Related Experiment Video
Updated: May 9, 2025
miRNA Expression Analyses in Prostate Cancer Clinical Tissues
Published on: September 8, 2015
Canine prostate cancer cell transcriptome reveals important dysregulation in PI3K/AKT/mTOR pathway
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, Botucatu, São Paulo, Brazil.
Abstract:
Dogs are the only large mammals, besides humans, that develop spontaneous prostate cancer, which has a poor prognosis and limited treatment efficacy. Considering the central role of mammalian target of rapamycin (mTOR) in carcinogenesis, the use of rapamycin, an mTOR inhibitor, has attracted considerable attention. In this study, we performed gene expression microarray analyses of normal canine prostate and prostate carcinoma cells. Among the 6,270 differentially expressed genes revealed in the transcriptome, 3,242 were upregulated and 3,028 were downregulated, and were related to phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway activation, as confirmed by enrichment analysis. Among the genes involved in this pathway, we found increased expression levels of FKBP1A, FKBP1B, AKT1S1, PDK2, PIP5K1 and PIP5KL1 in canine prostate cancer cells compared with normal prostate cells. We also treated two canine prostate cancer cell lines (PC1 and PC2) with rapamycin in vitro (6, 10 and 12 microM) for 24 h and observed a dose-dependent decrease in cell viability. Our results indicate that rapamycin significantly increased AKT transcript levels in both cell lines, indicating resistance to treatment. However, mTOR and 4E-BP1 expression were downregulated after rapamycin treatment. We suggest that mTOR inhibition is a potential treatment of choice for canine prostate cancer, which may guide and contribute to future prostate carcinoma clinical trials. However, the acquisition of resistance to treatment remains a challenge, and precision medicine may help overcome this problem.
Insights
Rapamycin shows potential for treating canine prostate cancer by inhibiting mTOR. However, canine prostate cancer cells developed resistance to rapamycin, highlighting the need for precision medicine approaches.
Area of Science:
- Oncology
- Molecular Biology
- Veterinary Medicine
Background:
- Dogs are unique large mammals, alongside humans, that spontaneously develop prostate cancer.
- Canine prostate cancer has a poor prognosis and limited treatment options.
- The mammalian target of rapamycin (mTOR) pathway plays a crucial role in cancer development.
Purpose of the Study:
- To investigate the role of the PI3K/AKT/mTOR pathway in canine prostate cancer.
- To evaluate the efficacy of rapamycin, an mTOR inhibitor, in canine prostate cancer models.
- To identify potential mechanisms of resistance to mTOR inhibition in canine prostate cancer.
Main Methods:
- Gene expression microarray analysis of normal and cancerous canine prostate tissues.
- Bioinformatic enrichment analysis to identify activated pathways.
- In vitro treatment of canine prostate cancer cell lines (PC1, PC2) with varying concentrations of rapamycin.
- Assessment of cell viability and gene expression (AKT, mTOR, 4E-BP1) post-treatment.
Main Results:
- Microarray analysis revealed significant differential gene expression related to PI3K/AKT/mTOR pathway activation in canine prostate cancer.
- Increased expression of FKBP1A, FKBP1B, AKT1S1, PDK2, PIP5K1, and PIP5KL1 was observed in cancer cells.
- Rapamycin treatment decreased cell viability in a dose-dependent manner but paradoxically increased AKT transcript levels, suggesting treatment resistance.
- Rapamycin downregulated mTOR and 4E-BP1 expression, indicating partial pathway inhibition.
Conclusions:
- mTOR inhibition is a promising therapeutic strategy for canine prostate cancer.
- Acquisition of resistance to rapamycin, particularly increased AKT levels, is a significant challenge.
- Further research and precision medicine approaches are needed to overcome treatment resistance in canine prostate cancer.
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:23Abnormal Proliferation
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...