PROTEASOME INHIBITION BY BORTEZOMIB INCREASES IL-8 EXPRESSION IN ANDROGEN-INDEPENDENT PROSTATE CANCER CELLS: THE ROLE OF IKKα1

Expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8), which is regulated at the transcriptional level by NFκB, is constitutively increased in the androgen independent metastatic prostate cancer and correlates with poor prognosis. Inhibition of NFκB-dependent transcription was used as an anti-cancer strategy for the development of the first clinically approved 26S proteasome inhibitor, bortezomib (BZ). Even though BZ has shown remarkable anti-tumor activity in hematological malignancies, it has been less effective in prostate cancer and other solid tumors; however, the mechanisms have not been fully understood. Here we report that the proteasome inhibition by BZ unexpectedly increases the IL-8 expression in androgen independent prostate cancer PC3 and DU145 cells, while expression of other NFκB-regulated genes is inhibited or unchanged. The BZ-increased IL-8 expression is associated with increased in vitro p65 NFκB DNA binding activity and p65 recruitment to the endogenous IL-8 promoter. In addition, proteasome inhibition induces a nuclear accumulation of IKKα and inhibition of IKKα enzymatic activity significantly attenuates the BZ-induced p65 recruitment to IL-8 promoter and IL-8 expression, demonstrating that the induced IL-8 expression is mediated, at least partly, by IKKα. Together, these data provide the first evidence for the gene specific increase of IL-8 expression by the proteasome inhibition in prostate cancer cells and suggest that targeting both IKKα and the proteasome may increase the BZ effectiveness in androgen independent prostate cancer treatment.