The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differ...

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Main Authors:	Rafia S. Al-Lamki, Nicholas J. Hudson, John R. Bradley, Anne Y. Warren, Tim Eisen, Sarah J. Welsh, Antony C. P. Riddick, Fiach C. O’Mahony, Arran Turnbull, Thomas Powles, SCOTRRCC Collaborative, Antonio Reverter, David J. Harrison, Grant D. Stewart
Format:	Article
Language:	English
Published:	MDPI AG 2020-04-01
Series:	Biology
Subjects:	renal cancer kidney cancer sunitinib PHAX organ culture
Online Access:	https://www.mdpi.com/2079-7737/9/4/74

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spelling	doaj-bdec240a0b9e42e0af0a9f88f0e825982020-11-25T02:10:45ZengMDPI AGBiology2079-77372020-04-019747410.3390/biology9040074The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In VitroRafia S. Al-Lamki0Nicholas J. Hudson1John R. Bradley2Anne Y. Warren3Tim Eisen4Sarah J. Welsh5Antony C. P. Riddick6Fiach C. O’Mahony7Arran Turnbull8Thomas Powles9SCOTRRCC Collaborative10Antonio Reverter11David J. Harrison12Grant D. Stewart13Department of Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UKSchool of Agriculture and Food Sciences, University of Queensland, Gatton, QLD 4343, AustraliaDepartment of Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UKCambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UKCambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UKCambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UKCambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UKScottish Collaboration on Translational Research into Renal Cell Cancer (SCOTRRCC)Scottish Collaboration on Translational Research into Renal Cell Cancer (SCOTRRCC)Bart’s Cancer Institute, Charterhouse Square, London EC1M 6BE, UKScottish Collaboration on Translational Research into Renal Cell Cancer (SCOTRRCC)CSIRO Agriculture and Food, Queensland Bioscience Precinct, St. Lucia, QLD 4067, AustraliaScottish Collaboration on Translational Research into Renal Cell Cancer (SCOTRRCC)Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UKAnti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; <i>p</i> < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; <i>p</i> < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (<i>p</i> < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.https://www.mdpi.com/2079-7737/9/4/74renal cancerkidney cancersunitinibPHAXorgan culture
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Rafia S. Al-Lamki Nicholas J. Hudson John R. Bradley Anne Y. Warren Tim Eisen Sarah J. Welsh Antony C. P. Riddick Fiach C. O’Mahony Arran Turnbull Thomas Powles SCOTRRCC Collaborative Antonio Reverter David J. Harrison Grant D. Stewart
spellingShingle	Rafia S. Al-Lamki Nicholas J. Hudson John R. Bradley Anne Y. Warren Tim Eisen Sarah J. Welsh Antony C. P. Riddick Fiach C. O’Mahony Arran Turnbull Thomas Powles SCOTRRCC Collaborative Antonio Reverter David J. Harrison Grant D. Stewart The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro Biology renal cancer kidney cancer sunitinib PHAX organ culture
author_facet	Rafia S. Al-Lamki Nicholas J. Hudson John R. Bradley Anne Y. Warren Tim Eisen Sarah J. Welsh Antony C. P. Riddick Fiach C. O’Mahony Arran Turnbull Thomas Powles SCOTRRCC Collaborative Antonio Reverter David J. Harrison Grant D. Stewart
author_sort	Rafia S. Al-Lamki
title	The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro
title_short	The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro
title_full	The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro
title_fullStr	The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro
title_full_unstemmed	The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro
title_sort	efficacy of sunitinib treatment of renal cancer cells is associated with the protein phax in vitro
publisher	MDPI AG
series	Biology
issn	2079-7737
publishDate	2020-04-01
description	Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; <i>p</i> < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; <i>p</i> < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (<i>p</i> < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.
topic	renal cancer kidney cancer sunitinib PHAX organ culture
url	https://www.mdpi.com/2079-7737/9/4/74
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The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro

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