Targeting cholesterol homeostasis in hematopoietic malignancies

Abstract

Cholesterol 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.

Graphical abstract

Figure 1.

Regulation of cholesterol homeostasis by SREBP2 and LXR. (A) In conditions of low cholesterol levels, SCAP escorts SREBP2 to Golgi apparatus, where it is cleaved and activated. Subsequently, SREBP2 binds and activates the expression of genes regulating de novo cholesterol synthesis. LXRs remain in a repressive state. (B) In conditions of high cholesterol levels, oxysterols, cholesterol, or desmosterol keeps the trimolecular complex INSIG/SCAP/SREBP2 in the ER, not allowing cholesterol synthesis. Oxysterols engage LXRs, which activate expression of the cholesterol transporters ABCA1 and ABCG1. These transporters induce the reverse cholesterol transport pathway, leading to elimination of excess cholesterol through bile acid formation and excretion.

Figure 2.

Cholesterol, CE, and oxysterol synthesis. The main enzymes involved in cholesterol, CE, and oxysterol synthesis (red). HMG-CoA reductase, squalene synthase, and ACAT-1 enzymes are also the target of specific drugs. The pathway leading to isoprenoid formation is shown (green).

Figure 3.

Drugs interfering with cholesterol and CE synthesis and LXR activity. (A) Drugs interfering with cholesterol and CE synthesis. Statins block both cholesterol synthesis and isoprenoid formation (green), whereas ZAA blocks cholesterol synthesis, leaving intact isoprenoid formation (green). Avasimibe blocks formation of CEs by inhibiting the ACAT-1. HDL-NPs promote cellular cholesterol efflux and restrain cholesterol delivery by targeting scavenger receptor type B-1. (B) LXRs can be inhibited by sulfate oxysterols through the activity of sulfotransferase 2B1b (SULT2B1b) enzyme and by the inverse agonist SR9243. LXRs are activated by oxysterols generated through the activity of cholesterol hydroxylases (eg, ch25h, Cyp27a1, Cyp46a1) or auto-oxidation and by LXRβ-selective (RGX-104) and nonselective LXR agonists (T0901317, GW3965, DDA).

Figure 4.

SREBP2 and LXR pathways regulating inflammation. Upregulation of cholesterol synthesis by SREBP2 also involves NLRP3 activation as SCAP forms a ternary complex and escorts both proteins to the Golgi apparatus (1). NLRP3 and inflammasome activation leads to IL-1β release. Increased cholesterol synthesis induces mitochondrial damage, release of mitochondrial DNA, and activation of the AIM2 component of the inflammasome (2). Oxysterols, such as 25-HC, inhibit inflammation by blocking cholesterol synthesis and inflammasome activation and activating LXRs through multiple mechanisms (3). Inflammasome activation is blocked by inhibition of cholesterol synthesis and avoidance of SCAP/SREBP2 and NLRP3 translocation to the Golgi apparatus. Cholesterol synthesis also leads to formation of GGPP and FPP isoprenoids, which induce prenylation and activation of RhoA, Ras, Rac, Cdc42, and Rab5 small GTPases, which are involved in inflammasome activation, antigen presentation, and cell movement (4). FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate.