Non-immunosuppressive triazole-based small molecule induces anticancer activity against human hormone-refractory prostate cancers: the role in inhibition of PI3K/AKT/mTOR and c-Myc signaling pathways.

Wohn-Jenn Leu,Jih-Hwa Guh,She-Hung Chan,Duen-Ren Hou,Shih-Ping Liu,Mei-Ling Chan,Sharada Prasanna Swain,Wei-Ling Chang,Yen-Lin Chou,Jui-Ling Hsu,Chia-Chun Yu,Lih-Ching Hsu

doi:10.18632/oncotarget.12765

Abstract

A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation. c-Myc overexpression replenished protein levels of cyclin D1 indicating that c-Myc was responsible for cell cycle regulation. PI3K/Akt/mTOR signaling pathways through p70S6K- and 4EBP1-mediated translational regulation are critical to cell proliferation and survival. SPS-7 significantly inhibited this translational pathway. Overexpression of Myr-Akt (constitutively active Akt) completely abolished SPS-7-induced inhibitory effect on mTOR/p70S6K/4EBP1 signaling and c-Myc protein expression, suggesting that PI3K/Akt serves as a key upstream regulator. SPS-7 also demonstrated substantial anti-tumor efficacy in an in vivo xenograft study using PC-3 mouse model. Notably, FTY720 but not SPS-7 induced a significant immunosuppressive effect as evidenced by depletion of marginal zone B cells, down-regulation of sphingosine-1-phosphate receptors and a decrease in peripheral blood lymphocytes. In conclusion, the data suggest that SPS-7 is not an immunosuppressant while induces anticancer effect against HRPC through inhibition of Akt/mTOR/p70S6K pathwaysthat down-regulate protein levels of both c-Myc and cyclin D1, leading to G1 arrest of cell cycle and subsequent apoptosis. The data also indicate the potential of SPS-7 since PI3K/Akt signalingis responsive for the genomic alterations in prostate cancer.

Highlights

Carcinoma of the prostate is one of the most frequently diagnosed cancers and leading causes of cancer death in men
The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation. c-Myc overexpression replenished protein levels of cyclin D1 indicating that c-Myc was responsible for cell cycle regulation
Cell proliferation was further examined in PC-3 cells by Carboxyfluorescein succinimidyl ester (CFSE) staining, a cell-tracking dye which conjugated to intracellular proteins and was evenly inherited by divided cells after cell proliferation

Summary

Introduction

Carcinoma of the prostate is one of the most frequently diagnosed cancers and leading causes of cancer death in men. PI3K/Akt is the most extensively investigated pathway in prostate cancer since its involvement is clearly identified in localized prostate cancers and is increased in HRPCs [3, 4]. PI3K/Akt and associated mTOR pathways are responsible for cell survival, growth, metastasis and both chemo- and radio-resistances in prostate cancer and other cancers. Targeting this pathway by inhibitors to increase both chemo- and radio-sensitivities may have great potential in clinical benefits [4, 5]

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Conclusion