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.
Highlights
Prostate cancer (PCa) is among the most common causes of death in males worldwide, with the highest mortality rates occurring in developed countries [1, 2]
NCX1 expression is increased in prostate cancer tissues and KB-R7943 induces autophagosome accumulation in prostate cancer cells
The immunohistochemistry assay revealed that NCX1 expression was higher in prostate cancer tissues than in benign prostatic hyperplasia tissues (Figure 1A), and NCX1 expression increased as prostate cancer grade increased
Summary
Prostate cancer (PCa) is among the most common causes of death in males worldwide, with the highest mortality rates occurring in developed countries [1, 2]. The pathogenesis of prostate cancer is not fully understood. Prostate cancer often is not diagnosed until late stages, contributing to poor prognoses [4, 5]. Autophagy dysfunctions are related to many diseases and affect cell survival, aging, and tumor and neurodegenerative disorders [6]. It has been reported that cancer cells use autophagy to survive nutrition shortages. Excessive autophagy promotes tumor growth, and increases resistance to anti-cancer treatments [7, 8]. Inhibition of autophagic flux has been proposed as a novel therapeutic strategy for the treatment of cancer [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
