JS-K, a nitric oxide pro-drug, regulates growth and apoptosis through the ubiquitin-proteasome pathway in prostate cancer cells

Abstract

BackgroundIn view of the fact that JS-K might regulate ubiquitin E3 ligase and that ubiquitin E3 ligase plays an important role in the mechanism of CRPC formation, the goal was to investigate the probable mechanism by which JS-K regulates prostate cancer cells.MethodsProliferation inhibition by JS-K on prostate cancer cells was examined usingCCK-8 assays. Caspase 3/7 activity assays and flow cytometry were performed to examine whether JS-K induced apoptosis in prostate cancer cells. Western blotting and co-immunoprecipitation analyses investigated JS-K’s effects on the associated apoptosis mechanism. Real time-PCR and Western blotting were performed to assess JS-K’s effect on transcription of specific AR target genes. Western blotting was also performed to detect Siah2 and AR protein concentrations and co-immunoprecipitation to detect interactions of Siah2 and AR, NCoR1 and AR, and p300 and AR.ResultsJS-K inhibited proliferation and induced apoptosis in prostate cancer cells. JS-K increased p53 and Mdm2 concentrations and regulated the caspase cascade reaction-associated protein concentrations. JS-K inhibited transcription of AR target genes and down-regulated PSA protein concentrations. JS-K inhibited Siah2 interactions and also inhibited the ubiquitination of AR. With further investigation, JS-K was found to stabilize AR and NCoR1 interactions and diminish AR and p300 interactions.ConclusionsThe present results suggested that JS-K might have been able to inhibit proliferation and induce apoptosis via regulation of the ubiquitin-proteasome degradation pathway, which represented a promising platform for the development of new compounds for PCa treatments.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3351-0) contains supplementary material, which is available to authorized users.

Protein phosphatase 2A activation mechanism contributes to JS-K induced caspase-dependent apoptosis in human hepatocellular carcinoma cells

“…NO is often derived from both the endogenous way by stimulating NO syntheses and the exogenous way through NO donor [ 12 ]. O 2 -(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K,C 13 H 16 N 6 O 8 ) is a diazeniumdiolate-based NO donor and is highly cytotoxic to several types of human cancer cells, such as acute lymphoblastic leukemia [ 13 ], hepatocellular carcinoma [ 14 ], prostate cancer cells [ 15 ] or murine erythroleukemia cells [ 16 ]. Moreover, JS-K as a lead NO donor selectively exhibits antitumor effects towards cancer cells while has no significant toxicity toward normal cells [ 17 ].…”

JS-K, a nitric oxide donor, induces autophagy as a complementary mechanism inhibiting ovarian cancer

“…In vitro experiments indicated that some regulatory mechanisms are involved in various tumors, such as the mitogen-activated protein kinase pathways, which modulate proliferation, motility, and cell death [9]. JS-K promotes apoptosis by inducing ROS production and the ubiquitin-proteasome pathway in human prostate cancer cells [21, 22]. In this study, we showed for the first time that JS-K induced ovarian cancer cells death via an autophagic mechanism in vitro .…”

Protein phosphatase 2A mediates JS‐K‐induced apoptosis by affecting Bcl‐2 family proteins in human hepatocellular carcinoma HepG2 cells

“…Therefore, the occurrence of apoptosis cancer cells is a useful method of treatment. JS‐K as a novel nitric oxide prodrug appears to have cytotoxic effects against various types of human cancers, which is attributed to its capability of releasing high levels of NO . Our previous studies have demonstrated that JS‐K significantly induced apoptosis of HepG2 cells, which were attributed to the high levels of NO production released from JS‐K .…”

“…JS-K as a novel nitric oxide prodrug appears to have cytotoxic effects against various types of human cancers, which is attributed to its capability of releasing high levels of NO. [13][14][15] Our previous studies have demonstrated that JS-K significantly induced apoptosis of HepG2 cells, which were attributed to the high levels of NO production released from JS-K. 12 To obtain an insight into the mechanism by which JS-K induces apoptosis we investigated the effect JS-K on the proliferation of HCC cells. In the present study, JS-K exerted more cytotoxic effects in the HepG2 cells than PLC5, Huh-7, Bel-7402, or SMMC-7721 hepatocellular carcinoma cells.…”