Abstract
The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19ARF tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the pro-apoptotic CtBP repression target Bik, and was rescued by CtBP over-expression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable therapeutic index for cancer therapy. In human colon cancer cell peritoneal xenografts, MTOB treatment decreased tumor burden and induced tumor cell apoptosis. To verify the potential utility of CtBP as a therapeutic target in human cancer, the expression of CtBP and its negative regulator ARF was studied in a series of resected human colon adenocarcinomas. CtBP and ARF levels were inversely-correlated, with elevated CtBP levels (compared with adjacent normal tissue) observed in greater than 60% of specimens, with ARF absent in nearly all specimens exhibiting elevated CtBP levels. Targeting CtBP may represent a useful therapeutic strategy in human malignancies.
Acknowledgements
The authors wish to thank C.C. Hsieh for assistance with statistical analysis, R. DePinho for Myc and Ras expression plasmids, M. Kelliher for helpful discussions, D. Garlick for pathology assistance, and K.M. Draheim for advice and assistance with quantitative RT-P.C.R. S.P. was supported by an ACS/UMASS Individual Research Grant, C.S. was supported by GM65347 from NIGMS, and S.R.G. was supported by an ACS Research Scholar Grant and CA143763 from NCI. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of ACS, NIGMS, NCI or NIH.