REDOX-REGULATED RELB-AR AXIS MEDIATES PROSTATE SPECIFIC ANTIGEN EXPRESSION: INSIGHT IN PROSTATE CANCER RESPONSE TO RADIATION THERAPY

Although the prostate specific antigen (PSA) test is widely used in clinical settings for prostate cancer (PCa) diagnosis and post-treatment follow-up monitoring, false positive PSA test results, which contribute to over-diagnosis of PCa, and false negative results, which miss some patients with aggressive PCa, remain problems of clinical importance. Our study demonstrates that radiation therapy, which is widely used for treatment of localized PCa, generates TNF-α in tumor cells and stromal fibroblasts, redox dependently. Interestingly, TNF-α rapidly and transiently triggers the RelA-mediated NF-κB canonical pathway, but its effect on RelB expression is more robust and long lasting, which leads to sustainable suppression of PSA expression. TNF-α further amplifies endogenous reactive oxygen species (ROS) partially through NADPH oxidase activation and mediates redox-dependent downstream signaling pathways. Addition of the NADPH oxidase inhibitor or ROS scavengers such as superoxide dismutase (SOD) mimetic can abrogate TNF-α-mediated suppression of PSA expression by inhibiting the RelB-AR axis. Treatment with TNF-α suppresses PSA expression and it confers minor yet statistically significant protection to LNCap cells against irradiation, indicating that radiation-induced TNF-α may not only interfere with the PSA-based PCa diagnosis and post-treatment monitoring but may also diminish the efficacy of radiotherapy. In addition, we uncover a role for RelB in suppressing PSA expression at the advanced stage of PCa, which could be a mechanism for the low PSA level in some patients bearing aggressive PCa. Experiments with both RelB overexpression and siRNA knockdown indicate that RelB negatively regulates androgen receptor (AR) and PSA levels in human prostate cancer, LNCap, cells. RelB directly interacts with AR to form a complex on the enhancer elements of the PSA promoter. Thus, the RelB-AR axis is an important contributor to PSA suppression at the advanced stage of PCa. Overall, this study is the first to reveal a redox-mediated association among radiation-generated TNF-α, activation of the RelB-mediated alternative NF-kappaB pathway and PSA suppression. This mechanistic information provides new insights with practical and clinical implications for PSA-based PCa diagnosis and post-treatment monitoring as well as redox intervention in radiation therapy

Electronic structures and magnetic orders of Fe-vacancies ordered ternary iron selenides TlFe1.5_{1.5}Se2_2 and AFe1.5_{1.5}Se2_2 (A=K, Rb, or Cs)

By the first-principles electronic structure calculations, we find that the ground state of the Fe-vacancies ordered TlFe$_{1.5}$Se$_2$ is a quasi-two-dimensional collinear antiferromagnetic semiconductor with an energy gap of 94 meV, in agreement with experimental measurements. This antiferromagnetic order is driven by the Se-bridged antiferromagnetic superexchange interactions between Fe moments. Similarly, we find that crystals AFe$_{1.5}$Se$_2$ (A=K, Rb, or Cs) are also antiferromagnetic semiconductors but with a zero-gap semiconducting state or semimetallic state nearly degenerated with the ground states. Thus rich physical properties and phase diagrams are expected.Comment: Add results about AFe$_{1.5}$Se$_2$ (A=K, Rb, or Cs);4 pages and 7 figure