The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux.
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.
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
Zhou
Z
Long
Department of Gastroenterology, First Affiliated Hospital, Medical College of Chengdu, Chengdu, 610500, China.
BaiJun
B
Chen
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
Qian
Q
Liu
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
Jiang
J
Zhao
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
ZhenXing
Z
Yang
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
XingYou
X
Dong
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
LiuBin
L
Xia
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
ShengQuan
S
Huang
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
XiaoYan
X
Hu
Department of Urology, First Affiliated Hospital, Third Military Medical University, Chongqing, 400038, China.
Bo
B
Song
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
LongKun
L
Li
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D002738:Chloroquine / Q000737:chemistry; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010588:Phagosomes; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D002738:Chloroquine; D048670:MAP Kinase Kinase 4; D013890:Thiourea
NCX1; apoptosis; autophagy; cell death; prostate cancer