Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

Abstract

Cell surface biochemical changes, notably excessive increase in outer leaflet sphingomyelin (SM) content, are important in cancer initiation, growth, and immune evasion. Innumerable reports describe methods to initiate, promote, or enhance immunotherapy of clinically detected cancer, notwithstanding the challenges, if not impossibility, of identification of tumor-specific, or associated antigens, the lack of tumor cell surface membrane expression of major histocompatibility complex (MHC) class I alpha and β2 microglobulin chains, and lack of expression or accessibility of Fas and other natural killer cell immune checkpoint molecules. Conversely, SM synthesis and hydrolysis are increasingly implicated in initiation of carcinogenesis and promotion of metastasis. Surface membrane SM readily forms inter- and intra- molecular hydrogen bond network, which excessive tightness would impair cell-cell contact inhibition, inter- and intra-cellular signals, metabolic pathways, and susceptibility to host immune cells and mediators. The present review aims at clarifying the tumor immune escape mechanisms, which face common immunotherapeutic approaches, and attracting attention to an entirely different, neglected, key aspect of tumorigenesis associated with biochemical changes in the cell surface that lead to failure of contact inhibition, an instrumental tumorigenesis mechanism. Additionally, the review aims to provide evidence for surface membrane SM levels and roles in cells resistance to death, failure to respond to growth suppressor signals, and immune escape, and to suggest possible novel approaches to cancer control and cure.

Investigating the Potential Use of Chemical Biopsy Devices to Characterize Brain Tumor Lipidomes

“…SMs are responsible for the formation of lipid rafts in membranes and signal transduction between the cells. Furthermore, higher SM content, which leads to impaired cell-cell and cell-matrix interactions, is also often observed in cancerous tissues [ 49 , 50 ]. Hence, although these reports do not support the observations in this work, the lack of significant changes in other SMs and ceramides (being central molecules in SM synthesis) do not merit further discussion of this phenomena [ 49 ].…”

High-throughput metabolomics reveals dysregulation of hydrophobic metabolomes in cancer cell lines by Eleusine indica

“…Upon arrival in the Golgi apparatus, Cer is converted into SM via the enzyme sphingomyelin synthase (SMS), which can induce cell proliferation, migration, and survival 72 . Metabolism of SM plays a role in cancer progression, whereby the breakdown of SM directly results in Cer production 73 . In addition, glucosylceramide (GlcCer), a pro-survival and antiapoptotic molecule generated from the transfer of glucose to Cer by glucosylceramide synthase (GCS), has been shown to be associated with multi-drug resistance in cancer cells 69 .…”

Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT

“…CERT plays a key role in the ceramide-sphingomyelin metabolic axis (reviewed in [11]). As more evidence has accumulated that ceramide and sphingomyelin participate in various physiological and pathophysiological events [15,16,23,24], more attention has been paid to CERT. Accordingly, it has been clarified that CERT and CERT L (also known as GPBP∆26 and GPBP, respectively) participate in various events and functions in mammalian cells, including polyploid cancer cell death [95], EGF receptor signaling [96], lipotoxicity and glucolipotoxicity in islet β-cells [97,98], muscle insulin signaling [99], myofibril formation [100], integrity of glomerular basement membrane [101], cytotoxic autophagy [102], mitochondrial maintenance [103], and senescence [104].…”

“…Sphingomyelin, in concert with cholesterol, generates nano-scale membrane domains (so-called "lipid rafts" or "detergent-resistant membranes"), in which the spatiotemporal confinement of various molecules needed for signaling and other dynamic events of membranes can efficiently occur (see [20,21] for recent reviews). Sphingomyelin may interact with specific membrane proteins as their functional modulator, while sphingomyelin is also an important metabolic reservoir for sphingolipid mediators such as ceramide, sphingosine, and sphingosine-1-phosphate, which are produced as catabolites of sphingomyelin (reviewed in [15,[22][23][24]). In mammalian cells, sphingomyelin is mainly located in the plasma membrane (PM), although the Golgi apparatus (where sphingomyelin is synthesized) and endosomes/lysosomes (to which the PM-derived endocytosis is directed) also have sphingomyelin [17,18].…”