Non–Cell-Autonomous Signaling Promotes Prostate Regeneration and CRPC

Activation of inflammatory pathways in response to injury promotes tissue regeneration and contributes to tumorigenesis. Recent studies have shown that in prostate cancer, androgen deprivation triggers B-cell infiltration and activation of IκB kinase α (IKKα), which accelerates the emergence of castration-resistant prostate cancer (CRPC). However, it is unclear how IKKα promotes CRPC or whether IKKα is also required for normal prostate regeneration. Ammirante and colleagues found that castration followed by androgen supplementation also resulted in B-cell infiltration and nuclear translocation of IKKα in nontransformed murine prostates. B-cell–mediated stimulation of IKKα was necessary for expansion of BMI1⁺ prostate epithelial progenitor cells, and depletion of B cells or IKKα mutation prevented androgen-induced prostate regeneration. IKKα inactivation also impaired the accumulation of prostate cancer progenitor cells and suppressed the development of CRPC in castrated mice, supporting a role for IKKα in the regulation of both normal and cancer stem cells in the prostate. The protumorigenic effect of IKKα was dependent on induction of BMI1 expression; BMI1 depletion diminished prostate tumor growth, whereas expression of BMI1 was sufficient to rescue progenitor cell expansion and castration-resistant tumor growth in the absence of IKKα via transcriptional repression of the Ink4a/Arf locus. IKKα directly contributed to the regulation of Bmi1 transcription through phosphorylation of E2F transcription factor 1 (E2F1), resulting in enhanced E2F1 nuclear localization, association with the histone acetyltransferase CREB binding protein (CBP), and recruitment to the Bmi1 promoter. Importantly, nuclear IKKα was also associated with elevated BMI1 expression and repressive chromatin marks in human prostate cancer samples, suggesting that this axis may also contribute to CRPC in patients. These findings identify a non–cell-autonomous mechanism that regulates prostate progenitor cell proliferation and suggest that IKKα inhibition combined with androgen ablation may limit CRPC recurrence.

Ammirante M, Kuraishy AI, Shalapour S, Strasner A, Ramirez-Sanchez C, Zhang W, et al. An IKKα–E2F1–BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence. Genes Dev 2013;27:1435–40.