Cytostatic effect of novel mTOR inhibitor, PRP-1 (galarmin) in MDA 231 (ER-) breast carcinoma cell line. PRP-1 inhibits mesenchymal tumors

Abstract

Activation of the PI3K-Akt-mTOR pathway is implicated both in the establishment of tumors and as well as a target for therapy in many types of solid malignancy, its blockade represents an opportunity to improve outcomes in patients with tumors that are associated with poor prognosis. Our experimental data indicates that proline-rich polypeptide-1 (PRP-1, galarmin) is immunomodulator cytokine, produced by hypothalamic neurosecretory cells and exerts its antiproliferative effect on the tumor cells of mesenchymal origin via inhibiting mTOR kinase activity and repressing cell cycle progression. The goal of these investigations was to elucidate the antiproliferative action of PRP-1 on the breast carcinoma cell line MDA 231 (ER-) and to compare PRP-1 action previously reported on other mesenchymal tumors. These experiments confirmed maximum inhibition of cell growth at 0.5 and 1 μg/ml PRP-1 (71% and 63%, respectively) and inhibition at 10 μg/ml of 44%. There was no inhibitory effect observed on luminal T47-D (ER+) cells. Videomicroscopy results demonstrated dividing cells in the cytokine-treated MDA 231 (ER-), suggesting that the cells were not in the state of dormancy. The flow cytometry experiments confirmed that PRP-1-treated cells were accumulated in S phase. No apoptosis, caspase activation, or senescence was detected after treatment with this cytokine. Experiments with mTOR with PRP-1 (10 μg/ml) indicated statistically significant 40% inhibition of mTOR kinase activity in immunoprecipitates of the MDA 231 (ER-) cell line. PRP-1 is a novel mTOR inhibitor with strong antiproliferative action in mesenchymal tumors mostly resistant to radiation and chemotherapy.