The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma

// Klara Fodor 1 , Nikoletta Dobos 1 , Andrew Schally 2 , 3 , Zita Steiber 4 , Gabor Olah 1 , Eva Sipos 1 , Lorant Szekvolgyi 5 and Gabor Halmos 1 , 2 1 University of Debrecen, Department of Biopharmacy, Debrecen, Hungary 2 Veterans Affairs Medical Center, Endocrine, Polypeptide and Cancer Insitute, Miami, FL, USA 3 University of Miami, Miller School of Medicine, Department of Pathology and Department of Medicine, Divisions of Oncology and Endocrinology, Sylvester Comprehensive Center, Miami, FL, USA 4 University of Debrecen, Department of Ophthalmology, Debrecen, Hungary 5 University of Debrecen, Faculty of Medicine, Department of Biochemistry and Molecular Biology, MTA-DE Momentum, Genome Architecture and Recombination Research Group, Debrecen, Hungary Correspondence to: Gabor Halmos, email: halmos.gabor@pharm.unideb.hu Keywords: uveal melanoma; luteinizing hormone-releasing hormone (LHRH) receptor; angiogenesis; MASPIN/SERPINB5 ; AEZS-108 (AN-152/Zoptarelin Doxorubicin Acetate) Received: December 05, 2019 Accepted: December 29, 2019 Published: January 14, 2020 ABSTRACT Uveal melanoma (UM) is the most common malignant tumor of the eye. Recently, we have established that 46% of UM specimens express LHRH receptors. This finding supports the idea of a LHRH receptor-targeted therapy of UM patients. Cytotoxic analog of LHRH, AEZS-108 exhibits effective anti-cancer activity in LHRH-receptor positive cancers. AEZS-108 is a hybrid molecule, composed of a synthetic peptide carrier and the cytotoxic doxorubicin (DOX). In the present study, we investigated AEZS-108 induced cytotoxicity and the altered mRNA expression profile of regulatory factors related to angiogenesis and metastasis in LHRH receptor positive OCM3 cells. Our results show that AEZS-108 upregulates the expression of MASPIN/SERPINB5 tumor suppressor gene, which is downregulated in normal uvea and UM specimens independently from the LHRH receptor-ligand interaction. AEZS-108 also substantially downregulates hypoxia-inducible factor 1 alpha (HIF1A) expression. In order to investigate the mechanism of the induction of MASPIN by AEZS-108, OCM3 cells were treated with free DOX, D-Lys 6 LHRH analog, or AEZS-108. qRT- PCR analysis revealed in OCM3 cells that AEZS-108 is a more potent inducer of MASPIN than free DOX. In conclusion, we show for the first time that AEZS-108 has a major impact in the regulation of angiogenesis thus plays a potential role in tumor suppression. Taken together, our results support the development of novel therapeutic strategies for UM focusing on LHRH receptors.