Abstract 1228: Indolo-pyrido-isoquinolin based alkaloid inhibits epithelial-mesenchymal transition and stemness via activation of p53-miR34a axis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.1228-1228
• Main Authors: Nagalingam, Arumugam, Avtanski, Dimiter. B, Tomaszewski, Joesph, Prabhakar, Risbood, Difillippantonio, Michael, Mears, Brian, Saxena, Neeraj, Malhotra, Sanjay, Sharma, Dipali
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-1228

The tumor suppressor p53 plays a critical role in suppressing cancer growth and progression and is the most frequently mutated and functionally inactivated gene in all human malignancies. Owing to its widespread alteration/inactivation in cancer, p53 is an attractive target for the development of new targeted therapies. We synthesized several indolo-pyrido-isoquinolin based alkaloids to restore/activate p53 function and examined their therapeutic efficacy using NCI-60 screening. Here, we provide molecular evidence that one of these compounds, 11-Methoxy-2,3,4,13-tetrahydro-1H-indolo[2’,3’:3,4]pyrido[1,2-b]isoquinolin-6-ylium-bromide (termed P18 or NSC-768219) inhibits growth and clonogenic potential of cancer cells. P18 treatment results in downregulation of mesenchymal markers and concurrent upregulation of epithelial markers as well as inhibition of migration and invasion. Experimental epithelial-mesenchymal-transition (EMT) induced by exposure to TGFβ/TNFα is also completely reversed by P18. Importantly, P18 also inhibits mammosphere-formation along with a reduction in the expression of stemness factors, Oct4, Nanog and Sox2. We show that P18 induces expression, phosphorylation and accumulation of p53 in cancer cells. P18-mediated induction of p53 leads to increased nuclear localization and elevated expression of p53 target genes. Using isogenic cancer cells differing only in p53 status, we show that the alteration of mesenchymal and epithelial genes, inhibition of migration and invasion of cancer cells mediated by P18 is p53-dependent. Furthermore, P18 increases miR-34a expression in p53-dependent manner and inhibition of mammosphere-formation by P18 is further enhanced by miR-34a mimic. Collectively, these data provide evidence that p53-miR-34a activation by P18 may represent a promising therapeutic strategy for the inhibition of growth and progression of cancer. Citation Format: Arumugam Nagalingam, Dimiter. B Avtanski, Joesph Tomaszewski, Risbood Prabhakar, Michael Difillippantonio, Brian Mears, Neeraj Saxena, Sanjay Malhotra, Sanjay Malhotra, Dipali Sharma. Indolo-pyrido-isoquinolin based alkaloid inhibits epithelial-mesenchymal transition and stemness via activation of p53-miR34a axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1228.