Androgen receptor is up-regulated by a BLT2-linked pathway to contribute to prostate cancer progression

► BLT2 is overexpressed in AR-positive prostate cancer cells. ► BLT2 mediates the survival of AR-positive prostate cancer cells. ► BLT2 plays a critical role in AR expression via a Nox4-ROS-NF-κB-linked pathway. The androgen receptor (AR) plays a central role in the development and progression of prostate cancer. AR expression is maintained throughout the progression of prostate cancer and is also associated with an aggressive, castration-resistant (CR) phenotype. Despite the critical roles of AR expression in prostate cancer progression, the exact signaling mechanism regulating AR expression remains unclear. In this study, we demonstrated that AR expression was increased by a low-affinity leukotriene B4 receptor (BLT2)-linked pathway. We found that BLT2 was overexpressed in AR-positive prostate cancer cells, such as LNCaP cells, and BLT2 inhibition, using an inhibitor or siRNA knockdown, clearly attenuated AR expression and triggered apoptosis in these cells. These results suggest a role for BLT2 in AR expression and the survival of AR-positive prostate cancer cells. Moreover, we found that the NADPH oxidase family protein, Nox4, lay downstream of BLT2 and mediated the production of reactive oxygen species (ROS) and subsequent NF-κB stimulation, thereby inducing AR expression. Taken together, our results demonstrate that BLT2 plays a critical role in AR expression via a Nox4-ROS-NF-κB-linked pathway, thereby mediating the survival of AR-positive prostate cancer cells. Our findings point to BLT2 as a key regulator of AR expression and will contribute to the development of novel therapies for AR-positive prostate cancers, including androgen-responsive and CR prostate cancers.