PACE4通过内质网应激和线粒体信号通路调节人前列腺癌细胞的凋亡。

PACE4 regulates apoptosis in human prostate cancer cells via endoplasmic reticulum stress and mitochondrial signaling pathways.

作者信息

Yao Zhiyong, Sun Bin, Hong Quan, Yan Jingmin, Mu Dawei, Li Jianye, Sheng Haibo, Guo Heqing

机构信息

Department of Urology, Air Force General Hospital of People's Liberation Army, Beijing, People's Republic of China.

出版信息

Drug Des Devel Ther. 2015 Nov 5;9:5911-23. doi: 10.2147/DDDT.S86881. eCollection 2015.

DOI:10.2147/DDDT.S86881

PMID:26604689

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4639519/

Abstract

BACKGROUND

PACE4 is a proprotein convertase capable of processing numerous substrates involved in tumor growth, invasion, and metastasis. However, the precise role of PACE4 during prostate cancer cell apoptosis has not been reported.

METHODS

In the present study, human prostate cancer cell lines DU145, LNCaP, and PC3 were transfected with PACE4 small interfering (si)RNA to investigate the underlying mechanisms of apoptosis.

RESULTS

We revealed that PACE4 siRNA exhibited antitumor activity by inducing apoptosis, as determined by Cell Counting Kit-8 (CCK-8), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltet-razolium bromide (MTT) assay, cell cycle analysis, Hoechst staining, caspase-3/7 activity, and western blot analysis. In addition, PACE4 siRNA significantly increased the ratio of Bax/Bcl-2, which led to the release of cytochrome c. Moreover, PACE4 siRNA also induced endoplasmic reticulum stress by increasing the expression of GRP78, GRP94, p-PERK, and p-eIF2α. The ratio of Bax/Bcl-2 and GRP78 were also increased in PACE4 gene knockdown prostate cancer cells compared with the control cells.

CONCLUSION

These data demonstrate that PACE4 siRNA may exert its antitumor activity through mitochondrial and endoplasmic reticulum stress signaling pathways, indicating it may be a novel therapeutic target for prostate cancer.

摘要

背景

PACE4是一种前体蛋白转化酶，能够加工多种参与肿瘤生长、侵袭和转移的底物。然而，PACE4在前列腺癌细胞凋亡过程中的具体作用尚未见报道。

方法

在本研究中，将PACE4小干扰（si）RNA转染至人前列腺癌细胞系DU145、LNCaP和PC3，以研究凋亡的潜在机制。

结果

我们发现，通过细胞计数试剂盒-8（CCK-8）、3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法、细胞周期分析、Hoechst染色、caspase-3/7活性及蛋白质印迹分析确定，PACE4 siRNA通过诱导凋亡表现出抗肿瘤活性。此外，PACE4 siRNA显著增加了Bax/Bcl-2的比值，导致细胞色素c释放。而且，PACE4 siRNA还通过增加GRP78、GRP94、p-PERK和p-eIF2α的表达诱导内质网应激。与对照细胞相比，PACE4基因敲低的前列腺癌细胞中Bax/Bcl-2比值和GRP78也增加。