TY - JOUR
T1 - The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma
AU - Fodor, Klara
AU - Dobos, Nikoletta
AU - Schally, Andrew
AU - Steiber, Zita
AU - Olah, Gabor
AU - Sipos, Eva
AU - Szekvolgyi, Lorant
AU - Halmos, Gabor
N1 - Funding Information:
This work was supported by Hungarian Scientific Research Fund (OTKA) K 81596 (G.H.), TAMOP 4.2.2.A-11/1/KONV-2012-0025 project (G.H.), GINOP-2.3.2-15-2016-00043 (G.H.), GINOP-2.3.2-15-2016-00024 (L.Sz.), LEND?LET Program, LP2015-9/2015 (L.Sz.) and the Gedeon Richter?s Talentum Foundation (K.F.) The research was also financed by the framework of the Biotechnology Thematic Programme of the University of Debrecen (20428-3/2018/FEKUTSRAT) (G.H.), and it was cofinanced by the European Union and the State of Hungary, by the European Social Fund in the framework of T?MOP-4.2.4.A/2-11-1-2012-0001 ?National Excellence? Program (K.F.).
Funding Information:
This work was supported by Hungarian Scientific Research Fund (OTKA) K 81596 (G.H.), TAMOP 4.2.2.A-11/1/KONV-2012-0025 project (G.H.), GINOP-2.3.2-15-2016-00043 (G.H.), GINOP-2.3.2-15-2016-00024 (L.Sz.), LENDÜLET Program, LP2015-9/2015 (L.Sz.) and the Gedeon Richter’s Talentum Foundation (K.F.) The research was also financed by the framework of the Biotechnology Thematic Programme of the University of Debrecen (20428-3/2018/FEKUTSRAT) (G.H.), and it was cofinanced by the European Union and the State of Hungary, by the European Social Fund in the framework of TÁMOP-4.2.4.A/2-11-1-2012-0001 ‘National Excellence’ Program (K.F.).
Publisher Copyright:
Copyright: Fodor et al.
PY - 2020/1/14
Y1 - 2020/1/14
N2 - 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.
AB - 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.
KW - AEZS-108 (AN-152/Zoptarelin doxorubicin acetate)
KW - Angiogenesis
KW - Luteinizing hormone-releasing hormone (LHRH) receptor
KW - MASPIN/SERPINB5
KW - Uveal melanoma
UR - http://www.scopus.com/inward/record.url?scp=85078872890&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078872890&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.27431
DO - 10.18632/oncotarget.27431
M3 - Article
AN - SCOPUS:85078872890
VL - 11
SP - 175
EP - 187
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 2
ER -