Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

Wagner, Klaus W.; Punnoose, Elizabeth A.; Januario, Thomas; Lawrence, David A.; Pitti, Robert M.; Lancaster, Kate; Lee, Dori; Goetz, Melissa von; Yee, Sharon; Tótpál, Klára; Huw, Ling; Katta, Viswanatham; Cavet, Guy; Hymowitz, S.G.; Amler, Lukas C.; Ashkenazi, Avi

doi:10.1038/nm1627

Cited by 544 publications

(537 citation statements)

References 35 publications

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“…Four invasive lobular carcinomas were evaluated and three (75%) were GalNAc-T14 negative, whereas one was immunostained weakly. The result is in agreement with GalNAc-T14 expression revealed by real-time quantitative PCR in several types of breast carcinomas tissues [36]. …”

Section: Resultssupporting

confidence: 86%

“…The expression of GalNAc-T14 mRNA was analyzed in normal and malignant tissue from breast, skin, lung, pancreas, ovary, endometrium, bladder and lymphoid cancers. A subset of tumor samples, ranging from 10% in lobular breast cancer to 30% in lung cancer and diffuse large B-cell lymphoma, showed GalNAc-T14 mRNA overexpression [36]. Under thees circumstances, we hypothesize the expression of GalNAc-T14 may be a useful biomarker for breast cancer by immunohistochemistry.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of the mRNA transcript which encodes the O-glycosylation initiating enzyme GalNAc-T14, was markedly higher in carcinoma tissue of lung, breast, ovary, endometrium, bladder versus normal tissue of those [36]. The members of the GalNAc-Tases family, GalNAc-T1, -T2, -T3, -T4 and -T6 were detected in a range of breast cell lines by immunocytochemistry with confocal scanning laser microscopy.…”

Section: Discussionmentioning

confidence: 99%

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N-Acetylgalactosaminyltransferase-14 as a potential biomarker for breast cancer by immunohistochemistry

Guo

Wang

et al. 2010

BMC Cancer

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BackgroundThe post-translational modification of proteins, including glycosylation, differs between normal and tumor cells. The UDP-N-acetyl-D-galactosamine polypeptide N-acetylgalactosaminyltransferases (GalNAc-Tases) family of enzymes regulates the initial steps of mucin O-glycosylation and is responsible for the altered glycosylation state observed in cancer cells. Recently it was found that GalNAc-T14 mRNA is heterogeneously expressed in breast carcinomas compared to normal tissue, however the expression profile of GalNAc-T14 protein in breast carcinomas compared to normal tissue is still unknown. In this study, we assessed the expression profile of GalNAc-T14 protein in malignant and non-malignant breast tissues by immunohistochemistry to evaluate whether GalNAc-T14 might be a potential biomarker for breast cancer.MethodsIn formalin-fixed tissues, the expression level of GalNAc-T14 protein was evaluated by immunohistochemistry assay in breast tissues. Expression profiles were assessed in normal tissues, benign fibroadenomas and several types of carcinomas.ResultsOur results showed that GalNAc-T14 was heterogeneously expressed in breast carcinomas compared to non-malignant tissue. GalNAc-T14 expression was observed in 47/56 (83.9%) carcinoma samples, 7/48 (14.6%) non-malignant breast tissue samples. GalNAc-T14 expression level was associated with histological grade. For this enzyme a significant association with invasive ductal type, mucinous adenocarcinoma and ductal carcinoma in situ (DCIS) type was found.ConclusionOur results provide evidence that GalNAc-T14 may be a potential biomarker for breast cancer by immunohistochemistry. GalNAc-T14 expression level was associated with histological grade. GalNAc-T14 expression can provide new insights about breast cancer glycobiology.

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Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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N-Acetylgalactosaminyltransferase-14 as a potential biomarker for breast cancer by immunohistochemistry

Guo

Wang

et al. 2010

BMC Cancer

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“…Additionally, changing density of reacting carbohydrate ligands may be accompanied with altering size and orientation of carbohydrates and the dimensional relationship between ligands and CBPs,25, 29 which will affect the accessibility of the carbohydrate ligands and finally promote or suppress the related processes. Moreover, alterations in protein glycosylations have been reported to perturb the structure and function of glycoproteins by changing their oligomerization, turnover, conformation, and interactions with other molecules 30, 31, 32, 33. Some computational models have also predicted that bulky glycoproteins favor transmembrane receptor organization (e.g., carbohydrate‐mediated integrin clustering would facilitate the assembly of mature adhesion complexes and enhance growth factor signaling) 34, 35.…”

Section: Resultsmentioning

confidence: 99%

Variation in Carbohydrates between Cancer and Normal Cell Membranes Revealed by Super‐Resolution Fluorescence Imaging

et al. 2016

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Carbohydrate alterations on cell membranes are associated with various cancer processes, including tumorigenesis, malignant transformation, and tumor dissemination. However, variations in the distributions of cancer‐associated carbohydrates are unclear at the molecular level. Herein, direct stochastic optical reconstruction microscopy is used to reveal that seven major types of carbohydrates tended to form obvious clusters on cancer cell membranes compared with normal cell membranes (both cultured and primary cells), and most types of carbohydrates present a similar distributed characteristic on various cancer cells (e.g., HeLa and Os‐Rc‐2 cells). Significantly, sialic acid is found to distribute in larger‐sized clusters with a higher cluster coverage percentage on various cancer cells than normal cells. These findings on the aberrant distributions of cancer‐associated carbohydrates can potentially serve as novel diagnostic and therapeutic targets, as well as making a contribution to clarify how abnormal glycosylations of membrane glycoconjugates participate in tumorigenesis and metastasis.

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“…The internal strategy of genetic and epigenetic regulation during progression of cancer, based on Darwinian selection, is to suppress death signaling at all levels, including downregulation of transcription of death receptor genes, inhibition of receptor's modification, suppression of translocation of death receptors to the cell surface, elevated mutagenesis in the death domains, the dramatic STAT3/NF-κB-dependent upregulation of expression of apoptotic inhibitors and upregulation of surface expression of decoy receptors, DcR1 and DcR2 [9,34,[43][44][45]. Investigation of natural and pharmacological inhibitors of STAT3 and NF-κB represents a significant and novel tactics in the struggle against cancer.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

Cited by 544 publications

References 35 publications

N-Acetylgalactosaminyltransferase-14 as a potential biomarker for breast cancer by immunohistochemistry

N-Acetylgalactosaminyltransferase-14 as a potential biomarker for breast cancer by immunohistochemistry

Variation in Carbohydrates between Cancer and Normal Cell Membranes Revealed by Super‐Resolution Fluorescence Imaging

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

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