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Sinularin stabilizes FOXO3 protein to trigger prostate cancer cell intrinsic apoptosis.
Meng, Xiang-Yu; Wang, Ke-Jie; Ye, Sha-Zhou; Chen, Jun-Feng; Chen, Zhao-Yu; Zhang, Zuo-Yan; Yin, Wei-Qi; Jia, Xiao-Long; Li, Yi; Yu, Rui; Ma, Qi.
Affiliation
  • Meng XY; Translational Research Laboratory for Urology, the Key Laboratory of Ningbo City, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China; Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Li
  • Wang KJ; Translational Research Laboratory for Urology, the Key Laboratory of Ningbo City, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China; Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Li
  • Ye SZ; Translational Research Laboratory for Urology, the Key Laboratory of Ningbo City, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China; Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Li
  • Chen JF; Translational Research Laboratory for Urology, the Key Laboratory of Ningbo City, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China; Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Li
  • Chen ZY; Translational Research Laboratory for Urology, the Key Laboratory of Ningbo City, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China; Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Li
  • Zhang ZY; Department of Pharmacy, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China.
  • Yin WQ; Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China; Department of Urology, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China.
  • Jia XL; Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China; Department of Urology, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China.
  • Li Y; Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, #88 Jiefang Road, Hangzhou 310009, Zhejiang, China. Electronic address: zrliyi@zju.edu.cn.
  • Yu R; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, #818 Fenghua Road, Ningbo 315211, Zhejiang, China. Electronic address: yurui@nbu.edu.cn.
  • Ma Q; Translational Research Laboratory for Urology, the Key Laboratory of Ningbo City, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China; Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Li
Biochem Pharmacol ; 220: 116011, 2024 02.
Article in En | MEDLINE | ID: mdl-38154548
ABSTRACT
Sinularin, a natural product that purified from soft coral, exhibits anti-tumor effects against various human cancers. However, the mechanisms are not well understood. In this study, we demonstrated that Sinularin inhibited the viability of human prostate cancer cells in a dose-dependent manner and displayed significant cytotoxicity only at high concentration against normal prostate epithelial cell RWPE-1. Flow cytometry assay demonstrated that Sinularin induced tumor cell apoptosis. Further investigations revealed that Sinularin exerted anti-tumor activity through intrinsic apoptotic pathway along with up-regulation of pro-apoptotic protein Bax and PUMA, inhibition of anti-apoptotic protein Bcl-2, mitochondrial membrane potential collapses, and release of mitochondrial proteins. Furthermore, we illustrated that Sinularin induced cell apoptosis via up-regulating PUMA through inhibition of FOXO3 degradation by the ubiquitin-proteasome pathway. To explore how Sinularin suppress FOXO3 ubiquitin-proteasome degradation, we tested two important protein kinases AKT and ERK that regulate FOXO3 stabilization. The results revealed that Sinularin stabilized and up-regulated FOXO3 via inhibition of AKT- and ERK1/2-mediated FOXO3 phosphorylation and subsequent ubiquitin-proteasome degradation. Our findings illustrated the potential mechanisms by which Sinularin induced cell apoptosis and Sinularin may be applied as a therapeutic agent for human prostate cancer.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Diterpenes / Apoptosis Regulatory Proteins / Heterocyclic Compounds, 3-Ring Limits: Humans / Male Language: En Journal: Biochem Pharmacol Year: 2024 Document type: Article Country of publication: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Diterpenes / Apoptosis Regulatory Proteins / Heterocyclic Compounds, 3-Ring Limits: Humans / Male Language: En Journal: Biochem Pharmacol Year: 2024 Document type: Article Country of publication: United kingdom