Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-10-05

AUTHORS

Kavya Ramkumar, Soma Samanta, Anahita Kyani, Suhui Yang, Shuzo Tamura, Elizabeth Ziemke, Jeanne A. Stuckey, Si Li, Krishnapriya Chinnaswamy, Hiroyuki Otake, Bikash Debnath, Vladimir Yarovenko, Judith S. Sebolt-Leopold, Mats Ljungman, Nouri Neamati

ABSTRACT

Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we show that silencing of GSTO1 with siRNA significantly impairs cancer cell viability, validating GSTO1 as a potential new target in oncology. We report on the development and characterization of a series of chloroacetamide-containing potent GSTO1 inhibitors. Co-crystal structures of GSTO1 with our inhibitors demonstrate covalent binding to the active site cysteine. These potent GSTO1 inhibitors suppress cancer cell growth, enhance the cytotoxic effects of cisplatin and inhibit tumour growth in colon cancer models as single agent. Bru-seq-based transcription profiling unravelled novel roles for GSTO1 in cholesterol metabolism, oxidative and endoplasmic stress responses, cytoskeleton and cell migration. Our findings demonstrate the therapeutic utility of GSTO1 inhibitors as anticancer agents and identify the novel cellular pathways under GSTO1 regulation in colorectal cancer. More... »

PAGES

13084

Journal

TITLE

Nature Communications

ISSUE

1

VOLUME

7

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ncomms13084

DOI

http://dx.doi.org/10.1038/ncomms13084

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1032273400

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27703239


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375 Life Sciences Institute, University of Michigan, 48109, Ann Arbor, Michigan, USA
376 Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, 48109, Ann Arbor, Michigan, USA
377 rdf:type schema:Organization
378 grid-institutes:grid.42505.36 schema:alternateName Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, 90033, Los Angeles, California, USA
379 schema:name Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, 90033, Los Angeles, California, USA
380 rdf:type schema:Organization
381 grid-institutes:grid.439283.7 schema:alternateName N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prospect, 119991, Moscow, Russia
382 schema:name N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prospect, 119991, Moscow, Russia
383 rdf:type schema:Organization
 




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