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The Journal of Antibiotics Dec 2019Tunicamycins are nucleoside natural products and show antibacterial, antiviral and antitumor activities, which are attributed to their inhibition of enzymatic reactions... (Review)
Review
Tunicamycins are nucleoside natural products and show antibacterial, antiviral and antitumor activities, which are attributed to their inhibition of enzymatic reactions between polyisoprenyl phosphate and UDP-GlcNAc or UDP-MurNAc-pentapeptide. Because of their various intriguing biological activities, tunicamycins have potential as therapeutic agents for infectious diseases or cancers. Structurally, tunicamycins have a unique structure composed of an undecodialdose skeleton, a lipid chain and a GlcNAc fragment linked by a 1,1-β,α-trehalose-type glycosidic bond. In this mini review, we summarize the total chemical syntheses and biosynthetic studies of tunicamycins.
Topics: Multigene Family; Streptomyces; Tunicamycin
PubMed: 31235901
DOI: 10.1038/s41429-019-0200-1 -
Journal of Experimental & Clinical... Nov 2018Multidrug resistance remains a major obstacle to successful treatment for patients with gastric cancer (GC). Recently, glycosylation has been demonstrated to play a...
BACKGROUND
Multidrug resistance remains a major obstacle to successful treatment for patients with gastric cancer (GC). Recently, glycosylation has been demonstrated to play a vital role in the acquisition of multidrug resistance. As a potent inhibitor of glycosylation, tunicamycin (Tu) has shown marked antitumor activities in various cancers. In the present study, we attempted to determine the exact effect of Tu on the chemoresistance of GC.
METHODS
The cytotoxic effects of drugs on GC cells were evaluated by cell viability assays, and apoptosis was detected by flow cytometry. PCR, western blot analysis, immunofluorescence staining and canonical inhibitors were employed to identify the underlying mechanisms of the specific effects of Tu on multidrug-resistant (MDR) GC cells.
RESULTS
For the first time, we found that MDR GC cells were more sensitive to Tu-induced cell death than the parental cells and that the increased sensitivity might correlate with basal endoplasmic reticulum (ER) stress. In addition, Tu dramatically increased chemotherapy-induced apoptosis by evoking ER stress in GC cells, particularly MDR cells. Further study indicated that these effects were highly dependent on glycosylation inhibition by Tu, rather than its role as a canonical ER stress inducer. Besides, autophagy was markedly triggered by Tu, and blocking autophagy enhanced the combined effects of Tu and chemotherapy on MDR GC cells.
CONCLUSIONS
Our results suggest that tumor-targeted glycosylation inhibition may be a feasible strategy to reverse chemoresistance in GC patients.
Topics: Anti-Bacterial Agents; Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Endoplasmic Reticulum Stress; Glycosylation; Humans; Stomach Neoplasms; Tunicamycin
PubMed: 30413206
DOI: 10.1186/s13046-018-0935-8 -
Autophagy Oct 2014Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this...
Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.
Topics: Animals; Apoptosis; Brain Ischemia; Endoplasmic Reticulum Stress; Glucose; Mice; Mitophagy; Neuroprotective Agents; Oxygen; Reperfusion Injury; Signal Transduction; Thapsigargin; Tunicamycin; Ubiquitin-Protein Ligases
PubMed: 25126734
DOI: 10.4161/auto.32136 -
Molecules and Cells Jun 2023N-glycosylation, a common post-translational modification, is widely acknowledged to have a significant effect on protein stability and folding. N-glycosylation is a... (Review)
Review
N-glycosylation, a common post-translational modification, is widely acknowledged to have a significant effect on protein stability and folding. N-glycosylation is a complex process that occurs in the endoplasmic reticulum (ER) and requires the participation of multiple enzymes. GlcNAc-1-P-transferase (GPT) is essential for initiating N-glycosylation in the ER. Tunicamycin is a natural product that inhibits N-glycosylation and produces ER stress, and thus it is utilized in research. The molecular mechanism by which GPT triggers N-glycosylation is discussed in this review based on the GPT structure. Based on the structure of the GPT-tunicamycin complex, we also discuss how tunicamycin reduces GPT activity, which prevents N-glycosylation. This review will be highly useful for understanding the role of GPT in the N-glycosylation of proteins, as well as presents a potential for considering tunicamycin as an antibiotic treatment.
Topics: Glycosylation; Tunicamycin; Protein Processing, Post-Translational; Endoplasmic Reticulum Stress; Endoplasmic Reticulum
PubMed: 37190766
DOI: 10.14348/molcells.2023.0001 -
MBio Aug 2021How cells exposed to one stress are later able to better survive other types of stress is not well understood. In eukaryotic organisms, physiological and pathological...
How cells exposed to one stress are later able to better survive other types of stress is not well understood. In eukaryotic organisms, physiological and pathological stresses can disturb endoplasmic reticulum (ER) function, resulting in "ER stress." Here, we found that exposure to tunicamycin, an inducer of ER stress, resulted in the acquisition of a specific aneuploidy, chromosome 2 trisomy (Chr2x3), in Candida albicans. Importantly, the resulting aneuploidy also conferred cross-tolerance to caspofungin, a first-line echinocandin antifungal, as well as to hydroxyurea, a common chemotherapeutic agent. Exposure to a range of tunicamycin concentrations induced similar ER stress responses. Extra copies of one Chr2 gene, , affected both tunicamycin and caspofungin tolerance, while at least 3 genes on chromosome 2 (, , and ) affected only tunicamycin and not caspofungin responses. Other Chr2 genes ( and ) affected hydroxyurea tolerance but neither tunicamycin nor caspofungin tolerance. Deletion of components of the protein kinase C (PKC) or calcineurin pathways affected tolerance to both tunicamycin and caspofungin, supporting the idea that the ER stress response and echinocandin tolerance are regulated by overlapping stress response pathways. Thus, antifungal drug tolerance can arise rapidly via ER stress-induced aneuploidy. Candida albicans is a prevalent human fungal commensal and also a pathogen that causes life-threatening systemic infections. Treatment failures are frequent because few therapeutic antifungal drug classes are available and because drug resistance and tolerance limit drug efficacy. We found that C. albicans rapidly overcomes the cellular stress induced by the drug tunicamycin by duplicating chromosome 2. Also, chromosome 2 duplication confers tolerance not only to tunicamycin but also to the following two unrelated drugs: caspofungin, an antifungal drug, and hydroxyurea, a chemotherapeutic. Cross tolerance to the three drugs involves different sets of genes, although some genetic pathways affect the tolerance to two of these three drugs. This work highlights a serious concern, namely, that changes in whole chromosome copy number can occur in response to one type of stress, and yet, they may facilitate the emergence of tolerance to multiple drugs, including the few antifungal drug classes available to treat infections.
Topics: Aneuploidy; Antifungal Agents; Candida albicans; Drug Resistance, Fungal; Stress, Physiological; Tunicamycin
PubMed: 34465026
DOI: 10.1128/mBio.02272-21 -
Biotechnic & Histochemistry : Official... Oct 2021Because the small intestine is exposed to variety of foreign substances, it participates in host immune response. We investigated whether the expression levels of...
Because the small intestine is exposed to variety of foreign substances, it participates in host immune response. We investigated whether the expression levels of intestinal MAdCAM-1, PECAM-1 (CD31) and CAV-1 are affected by endoplasmic reticulum (ER) stress following brief treatment with tunicamycin (TN). We administered a single dose of TN intraperitoneally. Twenty-four hours later, MAdCAM-1, PECAM-1 and CAV-1 expression levels in Peyer's patches and villi were examined using immunohistochemistry (IHC), immunofluorescence (IF) and western blotting. Immunostaining of MAdCAM-1 and CAV-1 in control and TN treated Peyer's patches and villi exhibited similar staining patterns. The immunoreactivity of PECAM-1 was similar for the control and TN treated Payer's patches, whereas staining was decreased significantly in TN treated villi. Our findings suggest that short term TN treatment did not affect leukocyte movement to lymphoid compartments of the small intestine, but it altered villus architecture due to decreased PECAM-1 expression.
Topics: Endoplasmic Reticulum Stress; Intestinal Mucosa; Intestine, Small; Peyer's Patches; Tunicamycin
PubMed: 32962446
DOI: 10.1080/10520295.2020.1823481 -
Advances in Experimental Medicine and... 2000Bovine adrenal medulla microvascular endothelial cells used in this study undergo cellular proliferation and differentiation upon culturing in vitro as observed both by... (Review)
Review
Bovine adrenal medulla microvascular endothelial cells used in this study undergo cellular proliferation and differentiation upon culturing in vitro as observed both by light and scanning electron microscopy. Cells also respond to the growth promoting activity of serum and basic fibroblast growth factor (FGF2). Flow cytometric analysis of a synchronized culture established that cells take 68 hours to complete one cell cycle spending 36 hours in the G1 phase, 8 hours in the S phase, and 24 hours in the G2 + M phase when cultured in EMEM containing 2% heat-inactivated fetal bovine serum (FBS). At 10% serum, or in the presence of FGF2 (10 ng/ml-100 ng/ml) length of the cell cycle is reduced to 56 hours due to shortening of the G1 phase by 12 hours. Tunicamycin (a glucosamine-containing pyrimidine nucleotide), and an inhibitor of glucosaminyl-1-phosphate (GlcNAc 1-P) transferase, the first step of Glc3Man9GlcNAc2-PP-Dol (OSL) biosynthesis is found to inhibit the endothelial cells proliferation by inducing apoptosis as observed by flow cytometry and DNA laddering. Cell shrinkage, compaction of nuclei, membrane fragmentation, etc., typical of apoptotic response are frequently seen by light microscopy in the presence of tunicamycin. Scanning electron microscopy also exhibited a considerable amount of cell surface blebbing. Accumulation of an immunopositive cell specific asparagine-linked (N-linked) glycoprotein, Factor VIII:C in the absence of Glc3Man9GlcNAc2-PP-Dol in tunicamycin treated cells has been proposed as an apoptotic triggering mechanism under the current experimental conditions.
Topics: Animals; Apoptosis; Asparagine; Capillaries; Cattle; Cell Division; Cells, Cultured; Clone Cells; Endothelium, Vascular; Factor VIII; Glycoproteins; Mannosyltransferases; Neovascularization, Pathologic; Polyisoprenyl Phosphate Sugars; Tunicamycin
PubMed: 10949666
DOI: No ID Found -
Natural Product Research Jun 2020Tunicamycin E (), featuring a methyl substitution at C-10', was isolated from marine-derived SCSIO S15077 originated from the South China Sea sediment together with six...
Tunicamycin E (), featuring a methyl substitution at C-10', was isolated from marine-derived SCSIO S15077 originated from the South China Sea sediment together with six known compounds, tunicamycin B (), tunicamycin X (), tunicamycin A (), streptovirudin D (), tunicamycin C (), and tunicamycin C (). The structure of compound was elucidated by detailed spectroscopic data analyses. All the compounds exhibited strong to moderate antibacterial activity against Gram-positive bacteria BT01 and W102 with MIC values ranging from 0.008 to 2 μg/mL. Moreover, compounds - exhibited moderate antifungal activity against ATCC 96901 and CMCC (F) 98001 with MIC values ranging from 2 to 32 μg/mL. This is the first report that tunicamycins exhibit antimicrobial activities against , CMCC (F) 98001 and a fluconazole resistant strain ATCC 96901.
Topics: Anti-Infective Agents; Bacillus thuringiensis; Candida albicans; China; Microbial Sensitivity Tests; Molecular Structure; Streptomyces; Tunicamycin
PubMed: 30445836
DOI: 10.1080/14786419.2018.1493736 -
Journal of Healthcare Engineering 2021Triple negative breast cancer (TNBC) has significantly threatened human health. Many aspects of TNBC are closely related to Wnt/-catenin pathway, and cell apoptosis...
Triple negative breast cancer (TNBC) has significantly threatened human health. Many aspects of TNBC are closely related to Wnt/-catenin pathway, and cell apoptosis induced by endoplasmic reticulum stress (ER stress) in TNBC may act as a potential target of non-chemotherapy treatment. However, how ER stress interacts with this pathway in TNBC has not yet been understood. Here, the tunicamycin and LiCl have been applied to MDA-MB-231. The related proteins' expression was measured by western blotting. Moreover, acridine orange/ethidium bromide (AO/EB) staining was applied to test the apoptosis degree of the cells, and cell viability was tested by MTT experiment. Then, we found the ER stress and apoptosis degree of MDA-MB-231 were induced after treatment with tunicamycin. Besides, tunicamycin dose dependently inhibited both Wnt/-catenin pathway and cells viability. Licl, an activator of Wnt/-catenin signaling pathway, could significantly inhibit cell apoptosis. In conclusion, our study found that the activation of ER stress could promote the MDA-MB-231 apoptosis by repressing Wnt/-catenin pathway, which provides some promising prospects and basic mechanism to the further research.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Endoplasmic Reticulum Stress; Humans; Triple Negative Breast Neoplasms; Tunicamycin; Wnt Signaling Pathway
PubMed: 34336161
DOI: 10.1155/2021/6394514 -
Cells Feb 2024The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one... (Review)
Review
The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleoside antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with the inhibition of cancer cell growth and progression of tumors. Like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Consequently, stress is induced in the endoplasmic reticulum (ER) that promotes apoptosis. TM can thus be considered a potent antitumor drug in various cancers and may promote chemosensitivity. However, its lack of cell-type-specific cytotoxicity impedes its anticancer efficacy. In this review, we focus on recent advances in our understanding of the benefits and pitfalls of TM therapies in various cancers, including breast, colon, and pancreatic cancers, and discuss the mechanisms identified by which TM functions. Finally, we discuss the potential use of nano-based drug delivery systems to overcome non-specific toxicity and enhance the therapeutic efficacy of TM as a targeted therapy.
Topics: Humans; Female; Tunicamycin; Endoplasmic Reticulum Stress; Cell Line, Tumor; Glycosylation; Breast Neoplasms
PubMed: 38474359
DOI: 10.3390/cells13050395