Transfection of ?(1,3)fucosyltransferase antisense sequences impairs the proliferative and tumorigenic ability of human colon carcinoma cells

Hiller, Kara M.; Mayben, John P.; Bendt, Katharine M.; Manousos, George A.; Senger, Kate; Cameron, H. Scott; Weston, Brent W.

doi:10.1002/(sici)1098-2744(200004)27:4<280::aid-mc6>3.0.co;2-l

Cited by 45 publications

(29 citation statements)

References 62 publications

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“…To this end, we found that ␣1,3 FT elevation was alone sufficient to complete sLe X synthesis and convert a non-E-selectin-binding PC-3 cell to a cell that binds E-selectin. Others have shown that ␣1,3 FTs are associated with progression of several solid cancers of the colon (34)(35)(36), breast (37), lung (38,39), liver (40), and pancreas (41,42). The question is whether PCa cells expressing abnormally high levels of ␣1,3 FTs enter BM at specific microvascular domains where E-selectin and SDF-1␣ are coexpressed constitutively and regulate leukocytic infiltration (9).…”

Section: Discussionmentioning

confidence: 99%

Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking

Barthel

Wiese

Cho

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

112

117

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How cancer cells bind to vascular surfaces and extravasate into target organs is an underappreciated, yet essential step in metastasis. We postulate that the metastatic process involves discrete adhesive interactions between circulating cancer cells and microvascular endothelial cells. Sialyl Lewis X (sLe X ) on prostate cancer (PCa) cells is thought to promote metastasis by mediating PCa cell binding to microvascular endothelial (E)-selectin. Yet, regulation of sLe X and related E-selectin ligand expression in PCa cells is a poorly understood factor in PCa metastasis. Here, we describe a glycobiological mechanism regulating E-selectin-mediated adhesion and metastatic potential of PCa cells. We demonstrate that ␣1,3 fucosyltransferases (FT) 3, 6, and 7 are markedly elevated in bone-and liver-metastatic PCa and dictate synthesis of sLe X and E-selectin ligands on metastatic PCa cells. (1). Delineating mediators of PCa metastasis to target organs may lead to identification of prognostic biomarkers and anti-metastatic therapeutics. Recently, our lab has advanced a scenario to account for organ metastasis involving PCa cell adhesion to surface receptors expressed on microvascular endothelial cells of the target organ (2-4). Bone-metastatic PCa cells are known to attach more avidly to bone marrow endothelial cells (BMEC) compared with endothelial linings of nontarget organs (5, 6). For example, human bone-metastatic PCa MDA PCa 2b (MDA) cells roll and adhere on BMEC by binding endothelial (E)-selectin, raising the possibility that PCa metastasis could be conferred through E-selectin Ϫ E-selectin ligand adhesive interactions (2-4). In fact, BM microvessels express E-selectin constitutively, while E-selectin is inducible on endothelial linings of inflamed tissues and of bronchial mucosa, a common PCa target tissue (7-9). Mechanistically, an identical traffic control axis involving selectins is well-known in the extravasation of hematopoietic progenitor cells (HPC) into BM (10, 11). HPC rolling on E-and platelet (P)-selectin is regulated by sLe X -bearing glycoforms of CD44 (HCELL), PSGL-1 and glycolipids (10,12,13). Synthesis of sLe X in HPC is catalyzed in the Golgi compartment by members of the glycosyltransferase gene family (14). The final step involves the transfer of fucose to N-acetylglucosamine at the terminal ␣2,3 sialo-lactosamine unit by ␣1,3 fucosyltransferases (FT) 3, 4, 5, 6, and/or 7, depending on cell type (13, 15). That metastatic PCa cells traverse the vasculature through 'hematopoietic mimicry' is consistent with several observations, including the association of sLe X with PCa grade and progression (2, 16, 17), cancer cell E-selectin ligand activity is a direct correlate with metastatic potential (18,19) and cancer cells can trigger E-selectin expression on liver sinusoidal microvasculature to steer circulating cancer cells to the liver (20,21). Thus, mapping glyco-metabolic pathways regulating E-selectin ligand synthesis may be vital for understanding PCa metastasis.In this report, we identify E-s...

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Section: Discussionmentioning

confidence: 99%

Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking

Barthel

Wiese

Cho

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

112

117

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“…Frequent fucosylation, the final step within the glycosylation machinery, results in glycans that are involved in various cellular processes such as cell-cell recognition, adhesion and inflammation or tumor metastasis. Fucosylation is suggested to have paramount importance in the invasion and metastatic process of cancer stem cells (CSCs) (6) neoplastic cell proliferation and hepatocellular carcinoma cell growth in vitro, respectively, and reducing FUT3/6 expression suppressed colon carcinoma cell proliferation (7,8). MicroRNAs (miRNAs) comprise a class of small noncoding RNAs implicated in post-transcriptional RNA regulation.…”

Section: Introductionmentioning

confidence: 99%

miR-493-5p attenuates the invasiveness and tumorigenicity in human breast cancer by targeting FUT4

et al. 2016

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Abstract. Breast cancer is a leading cause of cancer-related mortality among women. Altered fucosylation was found to be closely associated with tumorigenesis and metastasis of breast cancer. MicroRNAs (miRNAs) are important regulators of cell proliferation and metastasis, and aberrant miRNA expression has been observed in breast cancer. The present study aimed to evaluate the level of fucosyltransferase IV (FUT4) and miR-493-5p in breast cancer and investigate their relationship. In the present study, we demonstrated the differential expressional profiles of FUT4 and miR-493-5p in 29 clinical breast cancer tissues, matched adjacent tissue samples and two breast carcinoma cell lines (MCF-7 and MDA-MB-231). Briefly, altered expression levels of FUT4 modified the invasive activities and tumorigenicity of the MCF-7 and MDA-MB-231 cells. Further study demonstrated that miR-493-5p plays a role as a suppressor in breast cancer cell invasion and tumorigenicity. Moreover, the expression levels of miR-493-5p were inversely proportional to those of FUT4 both at the mRNA and protein levels. Luciferase reporter assays confirmed that miR-493-5p bound to the 3'-untranslated (3'-UTR) region of FUT4, and inhibited the expression of FUT4 in breast cancer cells. Taken together, our data suggest that FUT4 may have a potential role in the treatment of breast cancer, as well as miR-493-5p is a novel regulator of invasiveness and tumorigenicity of breast cancer cells through targeting FUT4. The miR-493-5p/FUT4 pathway has therapeutic potential in breast cancer. IntroductionBreast cancer is the most common invasive cancer and the second cause of cancer-related death in women (1,2). Each year more than a half a million new cases of breast cancer are diagnosed in the US and Europe (3), and in China. Breast cancer is a very heterogeneous disease. Some patients are cured by the surgical removal of the primary tumor while other patients suffer from metastasis and progression of the disease, despite adjuvant therapy. Therefore, it is essential to develop effective and safer therapeutic modalities against breast cancer.Glycosylation is one of the important steps of protein post-translational modifications, and ~50% of proteins are glycosylated (4). Protein glycosylation plays a role in a variety of cellular biological functions, such as cell-cell and cell-substrate adhesion, membrane organization, cell immunogenicity and protein targeting (5). Specific changes in the glycosylation patterns of cell surface glycoprotein have been shown to enhance the metastatic potential of tumor cells. Aberrant expression of fucosylated glycans has also been detected in various types of tumors.The fucosyltransferase (FUT) family is a group of fucosylation synthases that catalyze the transfer of L-fucose (Fuc) from an activated GDP-β-L-Fuc to various acceptor molecules such as N-acetyllactosamine. The transfer of Fuc residue from the donor substrate, GDP-Fuc, is catalyzed to the oligosaccharide acceptor in a1, a1, FUT4, FUT5, FUT6, FUT7, FUT9, FUT10 and FUT1...

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“…Furthermore, sLe X overexpressing tumors often exhibit increased transcription of ␣1, , and the increased expression of FUTs is linked to the metastatic ability of cancer cells (26,27). Consistent with ␣1,3-FUTs playing an important role in cancer, antisense-mediated decreases in FUTs, including FUT3, impair tumor growth (28) and limit metastasis (29).…”

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confidence: 97%

Metabolic Inhibition of Sialyl-Lewis X Biosynthesis by 5-Thiofucose Remodels the Cell Surface and Impairs Selectin-Mediated Cell Adhesion

Zandberg

Jayakanthan

Pinto

et al. 2012

Journal of Biological Chemistry

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Background: Sialyl-Lewis X (sLe X ) is a fucosylated oligosaccharide that plays critical roles in cell adhesion. Results: 5-thiofucose is metabolized by cells to produce a new nucleotide sugar that impairs sLe X biosynthesis and cell adhesiveness. Conclusion: 5-thiofucose blocks fucose transfer within treated cells. Significance: 5-thiofucose should be useful in further elucidating the biological roles of sLe X .

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Transfection of ?(1,3)fucosyltransferase antisense sequences impairs the proliferative and tumorigenic ability of human colon carcinoma cells

Cited by 45 publications

References 62 publications

Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking

Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking

miR-493-5p attenuates the invasiveness and tumorigenicity in human breast cancer by targeting FUT4

Metabolic Inhibition of Sialyl-Lewis X Biosynthesis by 5-Thiofucose Remodels the Cell Surface and Impairs Selectin-Mediated Cell Adhesion

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