RESUMO
Blood amino acid levels are maintained in a narrow physiological range. The pancreatic α cells have emerged as the primary aminoacidemia regulator through glucagon secretion to promote hepatic amino acid catabolism. Interruption of glucagon signaling disrupts the liver-α cells axis leading to hyperaminoacidemia, which triggers a compensatory rise in glucagon secretion and α cell hyperplasia. The mechanisms of hyperaminoacidemia-induced α cell hyperplasia remain incompletely understood. Using a mouse α cell line and in vivo studies in zebrafish and mice, we found that hyperaminoacidemia-induced α cell hyperplasia requires ErbB3 signaling. In addition to mechanistic target of rapamycin complex 1, another ErbB3 downstream effector signal transducer and activator of transcription 3 also plays a role in α cell hyperplasia. Mechanistically, ErbB3 may partner with ErbB2 to stimulate cyclin D2 and suppress p27 via mechanistic target of rapamycin complex 1 and signal transducer and activator of transcription 3. Our study identifies ErbB3 as a new regulator for hyperaminoacidemia-induced α cell proliferation and a critical component of the liver-α cells axis that regulates aminoacidemia.
Assuntos
Ciclina D2 , Células Secretoras de Glucagon , Hiperplasia , Alvo Mecanístico do Complexo 1 de Rapamicina , Receptor ErbB-3 , Peixe-Zebra , Animais , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Receptor ErbB-3/metabolismo , Receptor ErbB-3/genética , Hiperplasia/metabolismo , Hiperplasia/patologia , Camundongos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Ciclina D2/metabolismo , Ciclina D2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais , Proliferação de Células , Aminoácidos/metabolismo , Linhagem Celular , HumanosRESUMO
Encouraged by our previous findings and in continuation of our ongoing study project in designing and synthesis of novel Nur77-targeting anti-cancer agents, a series of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives were designed, synthesized and biologically evaluated as potent Nur77 modulators. Among synthesized compounds, 8b maintained good potency against different liver cancer cell lines and other types of cancer cell lines while exhibiting lower toxicity than the positive compound celastrol. Moreover, 8b displayed excellent Nur77-binding activity, superior to the lead compound 10g and comparable to the reference compound celastrol. The cytotoxic action of 8b towards cancer cells was associated with its induction of Nur77-mitochondrial targeting and Nur77-dependent apoptosis. Notably, 8b has good in vivo safety and anti-hepatocellular carcinoma (HCC) activity. Altogether, this study reveals that 8b is a novel Nur77 modulator with great promise for further research.