JS-K, a Nitric Oxide Pro-drug, Regulates Growth and Apoptosis Through the Ubiquitin-proteasome Pathway in Prostate Cancer Cells

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2017 May 28

PMID 28549433

Citations 12

Authors

Guobin Tan

Mingning Qiu

Lieqian Chen

Sai Zhang

Longzhi Ke

Jianjun Liu

Affiliations

Soon will be listed here.

Abstract

Background: In 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.

Methods: Proliferation 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.

Results: JS-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.

Conclusions: The 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.

Citing Articles

JS-K activates G2/M checkpoints through the DNA damage response and induces autophagy via CAMKKβ/AMPKα/mTOR pathway in bladder cancer cells.

Zhao Y, Lin S, Zeng W, Lin X, Qin X, Miu B J Cancer. 2024; 15(2):343-355.

PMID: 38169515 PMC: 10758033. DOI: 10.7150/jca.86393.

Functional roles of E3 ubiquitin ligases in prostate cancer.

Zhao Y, Li J, Chen J, Ye M, Jin X J Mol Med (Berl). 2022; 100(8):1125-1144.

PMID: 35816219 DOI: 10.1007/s00109-022-02229-9.

Gasotransmitters in the tumor microenvironment: Impacts on cancer chemotherapy (Review).

Salihi A, Al-Naqshabandi M, Khudhur Z, Housein Z, Hama H, Abdullah R Mol Med Rep. 2022; 26(1).

PMID: 35616143 PMC: 9178674. DOI: 10.3892/mmr.2022.12749.

A review of the relatively complex mechanism of JS-K induced apoptosis in cancer cells.

Tan G, Wu A, Li Z, Awasthi P Transl Cancer Res. 2022; 8(4):1602-1608.

PMID: 35116903 PMC: 8797525. DOI: 10.21037/tcr.2019.07.20.

S-Nitrosylation in Tumor Microenvironment.

Sharma V, Fernando V, Letson J, Walia Y, Zheng X, Fackelman D Int J Mol Sci. 2021; 22(9).

PMID: 33925645 PMC: 8124305. DOI: 10.3390/ijms22094600.

References

Lecker S, Goldberg A, Mitch W . Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol. 2006; 17(7):1807-19. DOI: 10.1681/ASN.2006010083. View

Yu Z, Geyer R, Maki C . MDM2-dependent ubiquitination of nuclear and cytoplasmic P53. Oncogene. 2000; 19(51):5892-7. DOI: 10.1038/sj.onc.1203980. View

Udupi V, Yu M, Malaviya S, Saavedra J, Shami P . JS-K, a nitric oxide prodrug, induces cytochrome c release and caspase activation in HL-60 myeloid leukemia cells. Leuk Res. 2006; 30(10):1279-83. DOI: 10.1016/j.leukres.2005.12.007. View

Um H, Jang J, Kim D, Lee C, Surh Y . Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells. Nitric Oxide. 2011; 25(2):161-8. DOI: 10.1016/j.niox.2011.06.001. View

Shami P, Saavedra J, Wang L, Bonifant C, Diwan B, Singh S . JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity. Mol Cancer Ther. 2003; 2(4):409-17. View

Sparks A, Dayal S, Das J, Robertson P, Menendez S, Saville M . The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a. Oncogene. 2013; 33(38):4685-96. PMC: 4051618. DOI: 10.1038/onc.2013.413. View

Waltering K, Urbanucci A, Visakorpi T . Androgen receptor (AR) aberrations in castration-resistant prostate cancer. Mol Cell Endocrinol. 2012; 360(1-2):38-43. DOI: 10.1016/j.mce.2011.12.019. View

Kitagaki J, Yang Y, Saavedra J, Colburn N, Keefer L, Perantoni A . Nitric oxide prodrug JS-K inhibits ubiquitin E1 and kills tumor cells retaining wild-type p53. Oncogene. 2008; 28(4):619-24. PMC: 2854646. DOI: 10.1038/onc.2008.401. View

Ren Z, Kar S, Wang Z, Wang M, Saavedra J, Carr B . JS-K, a novel non-ionic diazeniumdiolate derivative, inhibits Hep 3B hepatoma cell growth and induces c-Jun phosphorylation via multiple MAP kinase pathways. J Cell Physiol. 2003; 197(3):426-34. DOI: 10.1002/jcp.10380. View

10.

Weyerbrock A, Osterberg N, Psarras N, Baumer B, Kogias E, Werres A . JS-K, a glutathione S-transferase-activated nitric oxide donor with antineoplastic activity in malignant gliomas. Neurosurgery. 2011; 70(2):497-510. PMC: 3253212. DOI: 10.1227/NEU.0b013e31823209cf. View

11.

Le Moan N, Houslay D, Christian F, Houslay M, Akassoglou K . Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α. Mol Cell. 2011; 44(3):476-90. PMC: 3212815. DOI: 10.1016/j.molcel.2011.08.033. View

12.

Clemons N, Shannon N, Abeyratne L, Walker C, Saadi A, ODonovan M . Nitric oxide-mediated invasion in Barrett's high-grade dysplasia and adenocarcinoma. Carcinogenesis. 2010; 31(9):1669-75. DOI: 10.1093/carcin/bgq130. View

13.

Kiziltepe T, Hideshima T, Ishitsuka K, Ocio E, Raje N, Catley L . JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. Blood. 2007; 110(2):709-18. PMC: 1924477. DOI: 10.1182/blood-2006-10-052845. View

14.

Laschak M, Spindler K, Schrader A, Hessenauer A, Streicher W, Schrader M . JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells. BMC Cancer. 2012; 12:130. PMC: 3376035. DOI: 10.1186/1471-2407-12-130. View

15.

de Andres M, Maneiro E, Martin M, Arenas J, Blanco F . Nitric oxide compounds have different effects profiles on human articular chondrocyte metabolism. Arthritis Res Ther. 2013; 15(5):R115. PMC: 3978712. DOI: 10.1186/ar4295. View

16.

Muratani M, Tansey W . How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol. 2003; 4(3):192-201. DOI: 10.1038/nrm1049. View

17.

Chen X, Shen J, Li X, Wang X, Long M, Lin F . Rlim, an E3 ubiquitin ligase, influences the stability of Stathmin protein in human osteosarcoma cells. Cell Signal. 2014; 26(7):1532-8. DOI: 10.1016/j.cellsig.2014.03.018. View

18.

Cheng H, Wang L, Mollica M, Re A, Wu S, Zuo L . Nitric oxide in cancer metastasis. Cancer Lett. 2014; 353(1):1-7. PMC: 4150837. DOI: 10.1016/j.canlet.2014.07.014. View

19.

Trinh B, Ko S, Haria D, Barengo N, Naora H . The homeoprotein DLX4 controls inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer. Mol Cancer. 2015; 14:97. PMC: 4427985. DOI: 10.1186/s12943-015-0368-3. View

20.

Cronauer M, Ince Y, Engers R, Rinnab L, Weidemann W, Suschek C . Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression. Oncogene. 2006; 26(13):1875-84. DOI: 10.1038/sj.onc.1209984. View