Canine prostate cancer cell transcriptome reveals important dysregulation in PI3K/AKT/mTOR pathway.

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 μM) 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.