| First Author | Huang Z | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 17 | Pages | 4471-4484 |
| PubMed ID | 34158377 | Mgi Jnum | J:309418 |
| Mgi Id | MGI:6757926 | Doi | 10.1158/0008-5472.CAN-20-4194 |
| Citation | Huang Z, et al. (2021) MAP3K7-IKK Inflammatory Signaling Modulates AR Protein Degradation and Prostate Cancer Progression. Cancer Res 81(17):4471-4484 |
| abstractText | 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 IkappaB kinase beta (IKKbeta) by proinflammatory cytokines such as TNFalpha stimulates NF-kappaB 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 non-inflammatory 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. TNFalpha treatment increased AR protein ubiquitination and proteasomal degradation. Mechanistically, activation of IKKbeta by TNFalpha induced phosphorylation and TRCP1/2 E3 ligase-mediated polyubiquitination and degradation of AR protein. TNFalpha 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-IKKbeta 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. SIGNIFICANCE: This study identifies that MAP3K7-IKKbeta signaling plays a tumor-suppressive role in prostate cancer by degrading AR, revealing potential prognostic and therapeutic strategies for MAP3K7-deficient tumors. |
