Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation

• Published in: Cell death & disease Vol. 6; no. 6; p. e1778
• Main Authors: Brockmann, A, Bluwstein, A, Kögel, A, May, S, Marx, A, Tschan, M P, Brunner, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-06-2015; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/2; 13/31; 13/95; 42/89; 631/80/82/23; 631/80/86; 692/699/67/1059/602; 692/699/67/1504/1885; Antibodies; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; bcl-X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Caco-2 Cells; Cell Biology; Cell Culture; Cell Line; Cisplatin - pharmacology; Colorectal Neoplasms - pathology; Drug Resistance, Neoplasm; Enzyme Activation; Glutathione S-Transferase pi - metabolism; HEK293 Cells; Humans; Immunology; JNK Mitogen-Activated Protein Kinases - metabolism; Life Sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mitochondria - metabolism; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Original; original-article; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Binding - physiology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Reactive Oxygen Species - metabolism; RNA Interference; RNA, Small Interfering; Thiazoles - pharmacology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.137

While many anticancer therapies aim to target the death of tumor cells, sophisticated resistance mechanisms in the tumor cells prevent cell death induction. In particular enzymes of the glutathion-S-transferase (GST) family represent a well-known detoxification mechanism, which limit the effect of chemotherapeutic drugs in tumor cells. Specifically, GST of the class P1 (GSTP1-1) is overexpressed in colorectal tumor cells and renders them resistant to various drugs. Thus, GSTP1-1 has become an important therapeutic target. We have recently shown that thiazolides, a novel class of anti-infectious drugs, induce apoptosis in colorectal tumor cells in a GSTP1-1-dependent manner, thereby bypassing this GSTP1-1-mediated drug resistance. In this study we investigated in detail the underlying mechanism of thiazolide-induced apoptosis induction in colorectal tumor cells. Thiazolides induce the activation of p38 and Jun kinase, which is required for thiazolide-induced cell death. Activation of these MAP kinases results in increased expression of the pro-apoptotic Bcl-2 homologs Bim and Puma, which inducibly bind and sequester Mcl-1 and Bcl-x
L
leading to the induction of the mitochondrial apoptosis pathway. Of interest, while an increase in intracellular glutathione levels resulted in increased resistance to cisplatin, it sensitized colorectal tumor cells to thiazolide-induced apoptosis by promoting increased Jun kinase activation and Bim induction. Thus, thiazolides may represent an interesting novel class of anti-tumor agents by specifically targeting tumor resistance mechanisms, such as GSTP1-1.