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Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma D’Costa, Ninadh M; Lowerison, Matthew R; Raven, Peter A; Tan, Zheng; Roberts, Morgan E; Shrestha, Raunak; Urban, Matthew W; Monjaras-Avila, Cesar U; Oo, Htoo Z; Hurtado-Coll, Antonio; Chavez-Munoz, Claudia; So, Alan I

Abstract

Background: Renal cell carcinoma (RCC) is a highly vascular tumor and patients with low risk metastatic RCC of clear-cell histological sub-type (mccRCC) are treated with tyrosine-kinase inhibitors (TKIs), sunitinib, as the first-line of treatment. Unfortunately, TKI resistance eventually develops, and the underlying molecular mechanism is not well understood. Methods: RCC cell-line with metastatic clear-cell histology (Caki-1), and patient samples were analysed to identify the role of Y-box binding protein 1 (YB-1) and ATP-binding cassette sub-family B member 1 (ABCB-1) in acquired sunitinib-resistance development. Caki-1 was conditioned with increasing sunitinib doses to recapitulate acquired resistance development in clinics. Sunitinib-conditioned and wild-type Caki-1 were subjected to cell viability assay, scratch assay, chicken embryo chorioallantoic membrane engraftment and proteomics analysis. Classical biochemical assays like flow cytometry, immunofluorescent staining, immunohistochemical staining, optical coherence tomography imaging, Western Blot and RT-PCR assays were applied to determine the possible mechanism of sunitinib-resistance development and the effect of drug treatments. Publicly available data was also used to determine the role of YB-1 upregulation in ccRCC and the patients’ overall survival. Results: We demonstrate that YB-1 and ABCB-1 are upregulated in sunitinib-resistant in vitro, ex vivo, in vivo and patient samples compared to the sensitive samples. This provides evidence to a mechanism of acquired sunitinib-resistance development in mccRCC. Furthermore, our results establish that inhibiting ABCB-1 with elacridar, in addition to sunitinib, has a positive impact on reverting sunitinib-resistance development in in vitro, ex vivo and in vivo models. Conclusion: This work proposes a targeted therapy (elacridar and sunitinib) to re-sensitize sunitinib-resistant mccRCC and, possibly, slow disease progression.

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Title
Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma
Creator
D’Costa, Ninadh M; Lowerison, Matthew R; Raven, Peter A; Tan, Zheng; Roberts, Morgan E; Shrestha, Raunak; Urban, Matthew W; Monjaras-Avila, Cesar U; Oo, Htoo Z; Hurtado-Coll, Antonio; Chavez-Munoz, Claudia; So, Alan I
Contributor
Vancouver Prostate Centre
Publisher
BioMed Central
Date Issued
2020-02-10
Description
Background: Renal cell carcinoma (RCC) is a highly vascular tumor and patients with low risk metastatic RCC of clear-cell histological sub-type (mccRCC) are treated with tyrosine-kinase inhibitors (TKIs), sunitinib, as the first-line of treatment. Unfortunately, TKI resistance eventually develops, and the underlying molecular mechanism is not well understood. Methods: RCC cell-line with metastatic clear-cell histology (Caki-1), and patient samples were analysed to identify the role of Y-box binding protein 1 (YB-1) and ATP-binding cassette sub-family B member 1 (ABCB-1) in acquired sunitinib-resistance development. Caki-1 was conditioned with increasing sunitinib doses to recapitulate acquired resistance development in clinics. Sunitinib-conditioned and wild-type Caki-1 were subjected to cell viability assay, scratch assay, chicken embryo chorioallantoic membrane engraftment and proteomics analysis. Classical biochemical assays like flow cytometry, immunofluorescent staining, immunohistochemical staining, optical coherence tomography imaging, Western Blot and RT-PCR assays were applied to determine the possible mechanism of sunitinib-resistance development and the effect of drug treatments. Publicly available data was also used to determine the role of YB-1 upregulation in ccRCC and the patients’ overall survival. Results: We demonstrate that YB-1 and ABCB-1 are upregulated in sunitinib-resistant in vitro, ex vivo, in vivo and patient samples compared to the sensitive samples. This provides evidence to a mechanism of acquired sunitinib-resistance development in mccRCC. Furthermore, our results establish that inhibiting ABCB-1 with elacridar, in addition to sunitinib, has a positive impact on reverting sunitinib-resistance development in in vitro, ex vivo and in vivo models. Conclusion: This work proposes a targeted therapy (elacridar and sunitinib) to re-sensitize sunitinib-resistant mccRCC and, possibly, slow disease progression.
Subject
Renal cell carcinoma; Angiogenesis; Metastasis; Sunitinib; Resistance; Tyrosine kinase inhibitors (TKI)
Genre
Article
Type
Text
Language
eng
Date Available
2020-02-12
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0388607
URI
http://hdl.handle.net/2429/73515
Affiliation
Medicine, Faculty of; Other UBC; Non UBC; Urologic Sciences, Department of
Citation
Journal of Experimental & Clinical Cancer Research. 2020 Feb 10;39(1):33
Publisher DOI
10.1186/s13046-020-1527-y
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
The Author(s).
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)