Abnormal glycosylation due to dysregulated glycosyltransferases and glycosidases is a key phenomenon of many malignancies, including colorectal cancer (CRC). In particular, increased ST6 Gal I (β-galactoside α 2, 6 sialyltransferase) and subsequently elevated levels of cell-surface α 2, 6-linked sialic acids have been associated with metastasis and therapeutic failure in CRC. As many CRC patients experience metastasis to the liver or lung and fail to respond to curative therapies, intensive research efforts have sought to identify the molecular changes underlying CRC metastasis. ST6 Gal I has been shown to facilitate CRC metastasis, and we believe that additional investigations into the involvement of ST6 Gal I in CRC could facilitate the development of new diagnostic and therapeutic targets. This review summarizes how ST6 Gal I has been implicated in the altered expression of sialylated glycoproteins, which have been linked to CRC metastasis, radioresistance, and chemoresistance.
BackgroundKAI1 was initially identified as a metastasis-suppressor gene in prostate cancer. It is a member of the tetraspan transmembrane superfamily (TM4SF) of membrane glycoproteins. As part of a tetraspanin-enriched microdomain (TEM), KAI1 inhibits tumor metastasis by negative regulation of Src. However, the underlying regulatory mechanism has not yet been fully elucidated. CUB-domain-containing protein 1 (CDCP1), which was previously known as tetraspanin-interacting protein in TEM, promoted metastasis via enhancement of Src activity. To better understand how KAI1 is involved in the negative regulation of Src, we here examined the function of KAI1 in CDCP1-mediated Src kinase activation and the consequences of this process, focusing on HIF-1 α and VEGF expression.MethodsWe used the human prostate cancer cell line PC3 which was devoid of KAI1 expression. Vector-transfected cells (PC3-GFP clone #8) and KAI1-expressing PC3 clones (PC3-KAI1 clone #5 and #6) were picked after stable transfection with KAI1 cDNA and selection in 800 μg/ml G418. Protein levels were assessed by immunoblotting and VEGF reporter gene activity was measured by assaying luciferase activitiy. We followed tumor growth in vivo and immunohistochemistry was performed for detection of HIF-1, CDCP1, and VHL protein level.ResultsWe demonstrated that Hypoxia-inducible factor 1α (HIF-1α) and VEGF expression were significantly inhibited by restoration of KAI1 in PC3 cells. In response to KAI1 expression, CDCP1-enhanced Src activation was down-regulated and the level of von Hippel-Lindau (VHL) protein was significantly increased. In an in vivo xenograft model, KAI1 inhibited the expression of CDCP1 and HIF-1α.ConclusionsThese novel observations may indicate that KAI1 exerts profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1-mediated Src activation, followed by VHL-induced HIF-1α degradation and, ultimately, decreased VEGF expression.
BackgroundPreviously, we found that β-galactoside α2,6-sialyltransferase (ST6Gal I), an enzyme that adds sialic acids to N-linked oligosaccharides of glycoproteins and is frequently overexpressed in cancer cells, is up-regulated by ionizing radiation (IR) and cleaved to a form possessing catalytic activity comparable to that of the Golgi-localized enzyme. Moreover, this soluble form is secreted into the culture media. Induction of ST6Gal I significantly increased the migration of colon cancer cells via sialylation of integrin β1. Here, we further investigated the mechanisms underlying ST6Gal I cleavage, solubilization and release from cells, and addressed its functions, focusing primarily on cancer cell migration.MethodsWe performed immunoblotting and lectin affinity assay to analyze the expression of ST6 Gal I and level of sialylated integrin β1. After ionizing radiation, migration of cells was measured by in vitro migration assay. α2, 6 sialylation level of cell surface was analyzed by flow cytometry. Cell culture media were concentrated and then analyzed for soluble ST6Gal I levels using an α2, 6 sialyltransferase sandwich ELISA.ResultWe found that ST6Gal I was cleaved by BACE1 (β-site amyloid precursor protein-cleaving enzyme), which was specifically overexpressed in response to IR. The soluble form of ST6Gal I, which also has sialyltransferase enzymatic activity, was cleaved from the Golgi membrane and then released into the culture media. Both non-cleaved and cleaved forms of ST6Gal I significantly increased colon cancer cell migration in a sialylation-dependent manner. The pro-migratory effect of the non-cleaved form of ST6Gal I was dependent on integrin β1 sialylation, whereas that of the cleaved form of ST6Gal I was not, suggesting that other intracellular sialylated molecules apart from cell surface molecules such as integrin β1 might be involved in mediating the pro-migratory effects of the soluble form of ST6Gal I. Moreover, production of soluble form ST6Gal I by BACE 1 inhibited integrin β1 sialylation and migration by Golgi-anchored form of ST6Gal I.ConclusionsOur results suggest that soluble ST6Gal I, possibly in cooperation with the Golgi-bound form, may participate in cancer progression and metastasis prior to being secreted from cancer cells.
Background: There is a big controversy about how mitochondria dysfunction affects skeletal myogenesis and insulin signaling. Results: Mitochondrial complex I deficiency inactivates SIRT1 by decreasing the NAD ϩ /NADH ratio, leading to skeletal
Edited by Jeffrey PessinMitsugumin 53 (MG53) is an E3 ligase that interacts with and ubiquitinates insulin receptor substrate-1 (IRS-1) in skeletal muscle; thus, an MG53-IRS-1 interaction disruptor (MID), which potentially sensitizes insulin signaling with an elevated level of IRS-1 in skeletal muscle, is an excellent candidate for treating insulin resistance. To screen for an MID, we developed a bimolecular luminescence complementation system using an N-terminal luciferase fragment fused with IRS-1 and a C-terminal luciferase fragment fused with an MG53 C14A mutant that binds to IRS-1 but does not have E3 ligase activity. An MID, which was discovered using the bimolecular luminescence complementation system, disrupted the molecular association of MG53 with IRS-1, thus abolishing MG53-mediated IRS-1 ubiquitination and degradation. Thus, the MID sensitized insulin signaling and increased insulin-elicited glucose uptake with an elevated level of IRS-1 in C2C12 myotubes. These data indicate that this MID holds promise as a drug candidate for treating insulin resistance.Noninsulin-dependent diabetes mellitus (type 2 diabetes) has become a worldwide epidemic disease due to the increased incidence of obesity. Insulin receptor (IR) and insulin receptor substrate (IRS) 4 are inactivated by elevated serum levels of free fatty acids, leading to insulin resistance and noninsulin-dependent diabetes mellitus (1-3). Because skeletal muscle is the largest organ participating in glucose uptake, exercise-induced skeletal muscle development is an excellent treatment for insulin resistance. However, no current candidates target skeletal muscle to treat insulin resistance.Mitsugumin 53 (MG53), which is also called tripartite motifcontaining protein 72 (TRIM72) and which is largely expressed in skeletal muscle, was independently identified by proteomic analysis of lipid rafts and triad-rich membranes (4). MG53 contains a tripartite domain (an E3 ligase RING domain, a B-box, and two coiled-coil domains) and a SPRY domain. Insulin-like growth factor-1 (IGF-1) initiates MyoD activation via an IGF-1 receptor-PI3K-Akt pathway during skeletal myogenesis (5, 6). MyoD and myocyte enhancer factor 2 (MEF2) binds to two proximal E-boxes and an MEF2 site in MG53 promoter, activating MG53 gene transcription (7). The MG53 protein interacts with IRS-1 and focal adhesion kinase (FAK), inducing IRS-1 and FAK ubiquitination and degradation in skeletal muscle with the help of E2 ligase UBE2H (8 -10). Moreover, RING domain-disrupted MG53 mutants (⌬R and C14A) abolish IRS-1 and FAK ubiquitination and degradation in skeletal muscle, indicating that MG53 is an E3 ligase that targets IRS-1 and FAK.Systemic MG53 ablation abrogates IRS-1 ubiquitination and degradation in skeletal and cardiac muscle, leading to elevated IRS-1 expression level and increased insulin signaling (8, 9). Thus, MG53 knock-out mice do not develop diet-induced insulin resistance. In contrast, skeletal muscle-specific MG53 transgenic mice exhibit metabolic disorders such as obesity, ...
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