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Transcriptome of Two Canine Prostate Cancer Cells Treated With Toceranib Phosphate Reveals Distinct Antitumor
Priscila E Kobayashi1, Patrícia F Lainetti2, Antonio F Leis-Filho1
1Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University-UNESP, Botucatu, Brazil.
Abstract:
Canine prostate cancer (PC) presents a poor antitumor response, usually late diagnosis and prognosis. Toceranib phosphate (TP) is a nonspecific inhibitor of receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-KIT. This study aimed to evaluate VEGFR2, PDGFR-β, and c-KIT protein expression in two established canine PC cell lines (PC1 and PC2) and the transcriptome profile of the cells after treatment with TP. Immunofluorescence (IF) analysis revealed VEGFR2 and PDGFR-β protein expression and the absence of c-KIT protein expression in both cell lines. After TP treatment, only the viability of PC1 cells decreased in a dose-dependent manner. Transcriptome and enrichment analyses of treated PC1 cells revealed 181 upregulated genes, which were related to decreased angiogenesis and cell proliferation. In addition, we found upregulated PDGFR-A, PDGFR-β, and PDGF-D expression in PC1 cells, and the upregulation of PDGFR-β was also observed in treated PC1 cells by qPCR. PC2 cells had fewer protein-protein interactions (PPIs), with 18 upregulated and 22 downregulated genes; the upregulated genes were involved in the regulation of parallel pathways and mechanisms related to proliferation, which could be associated with the resistance observed after treatment. The canine PC1 cell line but not the PC2 cell line showed decreased viability after treatment with TP, although both cell lines expressed PDGFR and VEGFR receptors. Further studies could explain the mechanism of resistance in PC2 cells and provide a basis for personalized treatment for dogs with PC.
Insights
Tocerainib phosphate treatment reduced canine prostate cancer cell viability in the PC1 cell line by decreasing angiogenesis and proliferation. However, the PC2 cell line exhibited resistance, suggesting a need for personalized canine cancer therapies.
Area of Science:
- Veterinary Oncology
- Molecular Biology
- Cancer Research
Background:
- Canine prostate cancer (PC) often has a poor prognosis and late diagnosis.
- Tocerainib phosphate (TP) inhibits receptor tyrosine kinases (RTKs) like VEGFR, PDGFR, and c-KIT.
- Understanding RTK expression in canine PC is crucial for targeted therapies.
Purpose of the Study:
- To assess VEGFR2, PDGFR-β, and c-KIT protein expression in canine PC cell lines (PC1 and PC2).
- To analyze the transcriptome profile of these cell lines after TP treatment.
- To investigate differential responses to TP between PC1 and PC2 cell lines.
Main Methods:
- Immunofluorescence (IF) for protein expression analysis.
- Cell viability assays to determine TP efficacy.
- Transcriptome sequencing and quantitative PCR (qPCR) for gene expression profiling.
- Bioinformatic analyses including gene enrichment and protein-protein interaction (PPI) networks.
Main Results:
- Both PC1 and PC2 cell lines expressed VEGFR2 and PDGFR-β, but not c-KIT.
- TP treatment decreased PC1 cell viability in a dose-dependent manner.
- TP treatment upregulated genes associated with reduced angiogenesis and proliferation in PC1 cells.
- PC2 cells showed resistance to TP, with distinct gene expression patterns related to proliferation pathways.
Conclusions:
- Canine PC1 cells are sensitive to TP, showing reduced viability and altered gene expression post-treatment.
- Canine PC2 cells exhibit resistance to TP, potentially due to alternative proliferation mechanisms.
- Differential responses highlight the need for personalized treatment strategies in canine prostate cancer.
