NF-?B kinetics predetermine TNF-? sensitivity of colorectal cancer cells

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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–κB 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–κB activation and variable tumour responses. We analysed the kinetics of TNF-α induced NF–κB activation in colorectal cancer cells and determined whether it is possible to sensitize colorectal tumour cells to TNF-α by modulation of NF–κB signalling. Results We demonstrated that sustained NF–κB activation exceeding 16 h was observed in HRT18 and SW480 cells and was associated with TNF-α resistance. In contrast, transient NF–κB activation in HCT116 cells was associated with sensitivity to cytotoxic TNF-α effects, suggesting that NF–κB kinetics may have utility as clinical marker of TNF-α tumour resistance. Despite variable TNF-α responses and NF–κB 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–κB activation. This further supports the notion of a pre-determined NF–κB response influencing receptor-mediated cell death. We also show that stable transfection and adenoviral-mediated expression of IκB(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.