Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer

Br J Cancer. 2009 Aug 4;101(3):483-91. doi: 10.1038/sj.bjc.6605144.

Abstract

Background: Cyclooxygenase-2 (COX-2) is over-expressed in colorectal cancer (CRC), rendering tumour cells resistant to apoptosis. Selective COX-2 inhibition is effective in CRC prevention, although having adverse cardiovascular effects, thus focus has shifted to downstream pathways.

Methods: Microarray experiments identified genes regulated by COX-2 in HCA7 CRC cells. In vitro and in vivo regulation of DRAK2 (DAP kinase-related apoptosis-inducing kinase 2 or STK17beta, an apoptosis-inducing kinase) by COX-2 was validated by qRT-PCR.

Results: Inhibition of COX-2 induced apoptosis and enhanced DRAK2 expression in HCA7 cells (4.4-fold increase at 4 h by qRT-PCR, P=0.001), an effect prevented by co-administration of PGE(2). DRAK2 levels were suppressed in a panel of human colorectal tumours (n=10) compared to normal mucosa, and showed inverse correlation with COX-2 expression (R=-0.68, R2=0.46, P=0.03). Administration of the selective COX-2 inhibitor rofecoxib to patients with CRC (n=5) induced DRAK2 expression in tumours (2.5-fold increase, P=0.01). In vitro silencing of DRAK2 by RNAi enhanced CRC cell survival following COX-2 inhibitor treatment.

Conclusion: DRAK2 is a serine-threonine kinase implicated in the regulation of apoptosis and is negatively regulated by COX-2 in vitro and in vivo, suggesting a novel mechanism for the effect of COX-2 on cancer cell survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis*
  • Cell Line, Tumor
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Cyclooxygenase 2 / physiology*
  • Dinoprostone / physiology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics*
  • RNA Interference

Substances

  • Apoptosis Regulatory Proteins
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Protein-Serine-Threonine Kinases
  • STK17B protein, human
  • Dinoprostone