Identification of TGF-β-activated kinase 1 as a possible novel target for renal cell carcinoma intervention

• Inhibition of TAK1 kinase activity suppresses NF-κB activation and RCC cell survival.
• TAK1 inhibitors induces apoptotic cytotoxicity against RCC cells.
• RCC cells with TAK1 depletion show reduced cell viability and increased apoptosis.
• TAK1 and p-NF-κB are both over-expressed in human RCC tissues.
• Inhibition or depletion of TAK1 enhances the activity of vinblastine sulfate.

Renal cell carcinoma (RCC) is common renal malignancy within poor prognosis. TGF-β-activated kinase 1 (TAK1) plays vital roles in cell survival, apoptosis-resistance and carcinogenesis through regulating nuclear factor-κB (NF-κB) and other cancer-related pathways. Here we found that TAK1 inhibitors (LYTAK1, 5Z-7-oxozeanol (5Z) and NG-25) suppressed NF-κB activation and RCC cell (786-O and A489 lines) survival. TAK1 inhibitors induced apoptotic cytotoxicity against RCC cells, which was largely inhibited by the broad or specific caspase inhibitors. Further, shRNA-mediated partial depletion of TAK1 reduced 786-O cell viability whiling activating apoptosis. Significantly, TAK1 was over-expressed in human RCC tissues, and its level was correlated with phosphorylated NF-κB. Finally, kinase inhibition or genetic depletion of TAK1 enhanced the activity of vinblastine sulfate (VLB) in RCC cells. Together, these results suggest that TAK1 may be an important oncogene or an effective target for RCC intervention.