Faculty Collaboration Database

Therapeutic targeting of C-terminal binding protein in human cancer. Cell Cycle 2010 Sep 15;9(18):3740-50

Date

10/12/2010

Pubmed ID

20930544

Pubmed Central ID

PMC3047800

DOI

10.4161/cc.9.18.12936

Scopus ID

2-s2.0-77957003489 (requires institutional sign-in at Scopus site)   60 Citations

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/p19(ARF) 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 proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression 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.

Author List

Straza MW, Paliwal S, Kovi RC, Rajeshkumar B, Trenh P, Parker D, Whalen GF, Lyle S, Schiffer CA, Grossman SR

Author

Michael W. Straza MD, PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alcohol Oxidoreductases
Animals
Antineoplastic Agents
Apoptosis
Apoptosis Regulatory Proteins
Chromatin Immunoprecipitation
Colonic Neoplasms
DNA-Binding Proteins
HCT116 Cells
Humans
Membrane Proteins
Methionine
Mice
Mice, Nude
Mitochondrial Proteins
Repressor Proteins
Transplantation, Heterologous
Tumor Suppressor Protein p53