RESUMO
Cancer stem cell (CSC), the primary source of cancer-initiating population, is involved in cancer recurrence and drug-resistant phenotypes. This study demonstrates that the loss of DAB2IP, a novel Ras-GTPase activating protein frequently found in many cancer types, is associated with CSC properties. Mechanistically, DAB2IP is able to suppress stem cell factor receptor (c-kit or CD117) gene expression by interacting with a newly identified silencer in the c-kit gene. Moreover, DAB2IP is able to inhibit c-kit-PI3K-Akt-mTOR signaling pathway that increases c-myc protein to activate ZEB1 gene expression leading to the elevated CSC phenotypes. An inverse correlation between CD117 or ZEB1 and DAB2IP is also found in clinical specimens. Similarly, Elevated expression of ZEB1 and CD117 are found in the prostate basal cell population of DAB2IP knockout mice. Our study reveals that DAB2IP has a critical role in modulating CSC properties via CD117-mediated ZEB1 signaling pathway.
Assuntos
Proteínas de Homeodomínio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas Ativadoras de GTPase/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Recidiva Local de Neoplasia/metabolismo , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de ZincoAssuntos
Coagulação Sanguínea/efeitos dos fármacos , Cefotaxima/análogos & derivados , Unidades de Terapia Intensiva , Adulto , Idoso , Cefotaxima/efeitos adversos , Cefotaxima/uso terapêutico , Ceftriaxona , Feminino , Fibrinogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Tempo de TrombinaRESUMO
Treatment of fifteen patients with essential hypertension over four weeks using the beta 1-adrenoceptor blocking agent, metoprolol, resulted in a decrease in 24 h urinary excretion of kallikrein and aldosterone along with a decrease in plasma renin activity. There was no significant change in 24 h excretion rates of the free adrenal steroids deoxycorticosterone, 18-OH-deoxycorticosterone, corticosterone, cortisol or 18-OH-corticosterone during treatment, which were not significantly different from excretion rates of normal males, thus excluding inhibitory effects of adrenal steroids on urinary kallikrein activity. A positive correlation was found between plasma renin activity and urinary excretion of kallikrein during the control period and after 2 weeks on metoprolol, supporting the assumption of a preserved link between the renin-angiotensin-aldosterone system and the renal excretion of kallikrein in these patients. The decrease in kallikrein excretion during beta 1-adrenoceptor blockade in patients with essential hypertension may be explained by a reduction in sympathetic tone and by reduced activity of the renin-aldosterone system.
