Hyperglycemia exacerbates colon cancer malignancy through hexosamine biosynthetic pathway

Vasconcelos-dos-Santos, Andréia; Loponte, Hector F. B. R.; Mantuano, Natália Rodrigues; Oliveira, Isadora A.; Paula, Iron F. De; Teixeira, Leonardo K.; de-Freitas-Junior, Júlio Cesar Madureira; Gondim, Kátia C.; Heise, Norton; Mohana‐Borges, Ronaldo; Morgado‐Díaz, José Andrés; Dias, Wagner B.; Todeschini, Adriane R.

doi:10.1038/oncsis.2017.2

Cited by 85 publications

(80 citation statements)

References 92 publications

(105 reference statements)

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“…The GFAT expression was correlated with worse patient survival in breast, pancreatic, and liver cancer. Furthermore, GFAT was demonstrated to drive malignant cell growth in vitro and in vivo and to promote migration and invasion of various cancer cells in vitro . However, opposite to the above trend, GFAT1 was shown to exhibit tumor suppressive activities in gastric cancer, suggesting possible cell‐type specific functions of the enzyme in cancer biology.…”

Section: Discussionmentioning

confidence: 98%

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Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Chen

Kieu

Saxton

et al. 2019

Molecular Carcinogenesis

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Platinum anticancer agents are essential components in chemotherapeutic regimens for non–small‐cell lung cancer (NSCLC) patients ineligible for targeted therapy. However, platinum‐based regimens have reached a plateau of therapeutic efficacy; therefore, it is critical to implement novel approaches for improvement. The hexosamine biosynthesis pathway (HBP), which produces amino‐sugar N‐acetyl‐glucosamine for protein glycosylation, is important for protein function and cell survival. Here we show a beneficial effect by the combination of cisplatin with HBP inhibition. Expression of glutamine:fructose‐6‐phosphate amidotransferase (GFAT), the rate‐limiting enzyme of HBP, was increased in NSCLC cell lines and tissues. Pharmacological inhibition of GFAT activity or knockdown of GFATimpaired cell proliferation and exerted synergistic or additive cytotoxicity to the cells treated with cisplatin. Mechanistically, GFAT positively regulated the expression of binding immunoglobulin protein (BiP; also known as glucose‐regulated protein 78, GRP78), an endoplasmic reticulum chaperone involved in unfolded protein response (UPR). Suppressing GFAT activity resulted in downregulation of BiP that activated inositol‐requiring enzyme 1α, a sensor protein of UPR, and exacerbated cisplatin‐induced cell apoptosis. These data identify GFAT‐mediated HBP as a target for improving platinum‐based chemotherapy for NSCLC.

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Section: Discussionmentioning

confidence: 98%

“…In recent years, accumulating evidence revealed a tumor‐promoting function of GFAT. Increased expression of GFAT was detected in human breast, prostate, colon, pancreatic, and bile duct cancer tissues. The GFAT expression was correlated with worse patient survival in breast, pancreatic, and liver cancer.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Chen

Kieu

Saxton

et al. 2019

Molecular Carcinogenesis

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“…Tumor cells up-regulate GFAT2 expression (Simpson et al, 2012). Recently, our group showed that GFAT activity plays an important role in the tumorigenesis of the colon cancer (Vasconcelos-Dos-Santos et al, 2017). Recently, our group showed that GFAT activity plays an important role in the tumorigenesis of the colon cancer (Vasconcelos-Dos-Santos et al, 2017).…”

Section: Hbp Is Emerging As An Important Branch Of Glc Metabolism Inmentioning

confidence: 92%

“…In fact, high levels of GFAT can predict poor prognosis in patients with breast , pancreatic (Guillaumond et al, 2013;Yang et al, 2016), and colon cancer (Vasconcelos-Dos-Santos et al, 2017). In fact, high levels of GFAT can predict poor prognosis in patients with breast , pancreatic (Guillaumond et al, 2013;Yang et al, 2016), and colon cancer (Vasconcelos-Dos-Santos et al, 2017).…”

Section: Hbp Is Emerging As An Important Branch Of Glc Metabolism Inmentioning

confidence: 99%

Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

Carvalho-Cruz

Alisson-Silva

Todeschini

et al. 2017

Developmental Dynamics

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Epithelial to mesenchymal transition (EMT) is a developmental program reactivated by tumor cells that leads to the switch from epithelial to mesenchymal phenotype. During EMT, cells are transcriptionally regulated to decrease E-cadherin expression while expressing mesenchymal markers such as vimentin, fibronectin, and N-cadherin. Growing body of evidences suggest that cells engaged in EMT undergo a metabolic reprograming process, redirecting glucose flux toward hexosamine biosynthesis pathway (HBP), which fuels aberrant glycosylation patterns that are extensively observed in cancer cells. HBP depends on nutrient availability to produce its end product UDP-GlcNAc, and for this reason is considered a metabolic sensor pathway. UDP-GlcNAc is the substrate used for the synthesis of major types of glycosylation, including O-GlcNAc and cell surface glycans. In general, the rate limiting enzyme of HBP, GFAT, is overexpressed in many cancer types that present EMT features as well as aberrant glycosylation. Moreover, altered levels of O-GlcNAcylation can modulate cell morphology and favor EMT. In this review, we summarize some of the current knowledge that correlates glucose metabolism, aberrant glycosylation and hyper O-GlcNAcylation supported by HBP that leads to EMT activation. Developmental Dynamics 247:481-491, 2018. © 2017 Wiley Periodicals, Inc.

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“…The end‐product of hexosamine biosynthetic pathway (HBP) is the nucleotide sugar UDP‐GlcNAc, which is used by all GlcNAc transferases including OGT. UDP‐GlcNAc can be converted into UDP‐GalNAc and CMP‐NeuAc . The originator study on C. elegans showed that silencing ogt gene modifies UDP‐HexNAc and UDP‐Glc levels, which may affect general glycosylation patterns .…”

Section: Introductionmentioning

confidence: 99%

OGT Controls the Expression and the Glycosylation of E‐cadherin, and Affects Glycosphingolipid Structures in Human Colon Cell Lines

et al. 2019

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Colorectal cancer (CRC) affects both women and men living in societies with a high sedentary lifestyle. Amongst the phenotypic changes exhibited by tumor cells, a wide range of glycosylation has been reported for colon cancer‐derived cell lines and CRC tissues. These aberrant modifications affect different aspects of glycosylation, including an increase in core fucosylation and GlcNAc branching on N‐glycans, alteration of O‐glycans, upregulated sialylation, and O‐GlcNAcylation. Although O‐GlcNAcylation and complex glycosylations differ in many aspects, sparse evidences report on the interference of O‐GlcNAcylation with complex glycosylation. Nevertheless, this relationship is still a matter of debate. Combining different approaches on three human colon cell lines (HT29, HCT116 and CCD841CoN), it is herein reported that silencing O‐GlcNAc transferase (OGT, the sole enzyme driving O‐GlcNAcylation), only slightly affects overall N‐ and O‐glycosylation patterns. Interestingly, silencing of OGT in HT29 cells upregulates E‐cadherin (a major actor of epithelial‐to‐mesenchymal transition) and changes its glycosylation. On the other hand, OGT silencing perturbs biosynthesis of glycosphingolipids resulting in a decrease in gangliosides and an increase in globosides. Together, these results provide novel insights regarding the selective regulation of complex glycosylations by O‐GlcNAcylation in colon cancer cells.

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Hyperglycemia exacerbates colon cancer malignancy through hexosamine biosynthetic pathway

Cited by 85 publications

References 92 publications

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

OGT Controls the Expression and the Glycosylation of E‐cadherin, and Affects Glycosphingolipid Structures in Human Colon Cell Lines

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