Apoptosome-dependent caspase activation proteins as prognostic markers in Stage II and III colorectal cancer

Br J Cancer. 2012 Apr 24;106(9):1499-1505. doi: 10.1038/bjc.2012.133.

Abstract

Background: Critical to successful execution of mitochondrial-mediated apoptosis is apoptosome formation and subsequent activation of caspases. Defects in this pathway have an important role in colorectal carcinogenesis and chemoresistance; therefore, the expression of apoptosome-associated proteins may be associated with clinical outcome and response to chemotherapy.

Methods: Here we performed a systematic analysis of the immunohistochemical expression of the key proteins involved in apoptosome-dependent caspase activation (APAF1, Pro-caspases 9 and 3, SMAC, and XIAP) in a cohort of Stage II and III colorectal cancer patients from a Phase III trial of adjuvant 5-fluorouracil-based chemotherapy vs postoperative observation alone.

Results: Survival analysis indicated that of the apoptosome-associated proteins examined here, Pro-caspase 3 and APAF1 have potential clinical utility as predictive markers in Stage II and III colorectal cancer, respectively. Interestingly, we identified APAF1 staining to be associated with better recurrence-free and overall survival in patients receiving chemotherapy.

Conclusion: These studies reveal the importance of the apoptosome-dependent caspase activation pathway, specifically Pro-caspase 3 and APAF1 proteins, for predicting both prognosis and response to therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis*
  • Apoptosomes / metabolism*
  • Caspases / metabolism*
  • Chemotherapy, Adjuvant
  • Clinical Trials, Phase III as Topic
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Enzyme Activation
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Immunoenzyme Techniques
  • Leucovorin / administration & dosage
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Tissue Array Analysis

Substances

  • Apoptosomes
  • Caspases
  • Leucovorin
  • Fluorouracil