Natural compound Tetrocarcin-A downregulates Junctional Adhesion Molecule-A in conjunction with HER2 and inhibitor of apoptosis proteins and inhibits tumor cell growth. (January 2019)

• Record Type: Journal Article
• Authors: Vellanki, Sri HariKrishna; Cruz, Rodrigo G.B.; Jahns, Hanne; Hudson, Lance; Sette, Giovanni; Eramo, Adriana; Hopkins, Ann M.
• Is Part Of: Cancer letters. Volume 440-441(2019)
• Page Start: 23
• Page End: 34
• Publication Date: 2019-01
• Subjects: Breast cancer -- Tetrocarcin–A -- JAM-A -- HER2 -- Tight junction -- Apoptosis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.09.032
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Natural compound Tetrocarcin-A downregulates junctional adhesion molecule-A (JAM-A). JAM-A downregulation reduces viability of breast cells and lung cancer stem cells. Tetrocarcin-induced JAM-A downregulation removes a blockade on apoptosis.