Dataset Information

Role of fucosyltransferase IV in epithelial-mesenchymal transition in breast cancer cells.

ABSTRACT: Epithelial-mesenchymal transition (EMT) is a crucial step in tumor progression and has an important role during cancer invasion and metastasis. Although fucosyltransferase IV (FUT4) has been implicated in the modulation of cell migration, invasion and cancer metastasis, its role during EMT is unclear. This study explores the molecular mechanisms of the involvement of FUT4 in EMT in breast cancer cells. Breast cancer cell lines display increased expression of FUT4, which is accompanied by enhanced appearance of the mesenchymal phenotype and which can be reversed by knockdown of endogenous FUT4. Moreover, FUT4 induced activation of phosphatidylinositol 3-kinase (PI3K)/Akt, and inactivation of GSK3? and nuclear translocation of NF-?B, resulting in increased Snail and MMP-9 expression and greater cell motility. Taken together, these findings indicate that FUT4 has a role in EMT through activation of the PI3K/Akt and NF-?B signaling systems, which induce the key mediators Snail and MMP-9 and facilitate the acquisition of a mesenchymal phenotype. Our findings support the possibility that FUT4 is a novel regulator of EMT in breast cancer cells and a promising target for cancer therapy.

SUBMITTER: Yang X

PROVIDER: S-EPMC3730415 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Role of fucosyltransferase IV in epithelial-mesenchymal transition in breast cancer cells.

Yang X X Liu S S Yan Q Q

Cell death & disease 20130725

Epithelial-mesenchymal transition (EMT) is a crucial step in tumor progression and has an important role during cancer invasion and metastasis. Although fucosyltransferase IV (FUT4) has been implicated in the modulation of cell migration, invasion and cancer metastasis, its role during EMT is unclear. This study explores the molecular mechanisms of the involvement of FUT4 in EMT in breast cancer cells. Breast cancer cell lines display increased expression of FUT4, which is accompanied by enhance ...[more]

PMID: 23887626

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Project description:Modern treatment strategies provide better overall survival in cancer patients, primarily by controlling tumor growth. However, off-target and systemic toxicity, tumor recurrence, and resistance to therapy are still inadvertent hurdles in current treatment regimens. Similarly, metastasis is another deadly threat to patients suffering from cancer. This has created an urgent demand to come up with new drugs having anti-metastatic potential and minimum side effects. Thus, this study was aimed at exploring the anti-proliferative and anti-metastatic potential of colocynth medicinal plant. Results from MTT assay, morphological visualization of cells and scratch assay indicated a role of ethanol and acetone extracts of fruit pulp of the colocynth plant in inhibiting cell viability, enhancing cell cytotoxicity and preventing cell migration in various cancer cell types, including breast cancer cell lines MCF-7 and MDA-MB-231, and cervical cancer cell line SiHa, subsequently having a low cytotoxic effect on mononuclear PBMC and macrophage J774A cells. Our study in metastatic MDA-MB-231 cells showed that both ethanol and acetone pulp extracts decreased transcript levels of the anti-apoptotic genes BCL2 and BCLXL, and a reverse effect was observed for the pro-apoptotic genes BAX and caspase 3. Additionally, enhanced caspase 3 activity and downregulated BCL2 protein were seen, indicating a role of these extracts in inducing apoptotic activity. Moreover, MDA-MB-231 cells treated with both these extracts demonstrated up-regulation of the epithelial gene keratin 19 and down-regulation of the mesenchymal genes, vimentin, N-cadherin, Zeb1 and Zeb2 compared to control, suggesting a suppressive impact of these extracts in epithelial to mesenchymal transition (EMT). In addition, these extracts inhibited colony and sphere formation with simultaneous reduction in the transcript level of the stemness associated genes, BMI-1 and CD44. It was also found that both the plant extracts exhibited synergistic potential with the chemotherapeutic drug doxorubicin to inhibit cancer viability. Furthermore, GC-MS/MS analysis revealed the presence of certain novel compounds in both the extracts that are responsible for the anti-cancer role of the extracts. Overall, the results of this report suggest, for the first time, that colocynth fruit pulp extracts may block the proliferative as well as metastatic activity of breast cancer cells.

Project description:We propose the hypothesis that loss of estrogen receptor function which leads to endocrine resistance in breast cancer, also results in trans-differentiation from an epithelial to a mesenchymal phenotype that is responsible for increased aggressiveness and metastatic propensity. siRNA mediated silencing of the estrogen receptor in MCF7 breast cancer cells resulted in estrogen/tamoxifen resistant cells (pII) with altered morphology, increased motility with rearrangement and switch from a keratin/actin to a vimentin based cytoskeleton, and ability to invade simulated components of the extracellular matrix. Phenotypic profiling using an Affymetrix Human Genome U133 plus 2.0 GeneChip indicated geometric fold changes ≥ 3 in approximately 2500 identifiable unique sequences, with about 1270 of these being up-regulated in pII cells. Changes were associated with genes whose products are involved in cell motility, loss of cellular adhesion and interaction with the extracellular matrix. Selective analysis of the data also showed a shift from luminal to basal cell markers and increased expression of a wide spectrum of genes normally associated with mesenchymal characteristics, with consequent loss of epithelial specific markers. Over-expression of several peptide growth factors and their receptors are indicative of an increased contribution to the higher proliferative rates of pII cells as well as aiding their potential for metastatic activity. Signalling molecules that have been identified as key transcriptional drivers of epithelial to mesenchymal transition were also found to be elevated in pII cells. These data support our hypothesis that induced loss of estrogen receptor in previously estrogen/antiestrogen sensitive cells is a trigger for the concomitant loss of endocrine dependence and onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type. Inhibition of this transition through targeting of specific mediators may offer a useful supplementary strategy to circumvent the effects of loss of endocrine sensitivity.

Dataset Information

Role of fucosyltransferase IV in epithelial-mesenchymal transition in breast cancer cells.

Publications

Role of fucosyltransferase IV in epithelial-mesenchymal transition in breast cancer cells.

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