Proteasome Inhibitors Induce Death but Activate NF-κB on Endometrial Carcinoma Cell Lines and Primary Culture Explants

Abstract

Proteasome inhibitors are currently used as chemotherapeutic drugs because of their ability to block NF-B, a transcription factor constitutively activated in many different types of human cancer. In the present study, we demonstrate that proteasome inhibitors induce cell death in endometrial carcinoma cell lines and primary explants but, instead of blocking NF-B, they increase its transcriptional activity. Proteasome inhibitors induce phosphorylation of IKK␣/␤, phosphorylation and degradation of IB␣, and phosphorylation of the p65 NF-B subunit on serine 536. Proteasome inhibitor-induced NF-B activity can be blocked by a non-degradable form of IB␣ or dominant negative forms of either IKK␣ or IKK␤. Lentiviral delivery of shRNAs to either IKK␣ or IKK␤ cause blockade of NF-B transcriptional activity and inhibit phosphorylation of p65 on serine 536, but has no effect on IBa degradation. These results suggest a role for p65 phosphorylation in proteasome inhibitor-induced NF-B activation. Accordingly, siRNA knockdown of p65 inhibits proteasome inhibitor-induced NF-B transcriptional activity. Our results demonstrate that proteasome inhibitors, including bortezomib, induce cell death on endometrial carcinoma cells and primary explants. However, they activate NF-B instead of blocking its transcriptional potential. Therefore, the concept that proteasome inhibitors are blockers of NF-B activation should be carefully examined in particular cell types.

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