Abstract
AbstractCholesterol is a vital lipid for cellular functions. It is necessary for membrane biogenesis, cell proliferation, and differentiation. In addition to maintaining cell integrity and permeability, increasing evidence indicates a strict link between cholesterol homeostasis, inflammation, and hematological tumors. This makes cholesterol homeostasis an optimal therapeutic target for hematopoietic malignancies. Manipulating cholesterol homeostasis by either interfering with its synthesis or activating the reverse cholesterol transport via the engagement of liver X receptors affects the integrity of tumor cells both in vitro and in vivo. Cholesterol homeostasis has also been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials involving acute myeloid leukemia to test the combination of chemotherapy with drugs interfering with cholesterol synthesis (ie, statins). We review the role of cholesterol homeostasis in hematopoietic malignancies as well as in cells of the tumor microenvironment and discuss the potential use of lipid modulators for therapeutic purposes.
Highlights
Cholesterol homeostasis has been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials in acute myeloid leukemia (AML) to test the combination of chemotherapy with drugs interfering with cholesterol synthesis, i.e. statins
We review the role of cholesterol homeostasis in hematopoietic malignancies, as well as in cells of the tumor microenvironment, and discuss the potential use of lipid modulators for therapeutic purposes
From the results reported in CD34+ AML cells treated with lovastatin,[39] the induction of lethal autophagy by the liver X receptors (LXRs) agonist DDA occurred independently of their cytogenetic subgroups and did not distinguish bulk cancer cells from cancer cell progenitors.[44]
Summary
70 These include SREBP1-dependent production of monoor poly-unsaturated anti-inflammatory fatty acids uncoupling NF-kB binding from gene activation,[71] and a mechanism based on cholesterol efflux and LXR cis-repression involving direct binding of LXR to inflammatory gene enhancers.[72] It has been reported that the activation of LXRs induces the expression of the remodelling enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3).[73] Lpcat[3] catalyzes the formation of phosphatidylcholine (PC) from saturated lysophosphatidylcholines and unsaturated fatty acyl-CoAs and promotes membrane incorporation of polyunsaturated fatty acids into phospholipids, especially the arachidonoyl-containing phosphatidylcholine.[73] This results in the reduction of free arachidonate, the main precursor of lipid mediators of inflammation, such as prostaglandins, leukotrienes and thromboxanes.[74] changes in membrane composition regulate inflammatory kinase activation, the c-SrcJNK pathway that further modulates inflammatory reactions.[73]
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