Journal article
Differential effects of HIF2α antagonist and HIF2α silencing in renal cancer and sensitivity to repurposed drugs
- Abstract:
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Background
In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed.
Methods
We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385.
Results
PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity. Conclusions: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
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- Files:
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(Preview, Version of record, pdf, 2.2MB, Terms of use)
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- Publisher copy:
- 10.1186/s12885-021-08616-8
Authors
- Publisher:
- BioMed Central
- Journal:
- BMC Cancer More from this journal
- Volume:
- 21
- Article number:
- 896
- Place of publication:
- England
- Publication date:
- 2021-08-05
- Acceptance date:
- 2021-07-15
- DOI:
- EISSN:
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1471-2407
- ISSN:
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1471-2407
- Pmid:
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34353313
- Language:
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English
- Keywords:
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- Pubs id:
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1191072
- Local pid:
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pubs:1191072
- Deposit date:
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2024-02-20
Terms of use
- Copyright holder:
- Arnaiz et al.
- Copyright date:
- 2021
- Rights statement:
- © The Author(s). 2021 Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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