Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma

Autor: Morgan E. Roberts, Htoo Zarni Oo, Zheng Tan, Matthew W. Urban, Raunak Shrestha, Ninadh M. D'Costa, Peter A. Raven, Claudia Chavez-Munoz, Matthew R. Lowerison, César Monjarás-Ávila, Antonio Hurtado-Coll, Alan I. So
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
Cancer Research
Kidney Disease
medicine.medical_treatment
Resistance
Drug Resistance
urologic and male genital diseases
Targeted therapy
Metastasis
Mice
0302 clinical medicine
Renal cell carcinoma
Models
Sunitinib
Neoplasm Metastasis
Cancer
0303 health sciences
Tumor
medicine.diagnostic_test
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Immunohistochemistry
female genital diseases and pregnancy complications
Kidney Neoplasms
3. Good health
Phenotype
Treatment Outcome
Oncology
Subfamily B
030220 oncology & carcinogenesis
Female
medicine.drug
ATP Binding Cassette Transporter
Subfamily B
ATP Binding Cassette Transporter
Oncology and Carcinogenesis
Antineoplastic Agents
lcsh:RC254-282
Models
Biological
Flow cytometry
Cell Line
03 medical and health sciences
Rare Diseases
In vivo
Cell Line
Tumor
medicine
Animals
Humans
Viability assay
Oncology & Carcinogenesis
Carcinoma
Renal Cell
030304 developmental biology
Neoplasm Staging
Tyrosine kinase inhibitors
business.industry
Animal
Tyrosine kinase inhibitors (TKI)
Research
Carcinoma
Renal Cell
medicine.disease
Biological
Xenograft Model Antitumor Assays
Clear cell renal cell carcinoma
Disease Models
Animal
Drug Resistance
Neoplasm
Disease Models
Cancer research
Neoplasm
Antimicrobial Resistance
Angiogenesis
Y-Box-Binding Protein 1
business
Ex vivo
Zdroj: Journal of Experimental & Clinical Cancer Research : CR
Journal of experimental & clinical cancer research : CR, vol 39, iss 1
Journal of Experimental & Clinical Cancer Research, Vol 39, Iss 1, Pp 1-16 (2020)
ISSN: 1756-9966
0392-9078
Popis: 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.
Databáze: OpenAIRE
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