Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewDissecting lipid raft facilitated cell signaling pathways in cancer
Introduction
Maintenance of balance between cell proliferation and cell death is the main key of normal development. Cancer cells have higher rate of proliferation than death. Usually, deregulated cell cycle is the cause of such impairment. Deregulation of cell cycle is caused by aberrant signaling. The dynamicity of membranes and flip-flop flexibility of lipids within cell membrane play some vital roles in cells life and death. Plasma membrane gives a protection to cytoplasmic ingredients and organelles, it perform endocytosis and signaling, and increases the mechanical stability of cells during division, as well as the flexibility of lipids within the membrane causes decrease of shear forces during cell separation (for example, separation of individual cells from the host tumor during cancer metastasis). Within the membrane, there are specialized domains, known as lipid rafts. Many proteins of receptor tyrosine kinases (RTK) family members, including epidermal growth factor receptor (EGFR), and other proteins, including caveolin-1, CD44, uPAR, H-Ras, integrins and catenins have been implicated to various cellular functions, including stability and signaling. Some of these proteins precisely exhibit their function through lipid rafts, either structurally or functionally, or both, in immune signaling, angiogenesis, cell polarity and cancer progression. Function of proteins like, FAS and FASL virtually remain inert, which in turn facilitate tumor development by reduced rate of apoptosis. Also, impaired function of FAS and FASL results in tumor development, immune disorders and other diseases, including diabetes and Parkinson's disease. Investigations on the molecular mechanisms of cell transformation and development of various cancers, including breast, lung, prostate, gliomas and multiple sarcomas are given immense importance, since cancer is one of the major threats in our life. We have been working for years on molecular and epigenetic regulation of cancer, including lipid rafts, DNA methylation, and lipid rafts and cancer metastasis [1]. In this contribution, I shall discuss some important signaling events leading to cell transformation and cancer progression, which otherwise depend predominantly on lipid rafts. A handfull collective knowledge of lipid rafts and raft-assisted signaling pathways would help us to choose strategies for prevention, cure and better management of cancers using natural compounds, synthetic inhibitors, radiation or other forms of therapies.
Lipid/membrane rafts are small (10–200 nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that compartmentalize cellular processes. Caveolae, a subclass of rafts, are characterized by flask-like invaginations of the plasma membrane that are distinguished from bulk lipid rafts by the presence of caveolin-1 (cav-1). Hence, lipid rafts/caveolae are specialized molecular assemblages of sphingolipids and cholesterol, orchestrated by proteins and gangliosides that are known principally for their pivotal role in trans-cytosis, sorting of sphingolipids and cholesterol in the cell, and as platforms to concentrate receptors and assembling the signal transduction machinery; but their ability to influence the actin cytoskeleton, cell polarity, angiogenesis, membrane fusion is probably just as significant [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Fig. 1. shows a schematic view of lipid rafts, and caveolae like compositions. The lower half of the Fig. 1 depicts a typical composition of a cell death associated raft clustering enriched with ceramide (will be discussed below). All the components (lipids and proteins) presented in Fig. 1 are not available in the same type of raft. The raft composition largely depends on what fraction of lipids in the cytoplasmic leaflet form rafts in living cells and the type of cellular response after receiving signal/stimuli [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]. All tumor cells shed plasma membranes enriched in sphingomyelin (SM), cholesterol and gangliosides to counter possibly against hosts immune responses and keep themselves free from destruction by immune system (reviewed in ref. [1], see also [28], [29], [30], [31], [32]).
The lipid raft proteomics is the study of all the proteins that use, and most importantly need raft assemblage for their proper functioning, certainly expressed by a given cell, tissue or organism at a given time and under specific conditions. Some of those proteins are well illustrated in the case of signaling in hematopoietic cells, including T-cells and B-cells, in a variety of cancer cells and to some extent in model rafts [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [19], [20], [21], [22], [23], [24], [25], [26], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53]. The binding of actin is an important example of interaction of raft components with cytoplasmic proteins, which implies raft mediated signaling, cell surface organization and a role for rafts in mechanical properties of cell membranes. Actin forms protein-chains such as Cadherin–Catenin–Actin, CD44–(Ezrin, Radixin, Moesin; ERM)–Actin, and some others depending on tissue and cell types where catenin and ERM-like proteins constitute a molecular bridge. Table 1 summarizes the lipid components, and Table 2 shows a few protein components of rafts as identified by biophysical, biochemical, and immuno-localization methods. All raft components cited in Table 2 are authentic and supported from the works of at least four separate laboratories, and further confirmed by unbiased proteomics of lipid rafts [1], [4], [34], [35], [36], [40], [41], [42], [43], [44], [45]. The proteomics approach yielded, quantified and validated around 250 proteins as authentic raft proteins [4], [35], [36], [37], excluding the contaminations of non-raft detergent-resistant/insoluble membrane proteins [17], [38], [39]. From such a large set of true raft proteins, I have picked some structural as well as signaling molecules, including cav-1, CD44, EGFR, Ras, uPAR, MMPs, and FAS, Ezrin and a few related proteins for discussion in the following sections.
Manipulation of available data on lipid rafts by proteomics approach for various cancer cells and of model rafts have compelled to suggest that there may be two subsets of raft assemblage in cell membrane. One subset of raft is enriched with cholesterol–sphingomyeline–ganglioside (hereafter, “chol-raft”) containing proteins mainly Caveolins, CD44, and members of the RTKs family. “Chol-rafts” are responsible for cellular homeostasis, but when normal cellular signaling is dysregulated “chol-rafts” promote cell transformation, tumor progression, angiogenesis and metastasis. Another subset of raft is enriched with ceramide–sphingomyeline (hereafter, “cer-raft”) containing mainly, FAS, FASL, and the members of death-inducing signaling complex (DISC). “Cer-rafts” promote apoptosis. Ezrin like molecules function as molecular bridge in both types, the “chol-rafts” and the “cer-rafts”. Small rafts can sometimes be stabilized to form larger platforms through clustering of proteins, and lipid–protein–lipid raft (LPLR) reordering in living cells by elevated cholesterol induced coalescence of rafts. This reordering of “chol-raft” might serve to sequester proteins namely, CD44, EGFR, Ras and stimulate “start” signals to oncogenic pathways. When cells and tumors are exposed to radiation or challenged with therapeutic compounds acid sphingomyelinase (ASMase) becomes activated. The activated ASMase then translocates to membrane surfaces (Fig. 1) and hydrolyzes SM, which generates sphingosine and ceramide. This in situ breakdown of SM elevates ceramide level, which rapidly displaces cholesterol from membrane/lipid-“chol-raft” and forms “cer-raft”. This newly formed “cer-raft” serves to sequester proteins of the FAS–DISC and related proteins, which immediately triggers “start” signals to death/apoptosis following endocytosis. The displaced cholesterol may move to the other parts of the membrane enriched with phospholipid, and be continuously balanced by efflux of cellular cholesterol (See discussion and perspectives).
Section snippets
Lipid rafts/caveolae signaling and cancer
Epigenetic regulation of genes encoding raft components and its roles in cell transformation angiogenesis, immune escape, and metastasis, and roles for rafts in other diseased states have been reviewed earlier [1], [5], [8], [13], [14], [15], [24]. The role of cholesterol and rafts in non-genomic hormonal signaling in prostate cancer is intriguing and discussed recently [25], [52]. This contribution is devoted to focus on the cellular biochemistry and signaling function of some protein
Raft and epidermal growth factor receptor (EGFR) signaling
Cohen (1962) first described a growth factor that has a profound effect on the differentiation of specific cells in vivo, and which is a potent mitogenic factor for variety of cultured cells of both ectodermal and mesodermal origin that is known today as epidermal growth factor (EGF) or Urogastrone (URG). URG/EGF (OMIM 131530) is also a potent inhibitor of gastric acid secretion and promotes epithelial cell proliferation. Mature EGF is a single-chain polypeptide consisting of 53 amino acids and
Nuclear factor kappa B signaling
The oxidative stress sensitive transcription factor playing critical roles in the regulation of a variety of genes, important in multiple cellular responses, is the nuclear factor-kB (NFκB). NFκB remains inactive in the cytoplasm sequestered through its interaction with IkB and became activated in inflammation and cancer. IkB kinase phosphorylates IkB and subsequent ubiquitination cause degradation of the latter. Eventual release of NFκB is followed by its translocation to the nucleus. The NFκB
Rafts in MAP kinase, Ras, and activator protein 1 (AP1) signaling
MAP kinases have been shown to play important roles in many cellular physiologic processes, including proliferation, differentiation, and survival or death. In mammalian cells there are the three major types of MAP kinases: (i) c-Jun NH2-terminal kinases (JNK), (ii) p38 MAP kinases, and (iii) ERK. Activation of ERK1 and ERK2 (ERK 1/2) in this pathway modulate a wide variety of cellular activities via the regulation of several transcription factors. The ability of the ERK/MAPK pathway to promote
Raft and insulin like growth factor mediated signaling
Insulin like growth factor (IGF) family of ligands, associated proteins and its receptors is a significant essential growth factor system involved in the maintenance of cellular functions. Mastick et al [128] have shown that insulin stimulates the tyrosine phosphorylation of caveolin. The coupling of free IGFs to IGF-1 results in intracellular receptor autophosphorylation and phosphorylation of precise downstream targets, which leads to cross activation of several signaling pathways, including
Extracellular matrix and raft signaling
The ability of cells to respond appropriately to environmental cues is critical to maintaining cellular, tissue and organism homeostasis. One such environmental cue is derived from cellular adhesion to the extracellular matrix (ECM). The loss of adhesion-dependent cellular regulation can lead to increased cellular proliferation, decreased cell death, changes in cellular differentiation status, and altered cellular migratory capacity; all of which are critical components of cellular
Rafts in MMPs and uPAR signaling
The invasive nature of tumor cells vexed and bedeviled the current treatment pathways, as the remaining tumor cells inevitably invade the surrounding normal tissues, which leads to tumor recurrence. Such local invasion remains to be an important cause of mortality and underscores the need to understand in depth the mechanisms of invasion. Several proteases influence the malignant characteristics of various carcinomas, gliomas and sarcomas — their inhibition could prove to be a useful
Rafts in integrin and focal adhesion kinase mediated signaling
The focal adhesion kinase (FAK) family kinases (which include FAK and pyk2) regulate cell adhesion, migration, and proliferation in a variety of cell types ([136], reviewed in refs. [143], [144]). Adhesion of cells to the ECM is mediated by heterodimeric transmembrane integrin receptors located within sites of close apposition to the underlying matrix called focal adhesions. Integrin engagement and clustering stimulates FAK phosphorylation on Y397, creating a high affinity binding site for Src
Raft signaling and apoptosis
Programmed cell death (apoptosis) is a highly ordered protective mechanism through which unwanted, fatigued or damaged cells are eliminated from the system, which is essential for normal development, immunological competence, and homeostasis. Moreover, apoptotic cell death, which is preceded by the activation of effector proteases, known as caspases, which results in the cleavage of varied endogenous proteins involved in structure maintenance and signal transduction in an organism. Also,
FAS and raft mediated FAS signaling
cDNA encoding the Human FAS antigen (TNFRSF6/FAS/APT1/APO1/CD95, OMIM 134637) consist of a 16-amino acid signal sequence followed by a mature protein of 319 amino acids with a single transmembrane domain and a molecular mass of approximately 36 kD [157]. The protein contains three domains; a FAS death domain, a FAS ligand (FASL) binding domain, and the transmembrane domain. The FAS antigen shows structural homology with a number of cell surface receptors, including tumor necrosis factor (TNF)
Rafts and ezrin signaling
Ezrin (OMIM 123900) is a component of the microvilli of intestinal epithelial cells that serves as a major cytoplasmic substrate for certain protein–tyrosine kinases. It is the same as cytovillin (CVL), which is a microvillar cytoplasmic peripheral membrane protein that is expressed strongly in placental syncytiotrophoblasts and in certain human tumors. cDNA cloning, sequencing, and deduction of protein sequence indicated that human ezrin is a highly charged protein with an overall pI of 6.1
Acid sphingomyelinase and raft signaling
Acid sphingomyelinase (OMIM 607608) is a lysosomal sphingomyelin phosphodiesterase (EC 3.1.4.12). Stress is believed to activate sphingomyelinase to generate ceramide, which serves as a second messenger in initiating apoptotic response. The first conclusive evidence for this paradigm was provided by Santana et al. [213], who showed that lymphoblast from Niemann–Pick patients failed to respond to ionizing radiation with ceramide generation and apoptosis. Earlier, Suchi et al. [214] have
Discussion and perspectives
Structural and functional role of lipid rafts at the plasma membrane as well as in cell organelles, including Endoplasmic reticulum and Golgi apparatus has been analyzed and reviewed in detail in several studies [1], [3], [5], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [19], [20], [21], [22], [23], [24]. In recent years a specific activity of membrane sub-domains, including SM, sphingosine and ceramide has been observed to contribute to cell death by apoptosis [19], [20],
Acknowledgement
I apologise for many other important contributions that I have not been able to include and discuss.
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