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Endothelins Regulations in ovarian Cancer

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Information about Endothelins Regulations in ovarian Cancer
Health & Medicine

Published on March 3, 2014

Author: raghuippadi

Source: slideshare.net

Description

Endothelins are a class of endothelial origin peptides families consists of three closely related 21 amino acid peptides: ET -1, -2, and -3. They are ubiquitously expressed in mammalian cells, and exert paracrine and autocrine effects through cell-surface receptors to influence normal cellular processes, such as maintenance of vasomotor tone, cellular proliferation, tissue repair and development. Among three endothelial peptides, ET- 1 is important marker in cancer especially in ovarian cancer.
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03/03/14 By: Mr.Raghavendra Basavaraja, M.SC Animal sciences, Faculta, 1 Hebrew university of Jerusalem Raghuippadi

Introduction  Facts  Papers  Objectives  Material & Methods  Results  Future strategies for OC  03/03/14 Raghuippadi 2

 Ovary  Female reproductive organ Responsible for produce female sex hormones and Ovulation  Cancer   Abnormal growth of cells Caused by either Mutations or abnormal activation of genes 03/03/14 Raghuippadi 3

03/03/14 Raghuippadi 4

est ter e in om S OC 03/03/14 cts g fa in Raghuippadi ut bo a 5

Percent of Cases & 5-Year Relative Survival by Stage at Diagnosis: Ovary Cancer 5-Year Relative Survival Percent of Cases by Stage Localized (15%) Confined to Primary Site Regional (18%) Spread to Regional Lymph Nodes Distant (61%) Cancer Has Metastasized Unknown (6%) Upstaged Age Group: Ovary Cancer Courtesy: SEER 18 2006-2010, All Races, Females 03/03/14 Raghuippadi 6

Endothelins    A 21 amino acid peptide family ( EDN-1,2,3) Found in endothelial cells Pathophysiology…. 03/03/14 Raghuippadi 7

EDN’s Pathway gefitinib Zibotentan 03/03/14 Raghuippadi 8

Department of Animal Sciences, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Israel Department of Animal Sciences, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Israel 03/03/14 Raghuippadi 9

ETA-R & β-catenin     Expression of EDN’S In OC Epithelial cells. Cross talk b/w ETAR and EGFR enhances the metasatic nature of OC Role of β-catenin & ECE-1 in metastasis & effect of their inhibition Anticancer therapy Multi drug approach(Zibotetan+gefinib) Endothelin-1  RNA interference 03/03/14 Raghuippadi 10

Materials and methods  cell culture & Transfection: OVACR3(HTB61); Transfection ES2(CRL1978);EOC ;HEY & SKOV3  Real time PCR : CDNA-RNA( Gene expression)  Western blot : proteins Identification(MAPK;PKA)  ELISA & RIA: ET-1 and β-catenin concentration  Immuno histochemistry: location of cellular proteins  Zymography: protein activity (MMP)  Statistical Analysis: ± SEM & student t test( b/w groups) Multiple comparison by one way ANOVA & Tukey Kramer test 03/03/14 Raghuippadi 11

!!! lts su Re 03/03/14 Raghuippadi 12

The endothelin A receptor and epidermal growth factor receptor signaling  converge on β-catenin to promote ovarian cancer metastasis Fig. 1. A. Lysates of SKOV3 cells treated with 10 ng/ml EGF, or 100 nM ET-1, and/or 1 μM zibotentan, or 1 μM gefitinib, or 1 μM PP2, or  combination of zibotentan and gefitinib, were analysed by I... Roberta  Cianfrocca , Piera  Tocci , Francesca  Spinella , Valeriana  Di Castro , Anna  Bagnato , Laura  Rosanò Life Sciences Volume 91, Issues 13–14 2012 550 - 556 03/03/14 Raghuippadi 13

Effect of zibotentan and gefitinib treatments on metastatic potential of  ovarian cancer cells Fig. 3. A. HEY cells were injected i.p. into nude mice and one week after cell injection, mice were treated for 21 days with vehicle, or with  zibotentan (10 mg/kg... Roberta  Cianfrocca , Piera  Tocci , Francesca  Spinella , Valeriana  Di Castro , Anna  Bagnato , Laura  Rosanò 03/03/14 Life Sciences Volume 91, Issues 13–14 2012 550 - 556 Raghuippadi 14

Levels of ET-1 mRNA (A), peptide concentrations in culture medium (B), and ECE-1 (C) and ETA (D) mRNA expression in the ES2 and OVCAR3 ovarian carcinoma cell lines. Rayhman O et al. Cancer Res 2008;68:9265-9273 03/03/14 Raghuippadi 15

Suppression of ET-1 biosynthesis by ECE-1 siRNA molecules. Rayhman O et al. Cancer Res 2008;68:9265-9273 03/03/14 Raghuippadi 16

Effect of ECE-1 silencing on p44/42 MAPK phosphorylation. Rayhman O et al. Cancer Res 2008;68:9265-9273 ©2008 by American Association for Cancer Research

Conclusion       ET-1 is one of major EDN’s express in the ovarian cancer epithelial cells. ET-1 exerts its effects via transactivation of EGFR by binding with ETAR. From the above pathway also we know that EDN can activate β catenin to induce the metastasis Multi drug like zibotentan & geftinib is better rather than using single approach ECE-1 Silencing is a prominent tool in control of Endothelin-1expression in OC Finally we realized that even through EDN’s are 21 aa peptide play major role in OC. 03/03/14 Raghuippadi 18

Future Strategies in Ovarian Cancer 03/03/14 Raghuippadi 19

References      http://www.endothelins.com/Conferences/ http://seer.cancer.gov/statfacts/html/ovary.html. http://www.medicinenet.com/ovarian_cancer/article.htm . http://www.ncbi.nlm.nih.gov/pubmed/20625315 Cianfrocca R, Tocci P, Spinella F, Di Castro V, Bagnato A, Rosanò L.Life Sci. 2012 Oct 15;91(13-14):550-6. doi: 10.1016/j.lfs.2012.03.023. Epub 2012 Mar 28.PMID: 22480520 [PubMed - indexed for MEDLINE] Rayhman O, Klipper E, Muller L, Davidson B, Reich R, Meidan R. Small interfering RNA molecules targeting endothelin-converting enzyme-1 inhibit endothelin-1 synthesis and the invasive phenotype of ovarian carcinoma cells. Cancer Res. 2008;68:9265–9273. [PubMed]. 03/03/14 Raghuippadi 20

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