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

Zhou Long; BaiJun Chen; Qian Liu; Jiang Zhao; ZhenXing Yang; XingYou Dong; LiuBin Xia; ShengQuan Huang; XiaoYan Hu; Bo Song; LongKun Li

doi:10.18632/oncotarget.9806

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Research Papers:

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

Zhou Long, BaiJun Chen, Qian Liu, Jiang Zhao, ZhenXing Yang, XingYou Dong, LiuBin Xia, ShengQuan Huang, XiaoYan Hu, Bo Song and LongKun Li _

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Oncotarget. 2016; 7:42059-42070. https://doi.org/10.18632/oncotarget.9806

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Abstract

Zhou Long1,*, BaiJun Chen2,*, Qian Liu1, Jiang Zhao1, ZhenXing Yang1, XingYou Dong1, LiuBin Xia1, ShengQuan Huang1, XiaoYan Hu1, Bo Song3, LongKun Li1

1Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China

2Department of Gastroenterology, First Affiliated Hospital, Medical College of Chengdu, Chengdu, 610500, China

3Department of Urology, First Affiliated Hospital, Third Military Medical University, Chongqing, 400038, China

*These authors contributed equally to this work

Correspondence to:

LongKun Li, email: [email protected]

Keywords: autophagy, apoptosis, prostate cancer, NCX1, cell death

Received: March 16, 2016 Accepted: May 05, 2016 Published: June 03, 2016

ABSTRACT

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 μM, 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.

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Research Papers:

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

Abstract