A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance

Journal
International Journal of Molecular Sciences
ISSN
1422-0067
Date Issued
2023
Author(s)
Luis Vergara-Gómez
Carolina Bizama
Jun Zhong
Kurt Buchegger
Felipe Suárez
Lorena Rosa
Carmen Ili
Helga Weber
Javiera Obreque
Karena Espinoza
Juan C. Roa
Pamela Leal
Patricia García
Type
Resource Types::text::journal::journal article
Scopus ID
2-s2.0-85159243396
WoS ID
WOS:000979200000001
DOI
URL
URL Institutional Repository
Abstract
<jats:p>Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC.</jats:p>
Cite this document
Vergara-Gómez, L., Bizama, C., Zhong, J., Buchegger, K., Suárez, F., Rosa, L., Ili, C., Weber, H., Obreque, J., Espinoza, K., Repetto, G., Roa, J. C., Leal, P., & García, P. (2023). A novel gemcitabine-resistant gallbladder cancer model provides insights into molecular changes occurring during acquired resistance. International Journal of Molecular Sciences, 24(8), 7238. https://doi.org/10.3390/ijms24087238
Project(s)
Subjects
acquired drug resistance

; 

cytidine deaminase

; 

epithelial-to-mesenchymal transition

; 

gallbladder cancer

; 

gemcitabine

; 

gene expression profiling

; 

silac-based phosphoproteomics

; 

carcinoma in situ

; 

cell line, tumor

; 

deoxycytidine

; 

gallbladder neoplasms

; 

gemcitabine

; 

humans

; 

proteomics

; 

doxecitine

; 

gemcitabine

; 

carcinoma in situ

; 

gallbladder tumor

; 

genetics

; 

human

; 

metabolism

; 

proteomics

; 

tumor cell line