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, D; Brockmann, A; Mueller, J; Nachbur, U; Corazza, N; Renzulli, P; Hemphill, A; Brunner, T (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. Oncogene, 31(37), pp. 4095-106. Basingstoke, UK: Nature Publishing Group 10.1038/onc.2011.575

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Pathology 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
UniBE Contributor:	Sidler, Daniel (A), Müller, Heinz Joachim, Corazza, Nadia, Hemphill, Andrew, Brunner, Thomas (A)
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:18
Last Modified:	29 Mar 2023 23:32
Publisher DOI:	10.1038/onc.2011.575
PubMed ID:	22158036
Web of Science ID:	000308688900002
URI:	https://boris.unibe.ch/id/eprint/5517 (FactScience: 210270)