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Inflammatory Signaling is Regulated by Fucosylation in Metastatic Breast Cancer Cells

ABSTRACT: N-linked glycosylation results in a large branched tree-like sugar structure composed of several types of individual carbohydrates being attached to a protein. Fucosylation is one specific type of glycosylation that is defined by the addition of α-L-fucose to a carrier protein. Although fucosylation has been relatively well defined as a biomarker for progression in some human cancers, for example, pancreatic and hepatocellular carcinoma, its role in breast cancer is much less well defined. A growing body of evidence indicates that levels of fucosylation correlate with breast cancer progression and contributes to metastatic disease. However, very little is known about the signaling and functional outcomes that are driven by fucosylation. We performed tandem- mass-tag (TMT) proteomics on 4T1 metastatic mammary tumor cells that were treated with a fucosylation inhibitor, 2-fluorofucose (2FF) or vehicle (DMSO) control. This analysis identified >400 proteins that were significantly increased or decreased in 2FF treated samples compared to the DMSO treated samples. We found that two proteins, Tollip and Bcl-10, were downregulated in 4T1 cells in response to 2FF treatment. Functionally, Tollip and Bcl10 signaling induce pro-inflammatory responses through activation of NF-κB, a transcription factor that is pro-tumorigenic and a prime target in human cancer. Our results show that treatment of 4T1 cells with 2FF leads to a reduction in NF-κB expression and activity through increased IκBα. This observation is consistent with a reduction in inflammatory response due to the loss of Tollip and Bcl-10 expression. Collectively, our results indicate that fucosylation is a key mediator of inflammatory signaling in metastatic breast cancer cells.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Emma Doud

LAB HEAD: Elizabeth Yeh

PROVIDER: PXD021413 | Pride | 2020-12-21

REPOSITORIES: Pride

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			Action	DRS
	010_2019_10_020_R_Yeh_GlobalLumos2_F1.raw	Raw
	010_2019_10_020_R_Yeh_GlobalLumos2_F2.raw	Raw
	010_2019_10_020_R_Yeh_GlobalLumos2_F3.raw	Raw
	010_2019_10_020_R_Yeh_GlobalLumos2_F4.raw	Raw
	010_2019_10_020_R_Yeh_GlobalLumos2_F5.raw	Raw

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Project description:Preclinical studies of primary cancer cells are always done after tumors are removed from patients or animals at ambient atmospheric oxygen (O2, ~21%). However, O2 concentrations in organs are in the ~3-10% range, with most tumors in an hypoxic or 1-2% O2 environment in vivo. Although effects of O2 tension on tumor cell characteristics in vitro have been studied, these studies are done only after tumors are first collected and processed in ambient air. Similarly, sensitivity of primary cancer cells to anti-cancer agents is routinely examined at ambient O2. Here, using both mouse models and human cancers, we demonstrate that tumors collected, processed and propagated at physiologic (physioxia) O2 compared to ambient air display very distinct differences in key signaling networks including Lgr5/Wnt, Yap, and Nrf2/Keap1, nuclear reactive oxygen species levels, alternative splicing, and sensitivity to several targeted therapies including PIK3CAalpha-specific and EGFR inhibitors. Significance: Extra-physiologic oxygen shock/stress (EPHOSS), as noted in cells collected/processed under ambient air, has been demonstrated to have significant impact on numbers and engrafting ability of hematopoietic stem cells. We report deleterious effects of EPHOSS on cancer cell behavior and EPHOSS-mediated effects on cancer cells give misleading information on signaling pathway activation that could severely impact the relevance of these findings. Cancer cells under EPHOSS show higher proliferation rate compared to cells under physioxia and thus are sensitive to anti-proliferative agents. Thus, drugs that show effectiveness on cancer cells collected in ambient air and subjected to EPHOSS may not be effective or as relevant in vivo, results that could partially explain the limited clinical translation of laboratory findings. Evaluating cell signaling and effects of drugs on cancer cells under physiologic O2 prior to in vivo studies could substantially reduce cost and aid in drug discovery relevant to the actual physioxia/pathological status of the tumor cells in vivo.

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Inflammatory Signaling is Regulated by Fucosylation in Metastatic Breast Cancer Cells

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