels of cholesterol esters. Conversely, treatment with an inhibitor of cell proliferation such as the mTOR inhibitor, RAD, caused decline in population growth rate of leukaemia cells, which was preceded by sharp reduction in rate of cholesterol esterification. On the other hand, exposure of leukaemic cells to two inhibitors of cholesterol esterification, progesterone and SaH 58-035, caused 60% reduction in their proliferation rate. In addition to demonstrating tight correlation between cell number expansion and cholesterol esterification in leukaemic cells, these results suggest that pathways that control cholesterol esterification might represent a promising targets for novel anticancer strategies.

Biomimetic, synthetic HDL nanostructures for lymphoma

“…Recent evidence in lymphoblasts and myeloblasts from patients with acute lymphocytic leukemia and acute myeloid leukemia shows enhanced uptake of cholesterol through HDL carriers, which may result in increased cell proliferation (2). In addition, enhanced esterification of cholesterol within leukemia and lymphoma cells is correlated with increased cellular proliferation, and inhibition of cholesteryl ester formation was shown to inhibit cell growth (3,4). Together, these data suggest that interference with cellular cholesterol flux may provide a therapeutic target.…”

Lipoproteins and Cancer

“…We and others have proposed that accumulation of CE spares energy needed for de novo sterol synthesis, allowing greater proliferation and migration and perhaps a quicker return to growth after a period of stasis (Batetta, Pani et al 1999;Antalis, Arnold et al 2010;Antalis, Uchida et al 2011). The process of cholesterol esterification was linked to proliferation in multiple studies in different cancer cell lines (Batetta, Pani et al 1999;Peiretti, Dessi et al 2007;Paillasse, de Medina et al 2009;Antalis, Arnold et al 2010;Mulas, Abete et al 2011), implying a complex network of signaling pathways and gene expression that ties cholesterol accretion to tumorigenesis. However, the exact role of CE in tumorigenesis remains to be determined.…”

“…The CE content of lymphocytes from patients with acute or chronic lymphocytic leukemia (n = 30) was 6-fold higher as compared to lymphocytes from healthy age-matched controls (n = 15), and plasma HDL was >40% reduced in the leukemia patients compared to the controls (Mulas, Abete et al 2011). Phytohemaglutinin (PHA)-stimulated proliferation of the isolated leukemic cells was positively correlated to esterification of oleate to cholesterol, and inhibition of ACAT greatly reduced PHA-induced proliferation (Mulas, Abete et al 2011).…”

“…Similarly type 2 diabetes, a condition of multiple co-morbidities including hyperlipidemia, is associated with the incidence of and mortality from cancer (Faulds and Dahlman-Wright 2012). The association of hyperlipidemia with cancer began with early observations of an accumulation of cholesterol in tumors (reviewed, (Mulas, Abete et al 2011)). Higher levels of cholesterol and cholesteryl esters (CE) in malignant compared to less malignant tumors and normal tissues were first measured chemically (Yasuda and Bloor 1932).…”

Update on Nanotechnology-based Drug Delivery Systems in Cancer Treatment

“…Lymphoma and other cancers receive cholesterol from HDL for membrane synthesis and proliferation (24). An increased cell proliferation of lymphoma cells was correlated with enhanced esterification of cholesterol, and cell growth was prevented with the inhibition of cholesteryl ester formation (25). Based on this feature of lymphoma cells acquiring HDL cholesterol, we (26) tested targeting of HDL-NPs on lymphoma cells through scavenger receptor type B-1 (SR-B1).…”