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.
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.
authors.affiliation: Institute of Pathology, Experimental Pathology, University of Bern, Bern, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Sidler
authors.forename: A
authors.initials: A
authors.lastname: Brockmann
authors.forename: J
authors.initials: J
authors.lastname: Mueller
authors.forename: U
authors.initials: U
authors.lastname: Nachbur
authors.forename: N
authors.initials: N
authors.lastname: Corazza
authors.forename: P
authors.initials: P
authors.lastname: Renzulli
authors.forename: A
authors.initials: A
authors.lastname: Hemphill
authors.forename: T
authors.initials: T
authors.lastname: Brunner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides / Q000494:pharmacology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D015536:Down-Regulation; D051549:Glutathione S-Transferase pi / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C531315:RM 4819; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D013844:Thiazoles; D051549:Glutathione S-Transferase pi; D048031:JNK Mitogen-Activated Protein Kinases