Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy: Thematic Review Series: Biology of Lipid Rafts

Abstract

Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to regulatory or effector molecules. Thus, lipid rafts serve as sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels of intracellular cholesterol and lipid rafts than their normal non-tumorigenic counterparts. Many signal transduction processes involved in cancer development (insulin-like growth factor system and phosphatidylinositol 3-kinase-AKT) and metastasis [cluster of differentiation (CD)44] are dependent on or modulated by lipid rafts. Additional proteins playing an important role in several malignant cancers (e.g., transmembrane glycoprotein mucin 1) are also being detected in association with lipid rafts, suggesting a major role of lipid rafts in tumor progression. Conversely, lipid rafts also serve as scaffolds for the recruitment and clustering of Fas/CD95 death receptors and downstream signaling molecules leading to cell death-promoting raft platforms. The partition of death receptors and downstream signaling molecules in aggregated lipid rafts has led to the formation of the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER, which leads to apoptosis amplification and can be pharmacologically modulated. These death-promoting rafts can be viewed as a linchpin from which apoptotic signals are launched. In this review, we discuss the involvement of lipid rafts in major signaling processes in cancer cells, including cell survival, cell death, and metastasis, and we consider the potential of lipid raft modulation as a promising target in cancer therapy.

Keywords: cholesterol • cholesterol-rich membrane domains • IGF system • PI3K/AKT signaling • Fas/CD95 • death receptor • CASMER • raft targeting.

Fig. 1.

Pleiotropic effects of cholesterol positively and negatively affecting cancer development and deregulation of cholesterol homeostasis in cancer cells. See the text for further details.

Fig. 2.

Involvement of lipid rafts in different processes in cancer cells affecting cancer development and therapy. Lipid rafts act as scaffolds for many processes related to the hallmarks of cancer (80). See the text for further details.

Fig. 3.

Different types of lipid rafts harboring and modulating survival/proliferating, cell death/apoptosis and cell migration/invasion signaling pathways in cancer cells. Lipid rafts or membrane rafts are depicted in different colors (blue, green, and red) to highlight the heterogeneity of lipid rafts regarding both lipid and protein composition and their putative relationship to a cell signaling process or determined cell function. Irrespective of the color herein represented, lipid rafts are enriched in cholesterol and sphingolipids, but subtle changes in the raft lipidome are likely to occur to enable the recruitment of specific proteins that eventually trigger specific signaling events. Segregation of different signaling pathways in distinct raft platforms within the plasma membrane enhances signaling efficiency by increasing the proximity and effective concentration of components in the raft scaffold (a, b). Dynamic inclusion and exclusion of proteins into rafts modulate cell function (c). See the text for further details.

Fig. 4.

Time-related sequence of events in the formation of cell death-promoting rafts. Clustering of lipid rafts and S-palmitoylation are required for the redistribution of Fas/CD95 to lipid rafts. Clusters of rafts, generated by not yet clear protein-lipid and protein-protein interactions, offer a platform adequate for the recruitment of an increasing number of additional proteins in a rather protected and segregated membrane domain. Once Fas/CD95 has been recruited into rafts, multimeric complexes (DISC) are formed through homotypic DD and DED interaction motifs. This elevated concentration of procaspase-8 molecules in rafts leads to self-activation by auto-catalytic cleavage of procaspase-8, thus activating a caspase cascade and the initiation of the execution phase of apoptosis. See the text for further details.

Fig. 5.

The concept of the formation of CASMER. A number of death receptors and downstream signaling molecules, including DISC, are recruited and brought together in close proximity in large cholesterol- and sphingolipid-enriched lipid raft platforms (highlighted in green), thus facilitating protein-protein interactions, caspase-8 activation, and cross-talk signaling. The presence of Bid in CASMER facilitates the interaction between death receptor extrinsic apoptotic signaling and mitochondria-related intrinsic apoptosis signaling, thus potentiating apoptosis. Apoptotic signaling would be highly amplified by CASMER formation. See the text for further details.