TNFα induces tolerant production of CXC chemokines in colorectal cancer HCT116 cells via A20 inhibition of ERK signaling

Ubiquitin editing enzyme A20 functions as a tumor suppressor in various cancer. However, the mechanism for A20 regulation of cancer progress is not fully understood. In this study, we found that in human colorectal cancer HCT116 cells, TNF alpha induced a tolerant production of CXC chemokines, including CXCL1, 2, and 8 in a dose and time dependent manner. TNF alpha pre-treatment of HCT116 cells down-regulated the chemokine production induced by TNF alpha re-treatment. TNF alpha induced the phosphorylation of MAPKs ERK, JNK, P38 and NF-kappa B P65, but only ERK inhibition decreased TNF alpha-induced chemokine production. Both RT-PCR and FACS results showed that TNF alpha treatment did not regulate the expression of TNF receptors. However, TNF alpha up-regulated the expression of A20 at both mRNA and protein levels significantly. TNF alpha pre-treatment inhibited the signal transduction of MAPKs induced by TNF alpha re-stimulation, and A20 over-expression decreased the signal transduction of ERK and P38. Meanwhile, A20 inhibition by RNA interference reversed chemokine down-regulation induced by TNF alpha re stimulation after TNF alpha pre-treatment. Taken together, these results suggested that in human colorectal cancer cells, A20 may function to inhibit cancer progression via down-regulation of TNF alpha-induced chemokine production by suppression of ERK signaling.