RESUMO
Heat shock proteins (HSPs) are molecular chaperones that play a pivotal role in correct folding, stabilization and intracellular transport of many client proteins including those involved in oncogenesis. HSP70, which is frequently overexpressed in prostate cancer (PCa), has been shown to critically contribute to tumor cell survival, and might therefore represent a potential therapeutic target. We treated both the androgen receptor (AR)-positive LNCaP and the AR-negative PC-3 cell lines with the pharmacologic HSP70 inhibitor VER155008. Although we observed antiproliferative effects and induction of apoptosis upon HSP70 inhibition, the apoptotic effect was more pronounced in AR-positive LNCaP cells. In addition, VER155008 treatment induced G1 cell cycle arrest in LNCaP cells and decreased AR expression. Further analysis of the HSP system by Western blot analysis revealed that expression of HSP27, HOP and HSP90ß was significantly inhibited by VER155008 treatment, whereas the HSP40, HSP60, and HSP90α expression remained unchanged. Taken together, VER155008 might serve as a novel therapeutic option in PCa patients independent of the AR expression status.
Assuntos
Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico/metabolismo , Neoplasias da Próstata/patologia , Nucleosídeos de Purina/farmacologia , Receptores Androgênicos/metabolismo , Anexina A5/química , Antineoplásicos/farmacologia , Apoptose , Caspases/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Concentração Inibidora 50 , Masculino , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismoRESUMO
BACKGROUND: Effective treatment of atrial fibrillation (AF) remains an unmet need. Human K2P3.1 (TASK-1) K(+) channels display atrial-specific expression and may serve as novel antiarrhythmic targets. In rodents, inhibition of K2P3.1 causes prolongation of action potentials and QT intervals. We used a porcine model to further elucidate the significance of K2P3.1 in large mammals. OBJECTIVE: The purpose of this study was to study porcine (p)K2P3.1 channel function and cardiac expression and to analyze pK2P3.1 remodeling in AF and heart failure (HF). METHODS: The porcine K2P3.1 ortholog was amplified and characterized using voltage-clamp electrophysiology. K2P3.1 mRNA expression and remodeling were studied in domestic pigs during AF and HF induced by atrial burst pacing. RESULTS: Porcine K2P3.1 cDNA encodes a channel protein with 97% identity to human K2P3.1. K(+) currents recorded from Xenopus oocytes expressing pK2P3.1 were functionally and pharmacologically similar to their human counterparts. In the pig, K2P3.1 mRNA was predominantly expressed in atrial tissue. AF and HF were associated with reduction of K2P3.1 mRNA levels by 85.1% (right atrium) and 77.0% (left atrium) at 21-day follow-up. In contrast, ventricular K2P3.1 expression was low and not significantly affected by AF/HF. CONCLUSION: Porcine K2P3.1 channels exhibit atrial expression and functional properties similar to their human orthologs, supporting a general role as antiarrhythmic drug targets. K2P3.1 down-regulation in AF with HF may indicate functional relevance of the channel that remains to be validated in prospective interventional studies.
Assuntos
Fibrilação Atrial/genética , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio de Domínios Poros em Tandem/genética , RNA Mensageiro/genética , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Proteínas do Tecido Nervoso/biossíntese , Técnicas de Patch-Clamp , Canais de Potássio de Domínios Poros em Tandem/biossíntese , Reação em Cadeia da Polimerase em Tempo Real , SuínosRESUMO
AIMS: Recent accounts have suggested the involvement of interoceptive processes in consumption behavior for alcohol and other drugs. However, there is a paucity of empirical support for a direct association with physiologically assessed individual differences in interoceptive awareness (IA). The current research explored this postulated link and examined the interplay with positive outcome expectancies of alcohol consumption. METHOD: IA of alcohol-dependent adult in- and outpatients was measured with an objective electrocardiogram heart rate tracking task. Tension reduction expectancies (TRE) and drinking compulsions/obsessions were assessed with self-report questionnaires. RESULTS: No direct associations of IA with drinking compulsions/obsessions were found. However, IA and TRE interacted as predictors of drinking compulsions and drinking obsessions. CONCLUSION: The results corroborate the suggestion that neglect of bodily feedback might be a maintaining factor for drinking behavior.