Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase-Bim axis and reveals glutathione-S-transferase P1 as Achilles' heel

Sidler, Daniel; Brockmann, Anette; Müller, Joachim; Nachbur, Ueli; Corazza, Nadia; Renzulli, Pietro; Hemphill, Andrew; Brunner, Thomas

Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase-Bim axis and reveals glutathione-S-transferase P1 as Achilles' heel

Dateien

Sidler_196962.pdfGröße: 1.22 MBDownloads: 304

Datum

2012

Autor:innen

Sidler, Daniel

Brockmann, Anette

Müller, Joachim

Nachbur, Ueli

Corazza, Nadia

Renzulli, Pietro

Hemphill, Andrew

Brunner, Thomas

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Oncogene. 2012, 31(37), pp. 4095-4106. ISSN 0950-9232. eISSN 1476-5594. Available under: doi: 10.1038/onc.2011.575

Zusammenfassung

Glutathione-S-transferase of the Pi class (GSTP1) is frequently overexpressed in a variety of solid tumors and has been identified as a potential therapeutic target for cancer therapy. GSTP1 is a phase II detoxification enzyme and conjugates the tripeptide glutathione to endogenous metabolites and xenobiotics, thereby limiting the efficacy of antitumor chemotherapeutic treatments. In addition, GSTP1 regulates cellular stress responses and apoptosis by sequestering and inactivating c-Jun N-terminal kinase (JNK). Thiazolides are a novel class of antibiotics for the treatment of intestinal pathogens with no apparent side effects on the host cells and tissue. Here we show that thiazolides induce a GSTP1-dependent and glutathione-enhanced cell death in colorectal tumor cell lines. Downregulation of GSTP1 reduced the apoptotic activity of thiazolides, whereas overexpression enhanced it. Thiazolide treatment caused strong Jun kinase activation and Jun kinase-dependent apoptosis. As a critical downstream target of Jun kinase we identified the pro-apoptotic Bcl-2 homolog Bim. Thiazolides induced Bim expression and activation in a JNK-dependent manner. Downregulation of Bim in turn significantly blocked thiazolide-induced apoptosis. Whereas low concentrations of thiazolides failed to induce apoptosis directly, they potently sensitized colon cancer cells to TNF-related apoptosis-inducing ligand- and chemotherapeutic drug-induced cell death. Although GSTP1 overexpression generally limits chemotherapy and thus antitumor treatment, our study identifies GSTP1 as Achilles' heel and thiazolides as novel interesting apoptosis sensitizer for the treatment of colorectal tumors.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

Apoptosis, colon cancer, glutathione S-transferase, Bim, TRAIL, chemotherapy

Zitieren

ISO 690

SIDLER, Daniel, Anette BROCKMANN, Joachim MÜLLER, Ueli NACHBUR, Nadia CORAZZA, Pietro RENZULLI, Andrew HEMPHILL, Thomas BRUNNER, 2012. Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase-Bim axis and reveals glutathione-S-transferase P1 as Achilles' heel. In: Oncogene. 2012, 31(37), pp. 4095-4106. ISSN 0950-9232. eISSN 1476-5594. Available under: doi: 10.1038/onc.2011.575

BibTex

@article{Sidler2012-09-13Thiaz-19696,
  year={2012},
  doi={10.1038/onc.2011.575},
  title={Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase-Bim axis and reveals glutathione-S-transferase P1 as Achilles' heel},
  number={37},
  volume={31},
  issn={0950-9232},
  journal={Oncogene},
  pages={4095--4106},
  author={Sidler, Daniel and Brockmann, Anette and Müller, Joachim and Nachbur, Ueli and Corazza, Nadia and Renzulli, Pietro and Hemphill, Andrew and Brunner, Thomas}
}

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