The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation

Zahreddine, Hiba Ahmad; Culjkovic-Kraljacic, Biljana; Assouline, Sarit; Gendron, Patrick; Romeo, Andrea A.; Morris, Stephen; Cormack, Gregory; Jaquith, James B.; Cerchietti, Leandro; Cocolakis, Eftihia; Amri, Abdellatif; Bergeron, Julie; Leber, Brian; Becker, Michael W.; Pei, Shanshan; Jordan, Craig T.; Miller, Wilson H.; Borden, Katherine L. B.

doi:10.1038/nature13283

Cited by 163 publications

(208 citation statements)

References 18 publications

(27 reference statements)

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“…(Menard et al, 2013). However, some UGTs (UGT1A, UGT2B7, UGT2B15, and UGT2B17) are increased in other types of cancers, including those from the endometrium and in patients with acute myeloid leukemia and chronic lymphocytic leukemia, and emerge as a feature associated with drug resistance (Lepine et al, 2010;Dellinger et al, 2012;Gruber et al, 2013;Zahreddine et al, 2014), supporting the relevance to develop analytical tools that accurately establish the glucuronidation activity of various tissues. Although our absolute quantification of UGT proteins was conducted in kidney homogenates, they are well in line with previous reports that assessed UGT concentrations in normal kidney microsomes (Harbourt et al, 2012;Fallon et al, 2013a;Sato et al, 2014).…”

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confidence: 99%

Quantitative Profiling of Human Renal UDP-glucuronosyltransferases and Glucuronidation Activity: A Comparison of Normal and Tumoral Kidney Tissues

et al. 2015

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Renal metabolism by UDP-glucuronosyltransferase (UGT) enzymes is central to the clearance of many drugs. However, significant discrepancies about the relative abundance and activity of individual UGT enzymes in the normal kidney prevail among reports, whereas glucuronidation in tumoral kidney has not been examined. In this study, we performed an extensive profiling of glucuronidation metabolism in normal (n = 12) and tumor (n = 14) kidneys using targeted mass spectrometry quantification of human UGTs. We then correlated UGT protein concentrations with mRNA levels assessed by quantitative polymerase chain reaction and with conjugation activity for the major renal UGTs. Beyond the wide interindividual variability in expression levels observed among kidney samples, UGT1A9, UGT2B7, and UGT1A6 are the most abundant renal UGTs in both normal and tumoral tissues based on protein quantification. In normal kidney tissues, only UGT1A9 protein levels correlated with mRNA levels, whereas UGT1A6, UGT1A9, and UGT2B7 quantification correlated significantly with their mRNA levels in tumor kidneys. Data support that posttranscriptional regulation of UGT2B7 and UGT1A6 expression is modulating glucuronidation in the kidney. Importantly, our study reveals a significant decreased glucuronidation capacity of neoplastic kidneys versus normal kidneys that is paralleled by drastically reduced UGT1A9 and UGT2B7 mRNA and protein expression. UGT2B7 activity is the most repressed in tumors relative to normal tissues, with a 96-fold decrease in zidovudine metabolism, whereas propofol and sorafenib glucuronidation is decreased by 7.6-and 5.2-fold, respectively. Findings demonstrate that renal drug metabolism is predominantly mediated by UGT1A9 and UGT2B7 and is greatly reduced in kidney tumors.

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confidence: 99%

Quantitative Profiling of Human Renal UDP-glucuronosyltransferases and Glucuronidation Activity: A Comparison of Normal and Tumoral Kidney Tissues

et al. 2015

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“…9 Additionally, primary refractory and a few relapsed patients had markers of impaired drug uptake with low levels of the ribavirin transporter (ENT1) and/or an enzyme required for the pro-drug metabolism of ribavirin, adenosine kinase (ADK). 9 We examined these resistance markers here (Online Supplementary Table S1). For 5 of 27 patients, we observed lowered ADK and/or ENT1 mRNA and/or protein levels at baseline relative to healthy volunteers, suggesting that ribavirin pro-drug metabolism and drug uptake were impaired.…”

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confidence: 99%

A phase I trial of ribavirin and low-dose cytarabine for the treatment of relapsed and refractory acute myeloid leukemia with elevated eIF4E

et al. 2014

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“…[49][50][51] Recently, GLI1 was shown to drive resistance of AML cells to ribavirin and cytarabine through UGT1A-dependent glucuronidation of the compounds and inhibition of GLI1 with GANT61 restored sensitivity. 52 Additionally, SMO-independent GLI1 activity is important for adjusted p value < 0.05 adjusted p value ≥ 0.05 osteopontin-mediated resistance of breast cancer cells to the cytotoxic effects of doxorubicin, paclitaxel and cisplatin. 49 These studies provide strong evidence for the role of GLI1 in tumor cell resistance to a range of anticancer therapies; however, this is the first study to identify a role for GLI1 in response to HDACi.…”

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confidence: 99%

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

et al. 2016

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Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostatresistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 smallmolecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy.

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The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation

Cited by 163 publications

References 18 publications

Quantitative Profiling of Human Renal UDP-glucuronosyltransferases and Glucuronidation Activity: A Comparison of Normal and Tumoral Kidney Tissues

Quantitative Profiling of Human Renal UDP-glucuronosyltransferases and Glucuronidation Activity: A Comparison of Normal and Tumoral Kidney Tissues

A phase I trial of ribavirin and low-dose cytarabine for the treatment of relapsed and refractory acute myeloid leukemia with elevated eIF4E

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

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