NF-kappaB kinetics predetermine TNF-alpha sensitivity of colorectal cancer cells

J Gene Med. Sep-Oct 2000;2(5):334-43. doi: 10.1002/1521-2254(200009/10)2:5<334::AID-JGM129>3.0.CO;2-Q.

Abstract

Background: Tumour necrosis factor (TNF)-alpha has considerable anti-tumour activity and may have potential as a treatment for metastatic colorectal cancer. However, TNF-alpha responses in patients and cell lines are variable and TNF-alpha treatment is associated with dose limiting clinical toxicity. Activation of NF-kappaB is protective against TNF-alpha induced cell death, and this may explain tumour resistance.

Methods: In order to provide further understanding of determinants of TNF-alpha responses, we studied TNF-alpha induced NF-kappaB activation and variable tumour responses. We analysed the kinetics of TNF-alpha induced NF-kappaB activation in colorectal cancer cells and determined whether it is possible to sensitize colorectal tumour cells to TNF-alpha by modulation of NF-kappaB signalling.

Results: We demonstrated that sustained NF-kappaB activation exceeding 16 h was observed in HRT18 and SW480 cells and was associated with TNF-alpha resistance. In contrast, transient NF-kappaB activation in HCT116 cells was associated with sensitivity to cytotoxic TNF-alpha effects, suggesting that NF-kappaB kinetics may have utility as clinical marker of TNF-alpha tumour resistance. Despite variable TNF-alpha responses and NF-kappaB kinetics, all three colorectal cancer cell lines were highly sensitive to treatment with the TNF-related apoptosis-inducing ligand (TRAIL) which induced only transient NF-kappaB activation. This further supports the notion of a pre-determined NF-kappaB response influencing receptor-mediated cell death. We also show that stable transfection and adenoviral-mediated expression of IkappaB(A32/36) can be used to confer TNF-alpha sensitivity to colorectal tumour cells previously resistant.

Conclusions: These findings indicate that a combined approach using gene therapy and recombinant TNF-alpha merits further appraisal. Furthermore, the kinetics of the TNF-alpha response could be determined using a 'test-dose' to indicate whether individual patients might benefit from this gene therapy approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / therapy
  • DNA-Binding Proteins / genetics
  • Drug Resistance
  • Gene Expression
  • Genetic Therapy
  • Humans
  • I-kappa B Proteins*
  • Kinetics
  • Membrane Glycoproteins / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • NFKBIA protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha