Cross-Talk between Alternatively Spliced UGT1A Isoforms and Colon Cancer Cell Metabolism

Audet-Delage, Yannick; Rouleau, Michèle; Rouleau, Mélanie; Roberge, Jean; Miard, Stéphanie; Picard, Frédéric; Têtu, Bernard; Guillemette, Chantal

doi:10.1124/mol.116.106161

Cited by 16 publications

(23 citation statements)

References 65 publications

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“…1,3,25,28,29 Moreover, alternative functions of variant UGT1A_i2 proteins in the regulation of redox and glycolytic enzymes via protein-protein interactions have been reported, supporting roles diverging from conjugation reactions. 25,30 This is of particular interest in the context of cancer, where a preferential expression of some UGT alternates is observed. Many cancer-related genes are regulated by AS, with the encoded proteins often involved in all major aspects of cancer cell biology.…”

Section: Discussionmentioning

confidence: 99%

Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

et al. 2017

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“…53 This study also reveals that the localisation of UGT2B28 changes from predominantly nuclear in normal cells to nuclear, perinuclear and cytoplasmic in cancer cells, which might be secondary to alternative splicing processes, post-translational modifications and/or interactions with unknown binding partners. 53,[81][82][83] This alternative localisation may be representative of multifunctional proteins (moonlighting proteins). This suggests that UGT2B28 may have additional roles in tumour cells and raises the question of whether steroid inactivation is responsible for this influence.…”

Section: Ugt2b17mentioning

confidence: 99%

“…Beyond the enzymatic functions of UGTs in glucuronidation, their interactions with other metabolic enzymes, such as those involved in the catabolism of fatty acids and with the glycolytic enzyme pyruvate kinase (PKM2), are another means by which they might influence diverse metabolic pathways involved in cancer biology, with an impact on cancer-cell phenotypes. 81,82 These additional functions, which could also involve UGT isoforms produced by alternative splicing, will need to be assessed to comprehensively understand the contribution of UGTs to the oncogenic phenotype.…”

Section: Metabolic Influence Of Ugts On Cancer Progressionmentioning

confidence: 99%

Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression

et al. 2020

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The best-known role of UDP-glucuronosyltransferase enzymes (UGTs) in cancer is the metabolic inactivation of drug therapies. By conjugating glucuronic acid to lipophilic drugs, UGTs impair the biological activity and enhance the water solubility of these agents, driving their elimination. Multiple clinical observations support an expanding role for UGTs as modulators of the drug response and in mediating drug resistance in numerous cancer types. However, accumulating evidence also suggests an influence of the UGT pathway on cancer progression. Dysregulation of the expression and activity of UGTs has been associated with the progression of several cancers, arguing for UGTs as possible mediators of oncogenic pathways and/or disease accelerators in a drug-naive context. The consequences of altered UGT activity on tumour biology are incompletely understood. They might be associated with perturbed levels of bioactive endogenous metabolites such as steroids and bioactive lipids that are inactivated by UGTs or through non-enzymatic mechanisms, thereby eliciting oncogenic signalling cascades. This review highlights the evidence supporting dual roles for the UGT pathway, affecting cancer progression and drug resistance. Pharmacogenomic testing of UGT profiles in patients and the development of therapeutic options that impair UGT actions could provide useful prognostic and predictive biomarkers and enhance the efficacy of anti-cancer drugs.

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“…While there is ample biophysical evidence to support the existence of UGT dimers (Meech and Mackenzie, 1997 ; Lewis et al, 2011 ; Suzuki et al, 2014 ), the lack of structural data has hampered protein-protein interaction research with this enzyme class. Interestingly, the structural data that does exist for human UGT enzymes, that of a partial UGT2B7 structure, does provide an indication for the presence of homo dimers (Miley et al, 2007 ; Fujiwara et al, 2016 ; Audet-Delage et al, 2017 ). In the asymmetric unit, the C terminus of one monomer packs into the predicted UDPGA binding site of the other monomer (Miley et al, 2007 ).…”

Section: X-ray Crystallographymentioning

confidence: 99%

Advances in the Understanding of Protein-Protein Interactions in Drug Metabolizing Enzymes through the Use of Biophysical Techniques

Lampe

2017

Front. Pharmacol.

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In recent years, a growing appreciation has developed for the importance of protein-protein interactions to modulate the function of drug metabolizing enzymes. Accompanied with this appreciation, new methods and technologies have been designed for analyzing protein-protein interactions both in vitro and in vivo. These technologies have been applied to several classes of drug metabolizing enzymes, including: cytochrome P450's (CYPs), monoamine oxidases (MAOs), UDP-glucuronosyltransferases (UGTs), glutathione S-transferases (GSTs), and sulfotransferases (SULTs). In this review, we offer a brief description and assessment of the impact of many of these technologies to the study of protein-protein interactions in drug disposition. The still expanding list of these techniques and assays has the potential to revolutionize our understanding of how these enzymes carry out their important functions in vivo.

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Cross-Talk between Alternatively Spliced UGT1A Isoforms and Colon Cancer Cell Metabolism

Cited by 16 publications

References 65 publications

Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression

Advances in the Understanding of Protein-Protein Interactions in Drug Metabolizing Enzymes through the Use of Biophysical Techniques

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