Oncotarget

Research Papers:

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

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Oncotarget. 2016; 7:76995-77009. https://doi.org/10.18632/oncotarget.12765

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Abstract

Wohn-Jenn Leu1,*, Sharada Prasanna Swain2,*, She-Hung Chan1, Jui-Ling Hsu1, Shih-Ping Liu3, Mei-Ling Chan1, Chia-Chun Yu1, Lih-Ching Hsu1, Yen-Lin Chou2, Wei-Ling Chang1, Duen-Ren Hou2, Jih-Hwa Guh1

1School of Pharmacy, National Taiwan University, Taipei, Taiwan

2Department of Chemistry, National Central University, Jhong-li, Taoyuan, Taiwan

3Department of Urology, National Taiwan University Hospital, Taipei, Taiwan

*These authors contributed equally to this work

Correspondence to:

Duen-Ren Hou, email: [email protected]

Jih-Hwa Guh, email: [email protected]

Keywords: triazole-base, non-immunosuppression, PI3K/Akt/mTOR signaling, Myc, autophagy

Received: May 15, 2016     Accepted: October 14, 2016     Published: October 19, 2016

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.


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