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

Lorant Szekvolgyi,Andrew Schally,Gabor Halmos,Klara Fodor,Eva Sipos,Zita Steiber,Nikoletta Dobos,Gabor Olah

doi:10.18632/oncotarget.27431

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-Lys6 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.

Highlights

Uveal melanoma (UM) is a rare disease, it is the most prevalent lethal ophthalmological tumor [1, 2]
Our results shows that AEZS-108, as well as doxorubicin significantly inhibited the proliferation of ocular chorioideal melanoma 3 (OCM3) human uveal melanoma cells
Expression and cellular distribution of the full length Luteinizing Hormone-Releasing Hormone (LHRH) receptor type I in OCM3 cells was demonstrated by reverse transcription (RT)-quantitative reverse transcription- polymerase chain reaction (PCR) and by immunocytochemistry (Figure 1)

Summary

Introduction

Uveal melanoma (UM) is a rare disease, it is the most prevalent lethal ophthalmological tumor [1, 2]. 50% of the patients already manifests distant metastases, mostly in the liver at the time of the diagnosis [2]. In spite of the currently available systemic therapies, 90% of the patients with metastasis die within. Chemotherapy or partial hepatectomy only rarely prolongs the survival, emphasizing the necessity of developing more effective therapies [5]. The discovery of specific receptors for peptide hormones on cancer cells has led to the development of cytotoxic or radiolabeled hormone analogs that are appropriate for tumor localization and targeted therapy. Numerous preclinical studies have demonstrated the efficacy of chemotherapy based on cytotoxic peptide conjugates targeted to receptors on different tumors [6,7,8,9,10]. Clinical trials confirmed that targeted cytotoxic LHRH analog can improve the effectiveness of treatment and reduce general side effects [11,12,13]

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