RESUMEN
Oncogenic activation of PI3K/AKT signaling pathway, together with epigenetic aberrations are the characters of castration-resistant prostate cancer (CRPC). UHRF1 as a key epigenetic regulator, plays a critical role in prostate cancer (PCa) development, and its expression is positively correlated with the degree of malignancy. In this present study we investigated the potential regulatory mechanism of AKT1 on UHRF1, and further validated the in vitro and in vivo anticancer efficacy of AKT phosphorylation inhibitor MK2206 in combination with abiraterone. Both UHRF1 and p-AKT aberrantly overexpressed in the abiraterone-resistant PCa cells. Further studies revealed that AKT1 protein interacts with UHRF1, and AKT1 directly phosphorylates UHRF1 via the site Thr-210. MK2206 induced UHRF1 protein degradation by inhibiting AKT1-induced UHRF1 phosphorylation, and then reduced the interaction between UHRF1 and deubiquitinase USP7, while promoted the interaction between UHRF1 and E3 ubiquitin protein ligase BTRC. MK2206 significantly promoted the sensitivity of abiraterone-refractory PCa cells and xenografts to abiraterone by decreasing UHRF1 protein level, and reversed the phenotype of NEPC, evently induced cellular senescence and cell apoptosis. Altogether, our present study for the first time revealed a novel molecular mechanism of abiraterone resistance through PI3K/AKT-UHRF1 pathway, and provided a novel therapeutic modality by targeting PI3K/AKT1 to promote the drug sensitivity of abiraterone in PCa patients.
RESUMEN
BACKGROUND: A key challenge for unmanned aerial vehicle (UAV) spraying sometimes used in tea plantations is the downwash flow structure there stronger than in crops. In addition, the UAV spray is affected by the relationship between the nozzle design and the pesticide. However, there is little current research on this aspect. As a preliminary step this study focuses on the most appropriate pesticide for a designated nozzle in a six-rotor UAV according to the nozzle-pesticide relationship using a three-dimensional computational fluid dynamics model. This model considers the downwash flow structure effect and nozzle spray performance in hover. Nozzle FVP110-02, widely used in six-rotor UAVs, is used as a representative nozzle and bifenthrin and tea saponin water, commonly used in tea plantations, are used as the pesticides. RESULTS: The downwash flow structure of the six-rotor UAV in hover was conveniently controlled by the flight height and rotational speed, thereby causing the turbulence to be more stable. For nozzle FVP110-02, bifenthrin was more appropriate than tea saponin water at the same concentration, whilst bifenthrin and tea saponin water at a concentration of 1:1000 showed the best performance under identical working conditions. CONCLUSION: The numerical model developed here was shown to be effective for investigating the relationship between nozzle and pesticide. Our findings will help to not only improve UAV spraying for tea cultivation but also provide guidelines for pesticide selection in crops. Further work will address the comparison of the rigorous qualification of the numerical simulations with the measurements by the field test. © 2023 Society of Chemical Industry.