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

被引：17

作者：

Leu, Wohn-Jenn ^{[1
]}

Swain, Sharada Prasanna ^{[2
]}

Chan, She-Hung ^{[1
]}

Hsu, Jui-Ling ^{[1
]}

Liu, Shih-Ping ^{[3
]}

Chan, Mei-Ling ^{[1
]}

Yu, Chia-Chun ^{[1
]}

Hsu, Lih-Ching ^{[1
]}

Chou, Yen-Lin ^{[2
]}

Chang, Wei-Ling ^{[1
]}

Hou, Duen-Ren ^{[2
]}

Guh, Jih-Hwa ^{[1
]}

机构：

[1] Natl Taiwan Univ, Sch Pharm, Taipei, Taiwan

[2] Natl Cent Univ, Dept Chem, Taoyuan, Taiwan

[3] Natl Taiwan Univ Hosp, Dept Urol, Taipei, Taiwan

来源：

ONCOTARGET | 2016年 / 7卷 / 47期

关键词：

triazole-base; non-immunosuppression; PI3K/Akt/mTOR signaling; Myc; autophagy; CELL-CYCLE ARREST; ZONE B-CELLS; SPHINGOSINE; 1-PHOSPHATE; MARGINAL ZONE; MULTIPLE-SCLEROSIS; S-PHASE; FTY720; APOPTOSIS; ACTIVATION; AUTOPHAGY;

D O I：

10.18632/oncotarget.12765

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 path ways that 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 signaling is responsive for the genomic alterations in prostate cancer.

引用

页码：76995 / 77009

页数：15

共 57 条

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