Chloramphenicol Causes Mitochondrial Stress, Decreases ATP Biosynthesis, Induces Matrix Metalloproteinase-13 Expression, and Solid-Tumor Cell Invasion
Open Access
- 25 March 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Toxicological Sciences
- Vol. 116 (1), 140-150
- https://doi.org/10.1093/toxsci/kfq085
Abstract
Overuse and abuse of antibiotics can increase the risk of cancer. Chloramphenicol can inhibit both bacterial and mitochondrial protein synthesis, causing mitochondrial stress and decreased ATP biosynthesis. Chloramphenicol can accelerate cancer progression; however, the underlying mechanisms of chloramphenicol in carcinogenesis and cancer progression are still unclear. We found that chloramphenicol can induce matrix metalloproteinase (MMP)-13 expression and increase MMP-13 protein in conditioned medium, resulting in an increase in cancer cell invasion. Chloramphenicol also activated c-Jun N-terminal kinases (JNK) and phosphatidylinositol 3-kinase (PI-3K)/Akt signaling, leading to c-Jun protein phosphorylation. The activated c-Jun protein has been proven to activate binding to the MMP-13 promoter and also upregulate the amount of MMP-13. Both the SP 600125 (JNK inhibitor) and LY 294002 (PI-3K/Akt inhibitor) can inhibit chloramphenicol-induced c-Jun phosphorylation, MMP-13 expression, and cell invasion. Overexpression of the dominant-negative JNK and PI-3K p85 subunit also negate chloramphenicol-induced responses. Other antibiotics that cause mitochondrial stress and a decrease in ATP biosynthesis also induce MMP-13 expression. These findings suggest that chloramphenicol-induced PI-3K/Akt, JNK phosphorylation, and activator protein 1 activation might function as a novel mitochondrial stress signal that result in an increase of MMP-13 expression and MMP-13-associated cancer cell invasion. The findings of this study confirms that chloramphenicol, and other 70S ribosomal inhibitors, should be administered with caution, especially during cancer therapy.Keywords
This publication has 44 references indexed in Scilit:
- Up-regulation of cathepsin B expression and enhanced secretion in mitochondrial DNA-depleted osteosarcoma cellsBiology of the Cell, 2009
- Association between mitochondrial DNA copy number, blood cell counts, and occupational benzene exposureEnvironmental and Molecular Mutagenesis, 2008
- Tumor-derived matrix metalloproteinase-13 (MMP-13) correlates with poor prognosis of invasive breast cancerBMC Cancer, 2008
- Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signalingProceedings of the National Academy of Sciences of the United States of America, 2008
- Influence on Mitochondria and Cytotoxicity of Different Antibiotics Administered in High Concentrations on Primary Human Osteoblasts and Cell LinesAntimicrobial Agents and Chemotherapy, 2007
- Matrix metalloproteinase-13 expression is associated with bone marrow microinvolvement and prognosis in non-small cell lung cancerLung Cancer, 2006
- Smad3 Mediates Transforming Growth Factor-β-induced Collagenase-3 (Matrix Metalloproteinase-13) Expression in Human Gingival FibroblastsOnline Journal of Public Health Informatics, 2002
- Sustained Production of H2O2Activates Pro-matrix Metalloproteinase-2 through Receptor Tyrosine Kinases/Phosphatidylinositol 3-Kinase/NF-κB PathwayOnline Journal of Public Health Informatics, 2002
- Transcriptional regulation of cell invasion: AP-1 regulation of a multigenic invasion programmeEuropean Journal of Cancer, 2000
- Effects of Transforming Growth Factor-beta on Human Pulmonary Adenocarcinoma Cell Adhesion, Motility, and Invasion In VitroJNCI Journal of the National Cancer Institute, 1992