Natural compound Tetrocarcin-A downregulates Junctional Adhesion Molecule-A in conjunction with HER2 and inhibitor of apoptosis proteins and inhibits tumor cell growth.
Cancer Lett
; 440-441: 23-34, 2019 01.
Article
en En
| MEDLINE
| ID: mdl-30312728
ABSTRACT
Overexpression of the tight junction protein Junctional Adhesion Molecule-A (JAM-A) has been linked to aggressive disease in breast and other cancers, but JAM-targeting drugs remain elusive. Screening of a natural compound library identified the antibiotic Tetrocarcin-A as a novel downregulator of JAM-A and human epidermal growth factor receptor-2 (HER2) protein expression in breast cancer cells. Lysosomal inhibition partially rescued the downregulation of JAM-A and HER2 caused by Tetrocarcin-A, and attenuated its cytotoxic activity. Tetrocarcin-A treatment or JAM-A silencing reduced AKT and ERK phosphorylation, inhibited c-FOS phosphorylation at Threonine-232 (its transcriptional regulation site), inhibited nuclear localization of c-FOS, and downregulated expression of the inhibitor of apoptosis proteins (IAP). This was accompanied by Tetrocarcin-A-induced caspase-dependent apoptosis. To begin evaluating the potential clinical relevance of our findings, we extended our studies to other models. Encouragingly, Tetrocarcin-A downregulated JAM-A expression and caused cytotoxicity in primary breast cells and lung cancer stem cells, and inhibited the growth of xenografts in a semi-in vivo model involving invasion across the chicken egg chorioallantoic membrane. Taken together, our data suggest that Tetrocarcin-A warrants future evaluation as a novel cancer therapeutic by virtue of its ability to downregulate JAM-A expression, reduce tumorigenic signaling and induce apoptosis.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
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Moléculas de Adhesión Celular
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Receptores de Superficie Celular
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Receptor ErbB-2
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Proteínas Inhibidoras de la Apoptosis
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Aminoglicósidos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Año:
2019
Tipo del documento:
Article