Sinularin stabilizes FOXO3 protein to trigger prostate cancer cell intrinsic apoptosis.

FOXO3 Intrinsic apoptosis PUMA Sinularin Ubiquitination

Journal

Biochemical pharmacology
ISSN: 1873-2968
Titre abrégé: Biochem Pharmacol
Pays: England
ID NLM: 0101032

Informations de publication

Date de publication:
26 Dec 2023
Historique:
received: 03 09 2023
revised: 14 12 2023
accepted: 21 12 2023
medline: 29 12 2023
pubmed: 29 12 2023
entrez: 28 12 2023
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.bcp.2023.116011 PMID: 38154548
pubmed: 38154548
pii: S0006-2952(23)00604-4
doi: 10.1016/j.bcp.2023.116011
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

116011

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Xiang-Yu 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 Liuting Street, Ningbo 315010, Zhejiang, China.

Ke-Jie 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 Liuting Street, Ningbo 315010, Zhejiang, China.

Sha-Zhou 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 Liuting Street, Ningbo 315010, Zhejiang, China.

Jun-Feng 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 Liuting Street, Ningbo 315010, Zhejiang, China.

Zhao-Yu 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 Liuting Street, Ningbo 315010, Zhejiang, China.

Zuo-Yan Zhang (ZY)

Department of Pharmacy, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China.

Wei-Qi 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.

Xiao-Long 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.

Yi 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.

Rui 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.

Qi 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 Liuting Street, Ningbo 315010, Zhejiang, China; Comprehensive Genitourinary Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China; Yi-Huan Genitourinary Cancer Group, Ningbo 315010, Zhejiang, China. Electronic address: fyymaqi@nbu.edu.cn.

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