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

Abstract

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.

Fig. 1. Schematic overview of the glucuronidation reaction catalysed by UGT enzymes.

a Endogenous metabolites, carcinogens and drugs are conjugated to glucuronic acid (GlcA) taken from the preferential co-substrate UDP-GlcA by membrane-bound UDP-glucuronosyltransferase (UGT) enzymes. The glucuronidation reaction generally takes place in the lumen of the endoplasmic reticulum (ER), and requires active transport of cytosolic UDP-GlcA to the ER. b Four UGT families (UGT1, UGT2, UGT3 and UGT8) encode the 22 enzymes and alternative isoforms (≥180) that regulate the glucuronidation pathway in humans. UGTs are found in most organs, generally anchored to the luminal side of the ER. Some UGTs may also reside in the perinuclear membrane (not illustrated). The liver expresses the widest array of UGTs. Enzymes of the UGT3 and UGT8 families use the co-substrates UDP-glucose, UDP-xylose, UDP-galactose and UDP-N-acetylglucosamine rather than UDP-GlcA to catalyse the glycosylation of endogenous metabolites (see Box 1). c Examples of endogenous metabolites and anti-cancer agents targeted by UGTs. Hydroxyl, amine, and sulfhydryl are the main functional groups targeted by UGT enzymes. Each UGT is specialised in the conjugation of a specific set of substrates.

Fig. 2. UGTs as mediators of oncogenic pathways and drug response.

a UDP-glucuronosyltransferases (UGTs) regulate metabolic homoeostasis through the inactivation of endogenous metabolites (such as steroid hormones) and xenobiotics (such as carcinogens) by their conjugation with glucuronic acid (GlcA, G). b The modulation of UGT expression and activity observed in normal and cancer cells influences the bioactivity of metabolites, including some with oncogenic potential, thereby promoting tumour development and progression. Endogenous metabolites such as steroid hormones induce or repress the expression of specific UGTs. c Therapeutic drugs generally induce UGT expression, promote drug inactivation and resistance to treatment and further perturb endogenous metabolites.

Fig. 3. Cancer therapeutic drugs of all classes and targeting all types of cancers are regulated by the glucuronidation pathway.

A non-exhaustive list of over 70 therapeutic agents inactivated by UGTs is provided in Supplementary Table S1.

Fig. 4. Cancer progression and UGTs: the example of prostate cancer.

The glucuronidation pathway modulates the bioactivity of steroid hormones. The steroid-receptor-dependent activation of gene expression is in turn influenced by several UGTs whose activity is regulated by multiple factors, including germline deletions and transcriptional and translational regulation. Note that functions of UGTs unrelated to their glucuronidation activity discussed in the section ‘Metabolic influence of UGTs on cancer progression’ are not represented. In normal prostate tissues, UGT2B17 and UGT2B28 are predominantly nuclear enzymes, whereas in prostate tumour cells, nuclear and cytoplasmic distributions are observed.^, UGT expression is also reported to increase with prostate cancer progression and metastasis and influences patient outcome.^,,,,