NF-κB addiction and resistance to 5-fluorouracil in a multi-stage colon carcinoma model.

Colorectal cancer is one of the most frequently diagnosed malignancies in women and men. All systemic treatment options for colorectal cancer are based on 5-fluorouracil (5-FU), often administered in combination with oxaliplatin or irinotecan. Resistance to chemotherapy is a major obstacle to successful therapy. Nuclear factor kappa light chain enhancer of activated B cells (NF-κB) is a collection of heterodimeric transcription factors. Activation of NF-κB enables cells to protect themselves from environmental stress and its misregulation is associated with chronic inflammation and cancer-related phenomena such as proliferation, cell survival and cell invasion [1]. In colorectal cancer, NF-κB inhibition may overcome resistance against chemotherapy as well as enhance the cytotoxicity of drugs [2, 3, 4]. Physiologically, NF-κB is kept inactive in the cytoplasm by a family of NF-κBbinding proteins called the inhibitors of NFκB (IκB). Activation occurs via two different pathways: the non-canonical and the canonical pathway. Upon activation, NF-κB inhibitors are phosphorylated and subsequently ubiquitinated and degraded via the proteasome. Released NF-κB subunits translocate into the nucleus and control expression of hundreds of genes. In addition to the canonical activation of NF-κB, Tpl2 (also known as Cot) activates NF-κB when overexpressed. Tpl2, a serine/ threonine kinase, activates ERK-1/2 MAP kinases through a MEK1 pathway. Interestingly, all Tpl2 is stoichiometrically bound to NF-κB1/p105 in unstimulated cells and is thereby inactive [5]. It is now well known, that the activation of Tpl2, as in the case of other MAP3 kinases, is regulated by phosphorylation at Thr290 and S400.