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NF– κ B kinetics predetermine TNF‐ α sensitivity of colorectal cancer cells
Author(s) -
Zwacka Ralf M.,
Stark Lesley,
Dunlop Malcolm G.
Publication year - 2000
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/1521-2254(200009/10)2:5<334::aid-jgm129>3.0.co;2-q
Subject(s) - tumor necrosis factor alpha , cancer research , colorectal cancer , apoptosis , cell culture , transfection , medicine , biology , cancer , immunology , biochemistry , genetics
Abstract Background Tumour necrosis factor (TNF)‐ α has considerable anti‐tumour activity and may have potential as a treatment for metastatic colorectal cancer. However, TNF‐ α responses in patients and cell lines are variable and TNF‐ α treatment is associated with dose limiting clinical toxicity. Activation of NF– κ B is protective against TNF‐ α induced cell death, and this may explain tumour resistance. Methods In order to provide further understanding of determinants of TNF‐ α responses, we studied TNF ‐α induced NF– κ B activation and variable tumour responses. We analysed the kinetics of TNF‐ α induced NF– κ B activation in colorectal cancer cells and determined whether it is possible to sensitize colorectal tumour cells to TNF‐ α by modulation of NF– κ B signalling. Results We demonstrated that sustained NF– κ B activation exceeding 16 h was observed in HRT18 and SW480 cells and was associated with TNF‐ α resistance. In contrast, transient NF– κ B activation in HCT116 cells was associated with sensitivity to cytotoxic TNF‐ α effects, suggesting that NF– κ B kinetics may have utility as clinical marker of TNF‐ α tumour resistance. Despite variable TNF‐ α responses and NF– κ B 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– κ B activation. This further supports the notion of a pre‐determined NF– κ B response influencing receptor‐mediated cell death. We also show that stable transfection and adenoviral‐mediated expression of I κ B(A32/36) can be used to confer TNF‐ α sensitivity to colorectal tumour cells previously resistant. Conclusions These findings indicate that a combined approach using gene therapy and recombinant TNF‐ α merits further appraisal. Furthermore, the kinetics of the TNF‐ α response could be determined using a ‘test‐dose’ to indicate whether individual patients might benefit from this gene therapy approach. Copyright © 2000 John Wiley & Sons, Ltd.