Proteasome Inhibition by Bortezomib Increases IL-8 Expression in Androgen-Independent Prostate Cancer Cells: The Role of IKKα

Abstract

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.

Proteasome Inhibition Increases Recruitment of IκB Kinase β (IKKβ), S536P-p65, and Transcription Factor EGR1 to Interleukin-8 (IL-8) Promoter, Resulting in Increased IL-8 Production in Ovarian Cancer Cells

“…1B) cells. This was consistent with our previous studies demonstrating that in prostate cancer and leukemia cells, proteasome inhibition induces translocation of IB␣ from the cytoplasm to the nucleus, resulting in a gene-specific repression of NFB-dependent transcription (33)(34)(35). In contrast to p65 or IB␣, BZ did not have any pronounced effect on the nuclear levels of p50 in OVCAR3 and SKOV3 cells (Fig.…”

“…We have recently shown that bortezomib increases IL-8 expression in prostate cancer cells (33). But what are the differences between prostate and ovarian cancer cells in their responses to bortezomib?…”

“…Bortezomib Does Not Increase IL-8 Release in Multiple Myeloma Cells-We have recently shown that proteasome inhibition specifically induces IL-8 release also in metastatic prostate cancer cells, albeit by a different mechanism that involves IKK␣ but not IKK␤ (33). Despite the limited effectiveness of BZ as a single agent therapy in ovarian cancer, metastatic prostate cancer, and other solid tumors, proteasome inhibition has been remarkably effective in the treatment of multiple myeloma (25,26).…”

“…We have recently shown that in metastatic prostate cancer cells, bortezomib increases the IL-8 expression (33). This study was undertaken to investigate the mechanism of BZ resistance in ovarian cancer cells.…”

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“…There are two IκBα-related mechanisms for inhibiting the NF-κB pathway. Bortezomib, a clinical proteasome inhibitor, inhibits the NF-κB pathway in multiple myeloma cells via inhibition of proteasomes, stabilizing IκBα, and thus suppressing expression of p-p65 in the cytoplasm and its nuclear translocation (30,31). Different from bortezomib, DETT, an anti-leishmanial thiadiazine agent, induces multiple myeloma cell apoptosis via suppression of p-p65 expression in the cytoplasm and its nuclear translocation, in addition to suppression of the phosphorylation of IκBα in the cytoplasm (32).…”