Browsing by Subject "N-glycosylation"

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    Metabolic Links to Socioeconomic Stresses Uniquely Affecting Ancestry in Normal Breast Tissue at Risk for Breast Cancer
    (Frontiers Media, 2022-06-27) Rujchanarong, Denys; Scott, Danielle; Park, Yeonhee; Brown, Sean; Mehta, Anand S.; Drake, Richard; Sandusky, George E.; Nakshatri, Harikrishna; Angel, Peggi M.; Pathology and Laboratory Medicine, School of Medicine
    A primary difference between black women (BW) and white women (WW) diagnosed with breast cancer is aggressiveness of the tumor. Black women have higher mortalities with similar incidence of breast cancer compared to other race/ethnicities, and they are diagnosed at a younger age with more advanced tumors with double the rate of lethal, triple negative breast cancers. One hypothesis is that chronic social and economic stressors result in ancestry-dependent molecular responses that create a tumor permissive tissue microenvironment in normal breast tissue. Altered regulation of N-glycosylation of proteins, a glucose metabolism-linked post-translational modification attached to an asparagine (N) residue, has been associated with two strong independent risk factors for breast cancer: increased breast density and body mass index (BMI). Interestingly, high body mass index (BMI) levels have been reported to associate with increases of cancer-associated N-glycan signatures. In this study, we used matrix assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) to investigate molecular pattern changes of N-glycosylation in ancestry defined normal breast tissue from BW and WW with significant 5-year risk of breast cancer by Gail score. N-glycosylation was tested against social stressors including marital status, single, education, economic status (income), personal reproductive history, the risk factors BMI and age. Normal breast tissue microarrays from the Susan G. Komen tissue bank (BW=43; WW= 43) were used to evaluate glycosylation against socioeconomic stress and risk factors. One specific N-glycan (2158 m/z) appeared dependent on ancestry with high sensitivity and specificity (AUC 0.77, Brown/Wilson p-value<0.0001). Application of a linear regression model with ancestry as group variable and socioeconomic covariates as predictors identified a specific N-glycan signature associated with different socioeconomic stresses. For WW, household income was strongly associated to certain N-glycans, while for BW, marital status (married and single) was strongly associated with the same N-glycan signature. Current work focuses on understanding if combined N-glycan biosignatures can further help understand normal breast tissue at risk. This study lays the foundation for understanding the complexities linking socioeconomic stresses and molecular factors to their role in ancestry dependent breast cancer risk.
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    NF-κB Signaling Is Regulated by Fucosylation in Metastatic Breast Cancer Cells
    (MDPI, 2020-12-12) Doud, Emma H.; Shetty, Trupti; Abt, Melissa; Mosley, Amber L.; Corson, Timothy W.; Mehta, Anand; Yeh, Elizabeth S.; Biochemistry and Molecular Biology, School of Medicine
    A growing body of evidence indicates that the levels of fucosylation correlate with breast cancer progression and contribute to metastatic disease. However, very little is known about the signaling and functional outcomes that are driven by fucosylation. We performed a global proteomic analysis of 4T1 metastatic mammary tumor cells in the presence and absence of a fucosylation inhibitor, 2-fluorofucose (2FF). Of significant interest, pathway analysis based on our results revealed a reduction in the NF-κB and TNF signaling pathways, which regulate the inflammatory response. NF-κB is a transcription factor that is pro-tumorigenic and a prime target in human cancer. We validated our results, confirming that treatment of 4T1 cells with 2FF led to a decrease in NF-κB activity through increased IκBα. Based on these observations, we conclude that fucosylation is an important post-translational modification that governs breast cancer cell signaling.
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    The oligosaccharyltransferase complex is an essential component of multiple myeloma plasma cells
    (Elsevier, 2025-03-08) Nguyen, Hong Phuong; Liu, Enze; Le, Anh Quynh; Lamsal, Mahesh; Misra, Jagannath; Srivastava, Sankalp; Hemavathy, Harikrishnan; Kapur, Reuben; Zaid, Mohammad Abu; Abonour, Rafat; Zhang, Ji; Wek, Ronald C.; Walker, Brian A.; Tran, Ngoc Tung; Pediatrics, School of Medicine
    Multiple myeloma (MM) is an incurable malignancy characterized by mutated plasma cell clonal expansion in the bone marrow, leading to severe clinical symptoms. Thus, identifying new therapeutic targets for MM is crucial. We identified the oligosaccharyltransferase (OST) complex as a novel vulnerability in MM cells. Elevated expression of this complex is associated with relapsed, high-risk MM, and poor prognosis. Disrupting the OST complex suppressed MM cell growth, induced cell-cycle arrest, and apoptosis. Combined inhibition with bortezomib synergistically eliminated MM cells in vitro and in vivo, via suppressing genes related to bortezomib-resistant phenotypes. Mechanistically, OST complex disruption downregulated MM pathological pathways (mTORC1 pathway, glycolysis, MYC targets, and cell cycle) and induced TRAIL-mediated apoptosis. Notably, MYC translation was robustly suppressed upon inhibiting the OST complex. Collectively, the OST complex presents a novel target for MM treatment, and combining its inhibition with bortezomib offers a promising approach for relapsed MM patients.