Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB.

摘要: Resistance towards the drug 5-fluorouracil (5-FU) is a key challenge in adjuvant chemotherapy of colorectal cancer (CRC), and novel targeted approaches are required to improve therapeutic outcome. Necroptosis recently discovered form programmed cell death, which depends on receptor interacting protein 1 (RIP1) particularly occurs under caspase-deficient conditions. The induction necroptosis represents promising strategy overcome apoptosis resistance cancer. aim this study was systematically explore usage pan-caspase inhibitors sensitize resistant CRC cells for 5-FU. We found that facilitated 5-FU-induced necroptosis, mediated by autocrine secretion tumor necrosis factor α (TNF-α). TNF-α production driven nuclear κB (NF-κB) RIP1 kinase. In vivo xenograft experiments showed inhibitor IDN-7314 combination with 5-FU synergistically blocked growth. Ex fresh human tissue specimens further indicated subgroup patients could benefit from combinatory treatment. Thereby, elevated levels secreted expression components necroptotic pathway might help predict sensitivity pro-necroptotic therapies. Together, our results shed new light molecular regulation NF-κB RIP1. Moreover, we identify death as an important effector mechanism 5-FU-mediated anti-tumoral activity. On basis study, propose approach CRC.