RESUMEN
Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking ß2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.
Asunto(s)
AMP Cíclico/metabolismo , Depresión/complicaciones , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Neoplasias de la Próstata/patología , Regulación hacia Arriba , Animales , Línea Celular Tumoral , Depresión/genética , Depresión/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Clasificación del Tumor , Invasividad Neoplásica , Metástasis de la Neoplasia , Trasplante de Neoplasias , Fosforilación , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/psicología , Transducción de SeñalRESUMEN
A rapid, sensitive, and specific liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS-MS) method was developed and validated for simultaneous determination of aconitine (AC), mesaconitine (MA), and hypaconitine (HA), the three toxic constituents from Sini decoction (SND) in rat plasma. After the addition of citalopram as the internal standard (IS), plasma samples were basified with 100 microL 10% ammonium hydroxide, and then extracted with 1 mL ethyl acetate. Chromatographic separation was performed on a CN column (250 mm x 4.6 mm, 5 microm) with a mobile phase of methanol/40 mM ammonium acetate/formic acid (950:45:5, v/v/v) at the flow rate of 1.0 mL/min. Analytes were determined in a triple-quadrupole mass spectrometer in the selected reaction-monitoring (SRM) mode using electrospray source with positive mode. The method was validated over the concentration ranges of 0.01-10 ng/mL for AC, MA, and HA. The variation coefficients were always < 15% for both intraday and interday precision for each analyte. Mean accuracies were also within +/-15%. The method was proved to be sensitive, rapid, specific, accurate, and reproducible. It has been successfully applied to the pharmacokinetics study on rats after oral administration of SND.