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1.
Mol Oncol ; 12(9): 1596-1607, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30027683

RESUMEN

Prostate cancer often metastasizes to the bone, leading to morbidity and mortality. While metastasis-associated protein 1 (MTA1) is highly overexpressed in metastatic tumors and bone metastatic lesions, its exact role in the development of metastasis is unknown. Here, we report the role of MTA1 in prostate cancer progression and bone metastasis in vitro and in vivo. We found that MTA1 silencing diminished formation of bone metastases and impaired tumor growth in intracardiac and subcutaneous prostate cancer xenografts, respectively. This was attributed to reduced colony formation, invasion, and migration capabilities of MTA1 knockdown cells. Mechanistic studies revealed that MTA1 silencing led to a significant decrease in the expression of cathepsin B (CTSB), a cysteine protease critical for bone metastasis, with an expected increase in the levels of E-cadherin in both cells and xenograft tumors. Moreover, meta-analysis of clinical samples indicated a positive correlation between MTA1 and CTSB. Together, these results demonstrate the critical role of MTA1 as an upstream regulator of CTSB-mediated events associated with cell invasiveness and raise the possibility that targeting MTA1/CTSB signaling in the tumor may prevent the development of bone metastasis in prostate cancer.


Asunto(s)
Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Catepsina B/metabolismo , Histona Desacetilasas/genética , Neoplasias de la Próstata/patología , Proteínas Represoras/genética , Animales , Antígenos CD/biosíntesis , Cadherinas/biosíntesis , Línea Celular Tumoral , Movimiento Celular , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Silenciador del Gen , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Transgénicos , Invasividad Neoplásica , Transducción de Señal , Transactivadores
2.
Cancer Med ; 6(11): 2673-2685, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29024573

RESUMEN

The metastasis-associated protein 1(MTA1)/histone deacetylase (HDAC) unit is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific Pten-null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene (Pter), affect MTA1/HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1/HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamic acid, vorinostat), which also downregulates MTA1, could block prostate tumor progression in vivo. We generated and utilized a luciferase reporter in a prostate-specific Pten-null mouse model (Pb-Cre+ ; Ptenf/f ; Rosa26Luc/+ ) to evaluate the anticancer efficacy of Pter/SAHA combinatorial approach. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA1-associated proangiogenic factors HIF-1α, VEGF, and IL-1ß leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA1/HIF-1α than by high dose SAHA alone. Our study provides preclinical evidence that Pter/SAHA combination treatment inhibits MTA1/HIF-1α tumor-promoting signaling in PCa. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1-targeted therapies in PCa.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Hidroxámicos/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Estilbenos/farmacología , Factores de Transcripción/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Silenciador del Gen , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/administración & dosificación , Interleucina-1beta/sangre , Masculino , Ratones , Ratones Noqueados , Fosfohidrolasa PTEN/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Represoras , Transducción de Señal/efectos de los fármacos , Estilbenos/administración & dosificación , Transactivadores , Factores de Transcripción/genética , Factor C de Crecimiento Endotelial Vascular/sangre , Vorinostat
3.
Mol Biosyst ; 12(5): 1702-9, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27063447

RESUMEN

The androgen receptor (AR) is a therapeutic target for the treatment of prostate cancer. Androgen receptor reactivation during the androgen-independent stage of prostate cancer is mediated by numerous mechanisms including expression of AR mutants and splice variants that become non-responsive to conventional anti-androgenic agents. Resveratrol and its natural analogs exhibit varying degrees of anti-androgenic effects on tumor growth suppression in prostate cancer. However, the structural basis for the observed differential activity remains unknown. Here, anti-androgenic activities of resveratrol and its natural analogs, namely, pterostilbene, piceatannol and trimethoxy-resveratrol were studied in LNCaP cells expressing T877A mutant AR and atomistic simulations were employed to establish the structure activity relationship. Interestingly, essential hydrogen bonding contacts and the binding energies of resveratrol analogs with AR ligand binding domain (LBD), emerge as key differentiating factors for varying anti-androgenic action. Among all the analogs, pterostilbene exhibited strongest anti-androgenic activity and its binding energy and hydrogen bonding interactions pattern closely resembled pure anti-androgen, flutamide. Principal component analysis of our simulation studies revealed that androgenic compounds bind more strongly to AR LBD compared to anti-androgenic compounds and provide conformational stabilization of the receptor in essential subspace. The present study provides critical insight into the structure-activity relationship of the anti-androgenic action of resveratrol analogs, which can be translated further to design novel highly potent anti-androgenic stilbenes.


Asunto(s)
Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/farmacología , Simulación por Computador , Estilbenos/química , Estilbenos/farmacología , Línea Celular Tumoral , Flutamida/farmacología , Humanos , Enlace de Hidrógeno , Masculino , Conformación Molecular , Simulación de Dinámica Molecular , Proteínas Mutantes/metabolismo , Neoplasias de la Próstata/patología , Unión Proteica/efectos de los fármacos , Receptores Androgénicos/metabolismo , Resveratrol , Termodinámica
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