The expression profiles of ADME genes in human cancers and their associations with clinical outcomes

ADME genes are a group of genes that are involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes within tumours is proposed to impact on cancer patient survival; however, this has not been systematically examined. In this study, our comprehensive analyses of pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed di erential intratumoral expression profiles for ADME genes in 21 di erent cancer types. Most genes also showed high interindividual variability within cancer-specific patient cohorts. Using Kaplan-Meier plots and logrank tests, we showed that intratumoral expression levels of twenty of the thirty-two core ADME genes were associated with overall survival (OS) in these cancers. Of these genes, five showed significant association with unfavourable OS in three cancers, including SKCM (ABCC2, GSTP1), KIRC (CYP2D6, CYP2E1), PAAD (UGT2B7); sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (UGT2B15), BRCA (CYP2D6), COAD (NAT1), HNSC (ABCB1), KIRC (ABCG2, CYP3A4, SLC22A2, SLC22A6), KIRP (SLC22A2), LIHC (CYP2C19, CYP2C8, CYP2C9, CYP3A5, SLC22A1),LUAD(SLC15A2), LUSC (UGT1A1), PAAD (ABCB1), SARC (ABCB1), and SKCM (ABCB1, DYPD). Overall, these data provide compelling evidence supporting ADME genes as prognostic biomarkers and potential therapeutic targets. We propose that intratumoral expression of ADME genes may impact cancer patient survival by multiple mechanisms that can include metabolizing/transporting anticancer drugs, activating anticancer drugs, and metabolizing/transporting a variety of endogenous molecules involved in metabolically fuelling cancer cells and/or controlling pro-growth signalling pathways.Dong Gui Hu, Peter I. Mackenzie, Pramod C. Nair, Ross A. McKinnon and Robyn Meec

Human Resource Flexibility as a Mediating Variable Between High Performance Work Systems and Performance

Much of the human resource management literature has demonstrated the impact of high performance work systems (HPWS) on organizational performance. A new generation of studies is emerging in this literature that recommends the inclusion of mediating variables between HPWS and organizational performance. The increasing rate of dynamism in competitive environments suggests that measures of employee adaptability should be included as a mechanism that may explain the relevance of HPWS to firm competitiveness. On a sample of 226 Spanish firms, the study’s results confirm that HPWS influences performance through its impact on the firm’s human resource (HR) flexibility

Identification of residues that confer sugar selectivity to UDP-glycosyltransferase 3A (UGT3A) enzymes

Recent studies in this laboratory characterized the UGT3A family enzymes, UGT3A1 and UGT3A2, and showed that neither uses the traditional UGT co-substrate UDP-glucuronic acid. Rather, UGT3A1 uses N-acetylglucosamine as preferred sugar donor and UGT3A2 uses UDP-glucose. The enzymatic characterization of UGT3A mutants, structural modelling, and multispecies gene analysis have now been employed to identify a residue within the active site of these enzymes that confer their unique sugar preferences. An asparagine (N391) residue in the UGT signature sequence of UGT3A1 is necessary for utilization of UDP-N-acetylglucosamine. Conversely, a phenylalanine (F391) residue in UGT3A2 favors UDP-glucose use. Mutation of N391 to F in UGT3A1 enhances its ability to utilize UDP-glucose and completely inhibits its ability to use UDP-N-acetylglucosamine. An analysis of homology models docked with UDP-sugar donors indicates that N391 in UGT3A1 is able to accommodate the N-acetyl group on C2 of UDP N-acetylglucosamine so that the anomeric carbon atom (C1) is optimally situated for catalysis involving H35. Replacement of N by F at 391 disrupts this catalytically-productive orientation of UDP N-acetylglucosamine but allows a more optimal alignment of UDP-glucose for sugar donation. Multispecies sequence analysis reveals that only primates possess UGT3A sequences containing the N391 residue, suggesting that other mammals may not have the capacity to N-acetylglucosaminidate small molecules. In support of this hypothesis, N391-containing UGT3A forms from two non-human primates were found to use UDP-N-acetylglucosamine, while UGT3A isoforms from non-primates could not use this sugar donor. This work gives new insight into the residues that confer sugar specificity to UGT family members and suggests a primate-specific innovation in glycosidation of small molecule

The novel UDP Glycosyltransferase 3A2: cloning, catalytic properties, and tissue distribution

The human UDP glycosyltransferase (UGT) 3A family is one of three families involved in the metabolism of small lipophilic compounds. Members of these families catalyze the addition of sugar residues to chemicals, which enhances their excretion from the body. The UGT1 and UGT2 family members primarily use UDP glucuronic acid to glucuronidate numerous compounds, such as steroids, bile acids, and therapeutic drugs. We showed recently that UGT3A1, the first member of the UGT3 family to be characterized, is unusual in using UDP N-acetylglucosamine as sugar donor, rather than UDP glucuronic acid or other UDP sugar nucleotides (J Biol Chem 283:36205–36210, 2008). Here, we report the cloning, expression, and characterization of UGT3A2, the second member of the UGT3 family. Like UGT3A1, UGT3A2 is inactive with UDP glucuronic acid as sugar donor. However, in contrast to UGT3A1, UGT3A2 uses both UDP glucose and UDP xylose but not UDP N-acetylglucosamine to glycosidate a broad range of substrates including 4-methylumbelliferone, 1-hydroxypyrene, bioflavones, and estrogens. It has low activity toward bile acids and androgens. UGT3A2 transcripts are found in the thymus, testis, and kidney but are barely detectable in the liver and gastrointestinal tract. The low expression of UGT3A2 in the latter, which are the main organs of drug metabolism, suggests that UGT3A2 has a more selective role in protecting the organs in which it is expressed against toxic insult rather than a more generalized role in drug metabolism. The broad substrate and novel UDP sugar specificity of UGT3A2 would be advantageous for such a function