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

• Published in: Oncogene Vol. 31; no. 37; pp. 4095 - 4106
• Main Authors: Sidler, D, Brockmann, A, Mueller, J, Nachbur, U, Corazza, N, Renzulli, P, Hemphill, A, Brunner, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-09-2012; Nature Publishing Group
• Subjects: 631/80/82/23; 631/92/609; 692/699/67/1059/99; 692/699/67/1504/1885; Antibiotics; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2 protein; Bcl-2-Like Protein 11; Benzamides - pharmacology; BIM protein; c-Jun amino-terminal kinase; c-Jun protein; Caco-2 Cells; Cancer cells; Cancer therapies; Cell Biology; Cell death; Cell Line, Tumor; Cellular stress response; Chemotherapy; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Detoxification; Down-Regulation; Drug therapy; Enzymes; Glutathione; Glutathione S-Transferase pi - metabolism; Glutathione transferase; Health aspects; Human Genetics; Humans; Internal Medicine; Intestine; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Kinases; MAP Kinase Signaling System; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolites; Mitochondria - metabolism; Oncology; original-article; Pathogens; Pharmacology; Physiological aspects; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; RNA Interference; RNA, Small Interfering; Side effects; Solid tumors; Stress; Therapeutic targets; Thiazoles - pharmacology; TNF-Related Apoptosis-Inducing Ligand - metabolism; Transcription factors; Tumor cell lines; Tumor necrosis factor; Tumors; Xenobiotics; Switzerland; Germany; apoptosis; TRAIL; chemotherapy; colon cancer; glutathione S-transferase; Bim
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.575

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.