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Therapeutic targeting of C-terminal binding protein in human cancer

Michael W Straza1, Seema Paliwal, Ramesh C Kovi

  • 1Department of Cancer Biology, University of Massachusetts Medical School and UMass Memorial Cancer Center, Worcester, MA, USA.

Cell Cycle (Georgetown, Tex.)
|October 9, 2010
PubMed

Insights

Targeting CtBP, a protein promoting cancer cell survival, with MTOB shows promise. MTOB inhibits CtBP, leading to cancer cell death and reduced tumor growth, suggesting a potential new cancer therapy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Metabolic Regulation

Background:

  • CtBP transcriptional corepressors are crucial for cancer cell survival and migration.
  • CtBP activity is regulated by cellular metabolism and antagonized by tumor suppressors like p14/p19(ARF).
  • The CtBP substrate 4-methylthio-2-oxobutyric acid (MTOB) acts as a CtBP inhibitor and exhibits cytotoxicity to cancer cells.

Purpose of the Study:

  • To investigate the therapeutic potential of inhibiting CtBP using MTOB.
  • To elucidate the mechanism of MTOB-induced apoptosis.
  • To assess the expression of CtBP and ARF in human colon adenocarcinomas to validate CtBP as a therapeutic target.

Main Methods:

  • Treatment of cancer cells and xenografts with MTOB.
  • Analysis of apoptosis, p53-dependency, Bik expression, and CtBP/ARF rescue experiments.
  • Evaluation of MTOB cytotoxicity in different mouse embryonic fibroblast (MEF) cell lines.
  • Immunohistochemical analysis of CtBP and ARF expression in human colon cancer specimens.

Main Results:

  • MTOB induced p53-independent apoptosis, linked to Bik derepression, which was reversible by CtBP overexpression or Bik silencing.
  • MTOB demonstrated selective cytotoxicity towards immortalized and transformed MEFs, but not normal MEFs, indicating a potential therapeutic index.
  • MTOB treatment reduced tumor burden and increased apoptosis in human colon cancer xenografts.
  • Human colon adenocarcinomas showed an inverse correlation between CtBP and ARF levels, with elevated CtBP and absent ARF in over 60% of specimens.

Conclusions:

  • MTOB-induced apoptosis is mediated through CtBP inhibition and Bik derepression.
  • CtBP inhibition by MTOB shows therapeutic potential for cancer treatment with a favorable therapeutic index.
  • Elevated CtBP and diminished ARF expression in human colon cancers support CtBP as a viable therapeutic target.

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