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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Veröffentlicht in:Journal of personalized medicine 2020-11, Vol.10 (4), p.246
Hauptverfasser: Ulm, Michael A., Redfern, Tiffany M., Wilson, Ben R., Ponnusamy, Suriyan, Asemota, Sarah, Blackburn, Patrick W., Wang, Yinan, ElNaggar, Adam C., Narayanan, Ramesh
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container_end_page
container_issue 4
container_start_page 246
container_title Journal of personalized medicine
container_volume 10
creator Ulm, Michael A.
Redfern, Tiffany M.
Wilson, Ben R.
Ponnusamy, Suriyan
Asemota, Sarah
Blackburn, Patrick W.
Wang, Yinan
ElNaggar, Adam C.
Narayanan, Ramesh
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.
doi_str_mv 10.3390/jpm10040246
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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.</description><identifier>ISSN: 2075-4426</identifier><identifier>EISSN: 2075-4426</identifier><identifier>DOI: 10.3390/jpm10040246</identifier><identifier>PMID: 33256002</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>AKT protein ; Apoptosis ; Bioinformatics ; Cell culture ; Cell cycle ; Cell growth ; Cell proliferation ; CRISPR ; DNA microarrays ; Drug development ; Drug resistance ; Experiments ; Extracellular matrix ; Gene expression ; Genetic transformation ; Genomes ; ILK protein ; Kinases ; Metastasis ; Ovarian cancer ; Precision medicine ; Proteins ; Reagents ; Software ; Therapeutic applications ; Tumors ; Variance analysis ; Xenografts</subject><ispartof>Journal of personalized medicine, 2020-11, Vol.10 (4), p.246</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). 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source Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central
subjects AKT protein
Apoptosis
Bioinformatics
Cell culture
Cell cycle
Cell growth
Cell proliferation
CRISPR
DNA microarrays
Drug development
Drug resistance
Experiments
Extracellular matrix
Gene expression
Genetic transformation
Genomes
ILK protein
Kinases
Metastasis
Ovarian cancer
Precision medicine
Proteins
Reagents
Software
Therapeutic applications
Tumors
Variance analysis
Xenografts
title Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer
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