MAP3k7-ikk inflammatory signaling modulates ar protein degradation and prostate cancer progression

Androgen receptor (AR) is a major survival factor for prostate cancer. Inflammation is implicated in many cancer types, including prostate cancer. Activation of MAP3K7 (also termed TAK1) and downstream IkB kinase b (IKKb) by proinflammatory cytokines such as TNFa stimulates NF-kB survival pathways. Paradoxically, MAP3K7 is often deleted in human prostate cancer. Here, we demonstrate that AR protein expression is lower in inflammatory tumor areas compared with noninflammatory tissues in patients with prostate cancer. Map3k7 knockout increased AR protein levels and activity in the mouse prostate, and MAP3K7 and AR protein levels were inversely correlated in prostate cancer patient specimens. TNFa treatment increased AR protein ubiquitination and proteasomal degradation. Mechanistically, activation of IKKb by TNFa induced phosphorylation and TRCP1/2 E3 ligase-mediated polyubiquitination and degradation of AR protein. TNFa suppressed prostate cancer proliferation, which could be rescued by blockade of AR degradation. These findings reveal a previously unrecognized tumor suppressive function of the inflammation-activated MAP3K7-IKKb axis in degrading AR protein. Moreover, they suggest that aberrant elevation of AR protein could be a prognostic biomarker and therapeutic target for MAP3K7-deficient prostate cancer.