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

Department of Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK
School of Agriculture and Food Sciences, University of Queensland, Gatton, QLD 4343, Australia
Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, UK
Scottish Collaboration on Translational Research into Renal Cell Cancer (SCOTRRCC)
Bart’s Cancer Institute, Charterhouse Square, London EC1M 6BE, UK
CSIRO Agriculture and Food, Queensland Bioscience Precinct, St. Lucia, QLD 4067, Australia
School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, UK
Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Biology 2020, 9(4), 74;
Received: 23 January 2020 / Revised: 1 April 2020 / Accepted: 2 April 2020 / Published: 7 April 2020
(This article belongs to the Section Medical Biology)
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; p < 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; p < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (p < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib. View Full-Text
Keywords: renal cancer; kidney cancer; sunitinib; PHAX; organ culture renal cancer; kidney cancer; sunitinib; PHAX; organ culture
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Al-Lamki, R.S.; Hudson, N.J.; Bradley, J.R.; Warren, A.Y.; Eisen, T.; Welsh, S.J.; Riddick, A.C.P.; O’Mahony, F.C.; Turnbull, A.; Powles, T.; SCOTRRCC Collaborative; Reverter, A.; Harrison, D.J.; Stewart, G.D. The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro. Biology 2020, 9, 74.

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