Sinularin stabilizes FOXO3 protein to trigger prostate cancer cell intrinsic apoptosis

Xiang-Yu Meng; Ke-Jie Wang; Sha-Zhou Ye; Jun-Feng Chen; Zhao-Yu Chen; Zuo-Yan Zhang; Wei-Qi Yin; Xiao-Long Jia; Yi Li; Rui Yu; Qi Ma

doi:10.1016/j.bcp.2023.116011

Sinularin stabilizes FOXO3 protein to trigger prostate cancer cell intrinsic apoptosis

Biochem Pharmacol. 2024 Feb:220:116011. doi: 10.1016/j.bcp.2023.116011. Epub 2023 Dec 27.

Authors

Xiang-Yu Meng¹, Ke-Jie Wang¹, Sha-Zhou Ye¹, Jun-Feng Chen¹, Zhao-Yu Chen¹, Zuo-Yan Zhang², Wei-Qi Yin³, Xiao-Long Jia³, Yi Li⁴, Rui Yu⁵, Qi Ma⁶

Affiliations

¹ 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.
² Department of Pharmacy, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo 315010, Zhejiang, China.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 38154548
DOI: 10.1016/j.bcp.2023.116011

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.

Keywords: FOXO3; Intrinsic apoptosis; PUMA; Sinularin; Ubiquitination.

MeSH terms

Apoptosis
Apoptosis Regulatory Proteins* / metabolism
Cell Line, Tumor
Diterpenes*
Forkhead Box Protein O3
Heterocyclic Compounds, 3-Ring*
Humans
Male
Prostate / metabolism
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / metabolism
Proteasome Endopeptidase Complex
Proto-Oncogene Proteins c-akt / metabolism
Ubiquitins / metabolism

Substances

Apoptosis Regulatory Proteins
Diterpenes
Forkhead Box Protein O3
FOXO3 protein, human
Heterocyclic Compounds, 3-Ring
Proteasome Endopeptidase Complex
Proto-Oncogene Proteins c-akt
sinularin
Ubiquitins