The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux

被引：27

作者：

Long, Zhou ^{[1
]}

Chen, BaiJun ^{[2
]}

Liu, Qian ^{[1
]}

Zhao, Jiang ^{[1
]}

Yang, ZhenXing ^{[1
]}

Dong, XingYou ^{[1
]}

Xia, LiuBin ^{[1
]}

Huang, ShengQuan ^{[1
]}

Hu, XiaoYan ^{[1
]}

Song, Bo ^{[3
]}

Li, LongKun ^{[1
]}

机构：

[1] Third Mil Med Univ, Affiliated Hosp 2, Dept Urol, Chongqing 400037, Peoples R China

[2] Med Coll Chengdu, Affiliated Hosp 1, Dept Gastroenterol, Chengdu 610500, Peoples R China

[3] Third Mil Med Univ, Affiliated Hosp 1, Dept Urol, Chongqing 400038, Peoples R China

来源：

ONCOTARGET | 2016年 / 7卷 / 27期

基金：

中国国家自然科学基金;

关键词：

autophagy; apoptosis; prostate cancer; NCX1; cell death; NA+/CA2+ EXCHANGE; THERAPEUTIC TARGET; CALCIUM; METASTASIS; INDUCTION; RADIATION;

D O I：

10.18632/oncotarget.9806

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

We explored the effects of KB-R7943, an inhibitor of reverse-mode NCX1 activity, in prostate cancer (PCa). NCX1 was overexpressed in PCa tissues and cell lines, and higher NCX1 levels were associated higher PCa grades. At concentrations greater than 10 mu M, KB-R7943 dose-dependently decreased PC3 and LNCaP cell viability. KB-R7943 also increased cell cycle G1/S phase arrest and induced apoptosis in PC3 cells. KB-R7943 increased autophagosome accumulation in PCa cells as indicated by increases in LC3-II levels and eGFP-LC3 puncta. Combined treatment with chloroquine (CQ) and KB-R7943 decreased P62 and increased LC3-II protein levels in PC3 cells, indicating that KB-R7943 blocked autophagic flux. KB-R7943 induced autophagosome accumulation mainly by downregulating the PI3K/AKT/m-TOR pathway and upregulating the JNK pathway. In xenograft experiments, KB-R7943 inhibited tumor growth. Combined treatment with KB-R7943 and an autophagy inhibitor inhibited growth and increased apoptosis. These results indicate that KB-R7943 promotes cell death in PCa by activating the JNK signaling pathway and blocking autophagic flux.

引用

页码：42059 / 42070

页数：12