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

Oncogene volume 31, pages 4095–4106 (2012)Cite this article

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Abstract

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.

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Acknowledgements

The authors thank the members of the Brunner and Corazza lab for their excellent technical help and scientific advice, Thomas Kaufmann from the Institute of Pharmacology, University of Berne for providing the antibodies, Philippe Bouillet from the Walter and Eliza Hall Institute, Melbourne, for the Bim promoter construct, Christian Leumann from the Department of Chemistry and Biochemistry, University of Bern for the synthesis of RM4819, and Vicky Hätzig and Thomas Herdegen, University of Kiel for expression plasmids. This work was supported by grants from the Swiss National Science Foundation, Oncosuisse and AFF grant from the University of Konstanz to Thomas Brunner. Daniel Sidler was supported by an MD-PhD fellowship from the Swiss National Science Foundation. Anette Brockmann was supported by a fellowship from the Graduate School Chemical Biology of the University of Konstanz.

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Authors and Affiliations

  1. Institute of Pathology, Experimental Pathology, University of Bern, Bern, Switzerland

    D Sidler, N Corazza & T Brunner

  2. Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany

    A Brockmann & T Brunner

  3. Institute of Parasitology, Vetsuisse Faculty, University of Bern, Bern, Switzerland

    J Mueller & A Hemphill

  4. Division of Cell Signalling and Cell Death, Walter and Eliza Hall Institute, Parkville, Victoria, Australia

    U Nachbur

  5. Department of Surgery, Cantonal Hospital, Münsterlingen, Switzerland

    P Renzulli

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Correspondence to T Brunner.

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Sidler, D., Brockmann, A., Mueller, J. et al. Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase–Bim axis and reveals glutathione-S-transferase P1 as Achilles’ heel. Oncogene 31, 4095–4106 (2012). https://doi.org/10.1038/onc.2011.575

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