No abstract

The up-regulation of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been observed in several malignant cancers including liver, ovarian, thyroid, and colorectal cancers. However, the pathological role and the regulatory mechanism of FUT8 in cancers remain largely unknown. In the current study, we report that the expression of FUT8 is up-regulated in nonsmall cell lung cancer (NSCLC) and correlates with tumor metastasis, disease recurrence, and poor survival in patients with NSCLC. Knocking down FUT8 in aggressive lung cancer cell lines significantly inhibits their malignant behaviors including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The results of glycoproteomic and microarray analyses show that FUT8 globally modifies surface antigens, receptors, and adhesion molecules and is involved in the regulation of dozens of genes associated with malignancy, suggesting that FUT8 contributes to tumor progression through multiple mechanisms. Moreover, we show that FUT8 is up-regulated during epithelial-mesenchymal transition (EMT), a critical process for malignant transformation of tumor, via the transactivation of β-catenin/lymphoid enhancer-binding factor-1 (LEF-1). These results provide a model to illustrate the relation between FUT8 expression and lung cancer progression and point to a promising direction for the prognosis and therapy of lung cancer.TGF-beta | E-cadherin | fucose F ucosylation, the transfer of fucose from GDP-fucose to glycoconjugates such as glycoproteins and glycolipids, is catalyzed by a family of enzymes called fucosyltransferases (FUTs). So far, 13 FUTs are known to be encoded by the human genome, including FUT1 to 11, protein O-fucosyltransferase 1 (POFUT1), and POFUT2. Through these FUTs, fucoses could be attached to N-, O-, and lipid-linked glycans through an α1,2-(by FUT1 and 2), α1,3-(by FUT3 to 7 and FUT9 to 11), α1,4-(by FUT3 and 5), or α1,6-(by FUT8) linkage, or directly link to the serine/threonine residues of EGF-like or thrombospondin repeats (by POFUT1 and 2, respectively) (1, 2). In mammals, fucosylated glycans have pivotal roles in many aspects of biological processes such as lymphocyte homing, immune responses, fertilization, and development (3). Moreover, aberrant fucosylation, which results from the deficiency or overexpression of FUTs, is associated with a variety of human diseases, including cystic fibrosis, leukocyte adhesion deficiency type II, and cancers (3, 4).Unlike other FUTs, which are functionally redundant, FUT8 is the only enzyme responsible for the α1,6-linked (core) fucosylation by adding fucose to the innermost GlcNAc residue of an N-linked glycan. A growing body of evidence indicates that core fucosylation is important for regulating protein functions. For example, deletion of the core fucose from the Fc region of IgG1 greatly improves its binding affinity to Fcγ receptor IIIa, which in turn enhances antibody-dependent cell-mediated cytotoxicity for over 50 folds (5, 6). Co...

This study is the first study to investigate the anticancer effect of 6-shogaol in human non-small cell lung cancer A549 cells. 6-Shogaol inhibited cell proliferation by inducing autophagic cell death, but not, predominantly, apoptosis. Pretreatment of cells with 3-methyladenine (3-MA), an autophagy inhibitor, suppressed 6-shogaol mediated antiproliferation activity, suggesting that induction of autophagy by 6-shogaol is conducive to cell death. We also found that 6-shogaol inhibited survival signaling through the AKT/mTOR signaling pathway by blocking the activation of AKT and downstream targets, including the mammalian target of rapamycin (mTOR), forkhead transcription factors (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). Phosphorylation of both of mTOR's downstream targets, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, was also diminished. Overexpression of AKT by AKT cDNA transfection decreased 6-shogaol mediated autophagic cell death, supporting inhibition of AKT beneficial to autophagy. Moreover, reduction of AKT expression by siRNA potentiated 6-shogaol's effect, also supporting inhibition of AKT beneficial to autophagy. Taken together, these findings suggest that 6-shogaol may be a promising chemopreventive agent against human non-small cell lung cancer.