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Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer

Objective: The objective of this study is to identify and validate novel therapeutic target(s) in ovarian cancer. Background: Development of targeted therapeutics in ovarian cancer has been limited by molecular heterogeneity. Although gene expression datasets are available, most of them lack appropr...

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Autores principales: Ulm, Michael A., Redfern, Tiffany M., Wilson, Ben R., Ponnusamy, Suriyan, Asemota, Sarah, Blackburn, Patrick W., Wang, Yinan, ElNaggar, Adam C., Narayanan, Ramesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712057/
https://www.ncbi.nlm.nih.gov/pubmed/33256002
http://dx.doi.org/10.3390/jpm10040246
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author Ulm, Michael A.
Redfern, Tiffany M.
Wilson, Ben R.
Ponnusamy, Suriyan
Asemota, Sarah
Blackburn, Patrick W.
Wang, Yinan
ElNaggar, Adam C.
Narayanan, Ramesh
author_facet Ulm, Michael A.
Redfern, Tiffany M.
Wilson, Ben R.
Ponnusamy, Suriyan
Asemota, Sarah
Blackburn, Patrick W.
Wang, Yinan
ElNaggar, Adam C.
Narayanan, Ramesh
author_sort Ulm, Michael A.
collection PubMed
description Objective: The objective of this study is to identify and validate novel therapeutic target(s) in ovarian cancer. Background: Development of targeted therapeutics in ovarian cancer has been limited by molecular heterogeneity. Although gene expression datasets are available, most of them lack appropriate pair-matched controls to define the alterations that result in the transformation of normal ovarian cells to cancerous cells. Methods: We used microarray to compare the gene expression of treatment-naïve ovarian cancer tissue samples to pair-matched normal adjacent ovarian tissue from 24 patients. Ingenuity Pathway Analysis (IPA) was used to identify target pathways for further analysis. Integrin-linked kinase (ILK) expression in SKOV3 and OV90 cells was determined using Western blot. ILK was knocked down using CRISPR/Cas9 constructs. Subcutaneous xenograft study to determine the effect of ILK knockdown on tumor growth was performed in NOD SCID gamma mice. Results: Significant upregulation of the ILK pathway was identified in 22 of the 24 cancer specimens, identifying it as a potential player that could contribute to the transformation of normal ovarian cells to cancerous cells. Knockdown of ILK in SKOV3 cells resulted in decreased cell proliferation and tumor growth, and inhibition of downstream kinase, AKT (protein kinase B). These results were further validated using an ILK-1 chemical inhibitor, compound 22. Conclusion: Our initial findings validate ILK as a potential therapeutic target for molecular inhibition in ovarian cancer, which warrants further investigation.
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spelling pubmed-77120572020-12-04 Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer Ulm, Michael A. Redfern, Tiffany M. Wilson, Ben R. Ponnusamy, Suriyan Asemota, Sarah Blackburn, Patrick W. Wang, Yinan ElNaggar, Adam C. Narayanan, Ramesh J Pers Med Article Objective: The objective of this study is to identify and validate novel therapeutic target(s) in ovarian cancer. Background: Development of targeted therapeutics in ovarian cancer has been limited by molecular heterogeneity. Although gene expression datasets are available, most of them lack appropriate pair-matched controls to define the alterations that result in the transformation of normal ovarian cells to cancerous cells. Methods: We used microarray to compare the gene expression of treatment-naïve ovarian cancer tissue samples to pair-matched normal adjacent ovarian tissue from 24 patients. Ingenuity Pathway Analysis (IPA) was used to identify target pathways for further analysis. Integrin-linked kinase (ILK) expression in SKOV3 and OV90 cells was determined using Western blot. ILK was knocked down using CRISPR/Cas9 constructs. Subcutaneous xenograft study to determine the effect of ILK knockdown on tumor growth was performed in NOD SCID gamma mice. Results: Significant upregulation of the ILK pathway was identified in 22 of the 24 cancer specimens, identifying it as a potential player that could contribute to the transformation of normal ovarian cells to cancerous cells. Knockdown of ILK in SKOV3 cells resulted in decreased cell proliferation and tumor growth, and inhibition of downstream kinase, AKT (protein kinase B). These results were further validated using an ILK-1 chemical inhibitor, compound 22. Conclusion: Our initial findings validate ILK as a potential therapeutic target for molecular inhibition in ovarian cancer, which warrants further investigation. MDPI 2020-11-26 /pmc/articles/PMC7712057/ /pubmed/33256002 http://dx.doi.org/10.3390/jpm10040246 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ulm, Michael A.
Redfern, Tiffany M.
Wilson, Ben R.
Ponnusamy, Suriyan
Asemota, Sarah
Blackburn, Patrick W.
Wang, Yinan
ElNaggar, Adam C.
Narayanan, Ramesh
Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer
title Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer
title_full Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer
title_fullStr Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer
title_full_unstemmed Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer
title_short Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer
title_sort integrin-linked kinase is a novel therapeutic target in ovarian cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712057/
https://www.ncbi.nlm.nih.gov/pubmed/33256002
http://dx.doi.org/10.3390/jpm10040246
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