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1.
Cancer Med ; 13(9): e7207, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38686627

RESUMEN

BACKGROUND: Most high-risk neuroblastoma patients who relapse succumb to disease despite the existing therapy. We recently reported increased event-free and overall survival in neuroblastoma patients receiving difluoromethylornithine (DFMO) during maintenance therapy. The effect of DFMO on cellular processes associated with neuroblastoma tumorigenesis needs further elucidation. Previous studies have shown cytotoxicity with IC50 values >5-15 mM, these doses are physiologically unattainable in patients, prompting further mechanistic studies at therapeutic doses. METHODS: We characterized the effect of DFMO on cell viability, cell cycle, apoptosis, neurosphere formation, and protein expression in vitro using five established neuroblastoma cell lines (BE2C, CHLA-90, SHSY5Y, SMS-KCNR, and NGP) at clinically relevant doses of 0, 50, 100, 500, 1000, and 2500 µM. Limiting Dilution studies of tumor formation in murine models were performed. Statistical analysis was done using GraphPad and the level of significance set at p = 0.05. RESULTS: There was not a significant loss of cell viability or gain of apoptotic activity in the in vitro assays (p > 0.05). DFMO treatment initiated G1 to S phase cell cycle arrest. There was a dose-dependent decrease in frequency and size of neurospheres and a dose-dependent increase in beta-galactosidase activity in all cell lines. Tumor formation was decreased in xenografts both with DFMO-pretreated cells and in mice treated with DFMO. CONCLUSION: DFMO treatment is cytostatic at physiologically relevant doses and inhibits tumor initiation and progression in mice. This study suggests that DFMO, inhibits neuroblastoma by targeting cellular processes integral to neuroblastoma tumorigenesis at clinically relevant doses.


Asunto(s)
Apoptosis , Supervivencia Celular , Eflornitina , Neuroblastoma , Ensayos Antitumor por Modelo de Xenoinjerto , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Neuroblastoma/metabolismo , Humanos , Animales , Línea Celular Tumoral , Ratones , Apoptosis/efectos de los fármacos , Eflornitina/farmacología , Eflornitina/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Femenino
2.
Endocrinology ; 159(9): 3433-3445, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30060157

RESUMEN

Anti-Müllerian hormone (AMH) produced by ovarian granulosa cells (GCs) plays a crucial role in ovarian function. It is used as a diagnostic and/or prognostic marker of fertility as well as for pathophysiological conditions in women. In this study, we investigated the underlying mechanism for regulation of AMH expression in GCs using primary mouse GCs and a human GC tumor-derived KGN cell line. We find that growth differentiation factor 9 (GDF9) and bone morphogenetic factor 15 (BMP15) together (GDF9 + BMP15), but not when tested separately, significantly induce AMH expression in vitro and in vivo (serum AMH). Our results show that GDF9 + BMP15 through the PI3K/Akt and Smad2/3 pathways synergistically recruit the coactivator p300 on the AMH promoter region that promotes acetylation of histone 3 lysine 27 (H3K27ac), facilitating AMH/Amh expression. Intriguingly, we also find that FSH inhibits GDF9 + BMP15-induced increase of AMH/Amh expression. This inhibition occurs through FSH-induced protein kinase A/SF1-mediated expression of gonadotropin inducible ovarian transcription factor 1, a transcriptional repressor, that recruits histone deacetylase 2 to deacetylate H3K27ac, resulting in the suppression of AMH/Amh expression. Furthermore, we report that ovarian Amh mRNA levels are significantly higher in Fshß-null mice (Fshß-/-) compared with those in wild-type (WT) mice. In addition, ovarian Amh mRNA levels are restored in Fshß-null mice expressing a human WT FSHß transgene (FSHß-/-hFSHßWT). Our study provides a mechanistic insight into the regulation of AMH expression that has many implications in female reproduction/fertility.


Asunto(s)
Hormona Antimülleriana/genética , Proteína Morfogenética Ósea 15/metabolismo , Células de la Granulosa/metabolismo , Factor 9 de Diferenciación de Crecimiento/metabolismo , Oocitos/metabolismo , Ovario/metabolismo , Acetilación , Animales , Hormona Antimülleriana/metabolismo , Línea Celular Tumoral , Femenino , Hormona Folículo Estimulante de Subunidad beta/genética , Regulación de la Expresión Génica , Código de Histonas , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Transducción de Señal , Proteína Smad2/metabolismo , Proteína smad3/metabolismo
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