Curcumin modulates chronic myelogenous leukemia exosomes composition and affects angiogenic phenotype<i>via</i>exosomal miR-21

Abstract

// Simona Taverna 1 , Simona Fontana 1 , Francesca Monteleone 1 , Marzia Pucci 1 , Laura Saieva 1 , Viviana De Caro 2 , Valeria Giunta Cardinale 2 , Marco Giallombardo 1 , Emanuela Vicario 1 , Christian Rolfo 3 , Giacomo De Leo 1 , Riccardo Alessandro 1 1 Dipartimento di Biopatologia e Metodologie Biomediche, Sezione di Biologia e Genetica, Universit&agrave; di Palermo, Palermo, Italy 2 Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Universit&agrave; di Palermo, Palermo, Italy 3 Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital (UZA) and Center for Oncological Research (CORE) Antwerp University, Edegem, Antwerp, Belgium Correspondence to: Riccardo Alessandro, email: riccardo.alessandro@unipa.it Keywords: exosomes, curcumin, miR-21, CML Received: January 19, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: March 18, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: March 30, 2016 ABSTRACT Tumor derived exosomes are vesicles which contain proteins and microRNAs that mediate cell-cell communication and are involved in angiogenesis and tumor progression. Curcumin derived from the plant Curcuma longa, shows anticancer effects. Exosomes released by CML cells treated with Curcumin contain a high amount of miR-21 that is shuttled into the endothelial cells in a biologically active form. The treatment of HUVECs with CML Curcu-exosomes reduced RhoB expression and negatively modulated endothelial cells motility. We showed that the addition of CML control exosomes to HUVECs caused an increase in IL8 and VCAM1 levels, but Curcu-exosomes reversed these effects thus attenuating their angiogenic properties. This antiangiogenic effect was confirmed with in vitro and in vivo vascular network formation assays. SWATH analysis of the proteomic profile of Curcu-exosomes revealed that Curcumin treatment deeply changes their molecular properties, in particular, Curcumin induces a release of exosomes depleted in pro-angiogenic proteins and enriched in proteins endowed with anti-angiogenic activity. Among the proteins differential expressed we focused on MARCKS, since it was the most modulated protein and a target of miR-21. Taken together our data indicated that also Curcumin attenuates the exosome&rsquo;s ability to promote the angiogenic phenotype and to modulate the endothelial barrier organization.