Inhibition of CK2 activity by TGF-β1 promotes IκB-α protein stabilization and apoptosis of immortalized hepatocytes

Abstract

Nuclear factor κB (NF-κB) is an antiapoptotic factor involved in development, regeneration, and neoplastic progression of the liver. Previously, we have shown that stabilization of inhibitor κB (IκB)-α protein following treatment of hepatocytes with transforming growth factor (TGF)-β1 promoted NF-κB repression, which then permitted induction of AP-1/SMAD-mediated liver cell death. Because basal IκB-α protein turnover is regulated by protein kinase CK2, here we have elucidated the regulation of CK2 kinase activity and its role in control of NF-κB levels following treatment with TGF-β1. We show that both messenger RNA (mRNA) and protein levels of the CK2α catalytic subunit are down-regulated following TGF-β1 stimulation in murine hepatocyte cells. The ensuing inhibition of CK2 kinase activity promotes stabilization of IκB protein, which is followed by the shutoff of constitutive NF-κB activity and induction of apoptosis. Ectopic expression of CK2α inhibits TGF-β1-induced apoptosis through sustained activation of NF-κB. Conversely, expression of a kinase-dead mutant of CK2α potentiates TGF-β1 cell killing. Importantly, we show that hepatocellular carcinomas (HCCs) derived from TGF-β1 transgenic mice and human HCC cell lines display enhanced CK2 IκB kinase activity that contributes in part to an elevated NF-κB activity in vivo. In conclusion, inhibition of CK2 expression levels by TGF-β1 is crucial for the induction of apoptosis of hepatocytes. Circumvention of this process by up-regulation of CK2 activity in transformed cells may contribute to the promotion of TGF-β1-induced liver carcinogenesis. (H epatology 2003;38:1540-1551.)