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Buhrmann, Constanze; Yazdi, Mina; Popper, Bastian; Shayan, Parviz; Goel, Ajay; Aggarwal, Bharat B.; Shakibaei, Mehdi (2019): Evidence that TNF-beta induces proliferation in colorectal cancer cells and resveratrol can down-modulate it. In: Experimental Biology and Medicine, Vol. 244, No. 1: pp. 1-12
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Abstract

Although much is understood about the proinflammatory cytokine TNF-alpha, very limited data are available about TNF-beta (lymphotoxin). Whether TNF-beta can induce the proliferation of tumor cells, how TNF-beta-induced proliferation of tumor cells is affected by natural products such as resveratrol and the role of NF-kappa B in this process, is not understood. In the present study, we used clonogenic and cytotoxic methods to show the effect of TNF-beta on cell proliferation. We also examined the impact of resveratrol on TNF-beta-promoted proliferation and on NF-kappa B activation in HCT116 colorectal cancer (CRC). Our findings showed that TNF-beta induced the proliferation and invasion in CRC cells and this was comparable with that of TNF-alpha. TNF-beta-stimulated proliferation of CRC cells was blocked via anti-TNF-beta-receptor. We found that resveratrol reversed the TNF-beta-induced proliferation and invasion of CRC cells, and this correlated with the suppression of TNF-beta-stimulated NF-kappa B signaling. Like resveratrol, I kappa B-kinase (IKK) inhibitor (BMS-345541), also reversed TNF-beta-stimulated proliferation, NF-kappa B activation and these were mediated through inhibition of I kappa B-kinase, phosphorylation of I kappa B alpha, suppression of phosphorylation, and nuclear translocation of the p65 subunit of NF-kappa B. Furthermore, resveratrol similar to BMS-345541 suppressed TNF-beta-promoted NF-kappa B-mediated gene biomarkers linked with proliferation, apoptosis, and invasion. Overall, our findings indicate for the first time that TNF-beta/TNF-beta-receptor signaling is involved in proliferation of CRC cells in parallel to TNF-alpha, and that resveratrol down-modulates TNF-beta/TNF-beta-receptor-mediated inflammatory response, at least in part through down modulating NF-kappa B activation, thereby regulating tumor cell growth. Impact statement The mechanism by which natural products such as resveratrol suppresses TNF-beta-promoted tumor cell proliferation, invasion, and colony formation is unknown. In this study, we explored for the first time the effect of resveratrol on the proinflammatory cytokine TNF-beta-, compared to TNF-alpha-stimulated proliferative and pro-inflammatory signaling in HCT116 cells. Our findings suggest that expression of TNF-beta and TNF-beta-receptor, like TNF-alpha, can lead to activation of inflammatory transcription factor (NF-kappa B) and NF-kappa B-regulated gene biomarkers, which are involved in the promotion of cancer proliferation, invasion, metastasis, and cell survival of tumor. Resveratrol can block TNF-beta/TNF-beta-receptor-induced activation of NF-kappa B, NF-kappa B-modulated gene products, and inhibition of caspase-3 cleavage. These results highlight the therapeutic effect of resveratrol-mediated anti-tumor activity by multitargeting cellular signaling pathways.