CD36 tango in cancer: signaling pathways and functions

Abstract

CD36, a scavenger receptor expressed in multiple cell types, mediates lipid uptake, immunological recognition, inflammation, molecular adhesion, and apoptosis. CD36 is a transmembrane glycoprotein that contains several posttranslational modification sites and binds to diverse ligands, including apoptotic cells, thrombospondin-1 (TSP-1), and fatty acids (FAs). Beyond fueling tumor metastasis and therapy resistance by enhancing lipid uptake and FA oxidation, CD36 attenuates angiogenesis by binding to TSP-1 and thereby inducing apoptosis or blocking the vascular endothelial growth factor receptor 2 pathway in tumor microvascular endothelial cells. Moreover, CD36-driven lipid metabolic reprogramming and functions in tumor-associated immune cells lead to tumor immune tolerance and cancer development. Notable advances have been made in demonstrating the regulatory networks that govern distinct physiological properties of CD36, and this has identified targeting CD36 as a potential strategy for cancer treatment. Here, we provide an overview on the structure, regulation, ligands, functions, and clinical trials of CD36 in cancer.

Keywords: CD36; biomarker; cancer treatment; lipid metabolism; tumor-associated immune cell.

Figure 1

Structure of CD36. (Above) CD36 harbors two transmembrane domains, a large extracellular region containing ligand-binding sites, and one short cytoplasmic tail at each terminal (N and C). The extracellular domain of CD36 forms two hydrophobic cavities that bind to ligands such as fatty acids and oxidized LDL (ox-LDL). Moreover, the CLESH domain (CD36, LIMP-2, Emp sequence homologous domain) residues are negatively charged and interact with TSP-1 repeat domain 2 (TSR). CD36 undergoes multiple posttranslational modifications, including palmitoylation, acetylation, glycosylation, phosphorylation, ubiquitylation, and disulfide bonding (at three sites), and these modifications control CD36 maturation and localization in cells. Conversely, ligands bind to CD36 in different regions, and the binding leads to the activation of various downstream pathways. (Below) CD36 primary structure showing the hydrophobic domain and binding sites of general ligands. The numbers in different colors denote amino acid sites that undergo posttranslational modification: red, palmitoylation; green, glycosylation; blue, phosphorylation; dark blue, ubiquitylation; purple, acetylation.

Figure 2

Regulation of CD36. CD36 transcription can be modulated by several transcription factors and their ligands, including PPARs, C/EBP, STAT3, LXR, PXR, FoxO1, and HIF-1α. Noncoding RNAs, including miR-758-5p, MALAT1, miR-4668, and RNAs372, can also regulate CD36 mRNA levels. CD36 is posttranslationally modified in the ER during maturation, and these posttranslational modifications and the AMPK and PI3K/AKT signaling pathways modulate the translocation of CD36 to the membrane. CD36 trafficked to mitochondria functions in cooperation with CPT1 to promote FAO.

Figure 3

TSP-1-CD36 signaling induces apoptosis of tumor-associated endothelial cells. TSP-1 binds to CD36 on microvascular endothelial cells and induces the phosphorylation of the cytoplasmic protein tyrosine kinase P59^fyn. Activated P59^fyn stimulates caspase-3-like proteases, which activate and induce the phosphorylation of p38 mitogen-activated protein kinase (MAPK). Nuclear translocation of MAPK results in increased expression of caspase-3 and proapoptotic receptors, which leads to apoptosis. Furthermore, mitochondrial damage releases cytochrome C and reactive oxygen species (ROS), which also trigger the caspase-3 cascade to induce apoptosis. Moreover, TSP-1 biding to CD36 results in the recruitment of Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 to the VEGFR2 complex and SHP-1-mediated dephosphorylation of VEGFR2, which inhibits the VEGF pathway and thus leads to anti-angiogenesis.

Figure 4

CD36 functions in tumor microenvironment. CD36 regulates downstream Src-family kinases to promote anti-angiogenesis, FAO, and chemoresistance and radioresistance, which lead to tumor metastasis. CD36 also activates Wnt/TGF-β signaling to facilitate tumor metastasis through EMT. CD36 uptakes multiple lipids, such as ox-LDL, LCFAs, and cholesterol. The lipid deposition in immune cells leads to aseptic inflammation and dysfunction of antigen presentation in DCs, which induce tumor immunosuppression. Moreover, CD36 can bind to apoptotic cells and activate cross-priming, which might lead to immunosuppression and tumor development.