Why make it if you can take it: review on extracellular cholesterol uptake and its importance in breast and ovarian cancers

Abstract

Cholesterol homeostasis is essential for healthy mammalian cells and dysregulation of cholesterol metabolism contributes to the pathogenesis of various diseases including cancer. Cancer cells are dependent on cholesterol. Malignant progression is associated with high cellular demand for cholesterol, and extracellular cholesterol uptake is often elevated in cancer cell to meet its metabolic needs. Tumors take up cholesterol from the blood stream through their vasculature. Breast cancer grows in, and ovarian cancer metastasizes into fatty tissue that provides them with an additional source of cholesterol. High levels of extracellular cholesterol are beneficial for tumors whose cancer cells master the uptake of extracellular cholesterol. In this review we concentrate on cholesterol uptake mechanisms, receptor-mediated endocytosis and macropinocytosis, and how these are utilized and manipulated by cancer cells to overcome their possible intrinsic or pharmacological limitations in cholesterol synthesis. We focus especially on the involvement of lysosomes in cholesterol uptake. Identifying the vulnerabilities of cholesterol metabolism and manipulating them could provide novel efficient therapeutic strategies for treatment of cancers that manifest dependency for extracellular cholesterol.

Keywords: Chemoresistant cancer; Cholesterol homeostasis; High-grade serous ovarian cancer; Lipid; Macropinocytosis; Obese; Receptor-mediated endocytosis; Statin.

Fig. 1

Overview of cholesterol homeostasis pathways utilized in cancer. Cells obtain cholesterol by taking it up from the extracellular environment or by de novo synthesis. Excess intracellular cholesterol can be transported out of cells with specific efflux mechanisms including ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Cholesterol uptake involves receptor mediated endocytosis, macropinocytosis and the cooperation of lysosomes resulting in a release of the free cholesterol from cholesteryl ester. The cholesterol levels will affect the regulatory machinery, low cholesterol levels lead to increase transcription through SREBP-2 activation and high cholesterol levels leads to the deactivation of SREBP-2, activation of LXR and the storage of cholesteryl esters in lipid droplets. ABCA1 (ATP-binding cassette transporter A1), ABCG1 (ATP Binding Cassette Subfamily G Member 1), HDL (high density lipoprotein), LDL (low density lipoprotein), LDLR (Low density lipoprotein receptor) LXR (Liver X receptor), NPC1 and NPC2 (Niemann-Pick type C protein 1 and 2), HMGCR (HMG-CoA reductase), SR-B1 (Scavenger receptor class B type 1), SREBP-2 (Sterol regulatory element-binding protein 2), SCAP (SREBP-2 cleavage activation protein), INSIG (Insulin-induced gene protein)

Fig. 2

Overview of extracellular cholesterol uptake pathways utilized in cancer cells. Cells can efficiently take up and utilize extracellular cholesterol mainly by two different mechanisms: a receptor-mediated endocytosis involving LDLR or SR-B1, or by macropinocytosis, a receptor independent internalization mechanism which involves actin filament reorganization under the plasma membrane. Cholesteryl esters that are taken up from the extracellular environment are hydrolysed to cholesterol in lysosomes and transferred to NPC2 and then outside of lysosome through NPC1. All these pathways are often upregulated in cancer

Fig. 3

Overview of the cholesterol efflux and storage system. Excess intracellular cholesterol is stored as lipid droplets in cytosol or transported out of the cell via ABC transporter here represented by ABCA1 and ABCG1. Lecithin-Cholesterol Acyltransferase (LCAT) esterifies free cholesterol into cholesteryl ester on the surface of the HDL forming HDL2 and HDL3 which are modified forms of HDL with decreasing amount of cholesterol on their surface. HDL particles are transported to the liver for excretion through the intestine. Cholesterol Acyltransferase 1 (ACAT1/SOAT) esterifies intracellular free cholesterol to be stored in lipid droplets. When stored cholesterol is needed, Neutral Lipid Ester Hydrolase (NEH) releases stored lipids and cholesterol for cellular use

Fig. 4

Cellular mechanisms for sensing and responding to altered cholesterol levels. Left: Low cholesterol levels lead to upregulation of cholesterol synthesis and uptake. SCAP senses low cholesterol levels and takes SREBP2 from Golgi to the endoplasmic reticulum (ER) for activation, after which SREBP2 enters nucleus and activates target gene transcription. Right: High cholesterol levels lead to increased cholesterol efflux and decreased cholesterol uptake and synthesis. Here also SCAP acts as a cholesterol sensor. Cholesterol binds to SCAP causing it to retain the SREBP2 in the ER to prevent its transport to the nucleus. INSIG proteins play a central role in this process by regulating the SREBP2-SCAP complex assembly

Fig. 5

Illustration of cholesterol uptake mechanisms in breast cancer. The illustration highlights central molecular mechanisms that confer altered cholesterol metabolism in breast cancer cells. The figure includes mechanisms found in ER-negative, ER-positive and triple negative breast cancer. Abbreviations: LDL (low density lipoprotein), HDL (High density lipoprotein), NPC1 (Niemann-Pick disease, type C1), STARD3 (StAR-related lipid transfer protein 3), MZF1 (Myeloid zinc finger 1), EGFR (Epidermal growth factor receptor), ErbB2 (erythroblastic oncogene B 2)

Fig. 6

Illustration of cholesterol uptake mechanisms in ovarian cancer. The illustration highlights central molecular mechanisms that lead to altered cholesterol metabolism in ovarian cancer cells. Abbreviations: LDL (low density lipoprotein), HDL (High density lipoprotein), ABCA1 (ATP-binding cassette transporter A1), ABCG2 (ATP-binding cassette transporter G2), MDR1 (Multidrug Resistance 1), SR-B1 (Scavenger receptor B1), INSIG (Insulin-induced gene 1 protein), SOAT1 (Sterol O-acyltransferase 1), SREBP2 (Sterol regulatory element-binding protein 2), SCAP (SREBP cleavage-activating protein), HMGCR (HMG-CoA reductase)