Endothelial nitric oxide synthase (eNOS)-NO signaling axis functions to promote the growth of prostate cancer stem-like cells

Weijie Gao; Yuliang Wang; Shan Yu; Zhu Wang; Taiyang Ma; Andrew Man-Lok Chan; Peter Ka-Fung Chiu; Chi-Fai Ng; Dinglan Wu; Franky Leung Chan

doi:10.1186/s13287-022-02864-6

Endothelial nitric oxide synthase (eNOS)-NO signaling axis functions to promote the growth of prostate cancer stem-like cells

Stem Cell Res Ther. 2022 May 7;13(1):188. doi: 10.1186/s13287-022-02864-6.

Authors

Weijie Gao^{1

2}, Yuliang Wang², Shan Yu², Zhu Wang², Taiyang Ma², Andrew Man-Lok Chan², Peter Ka-Fung Chiu³, Chi-Fai Ng³, Dinglan Wu⁴, Franky Leung Chan⁵

Affiliations

¹ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
² School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
³ Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
⁴ Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China. wudinglan123@smu.edu.cn.
⁵ School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China. franky-chan@cuhk.edu.hk.

Abstract

Background: Accumulating evidence supports that prostate cancer stem-like cells (PCSCs) play significant roles in therapy resistance and metastasis of prostate cancer. Many studies also show that nitric oxide (NO) synthesized by NO synthases can function to promote tumor progression. However, the exact roles of NOSs and NO signaling in the growth regulation of PCSCs and castration-resistant prostate cancer (CRPC) are still not fully understood.

Methods: The regulatory functions of NOS-NO signaling were evaluated in prostate cancer cells, especially in PCSCs enriched by 3D spheroid culture and CD133/CD44 cell sorting. The molecular mechanisms of NOS-NO signaling in PCSCs growth regulation and tumor metastasis were investigated in PCSCs and mice orthotopic prostate tumor model.

Results: Endothelial NOS (eNOS) exhibited a significant upregulation in high-grade prostate cancer and metastatic CRPC. Xenograft models of CRPC exhibited notable increased eNOS expression and higher intracellular NO levels. PCSCs isolated from various models displayed significant enhanced eNOS-NO signaling. Functional analyses demonstrated that increased eNOS expression could promote in vivo tumorigenicity and metastatic potential of prostate cancer cells. Characterization of eNOS-NO involved downstream pathway which confirmed that enhanced eNOS signaling could promote the growth of PCSCs and antiandrogen-resistant prostate cancer cells via an activated downstream NO-sGC-cGMP-PKG effector signaling pathway. Interestingly, eNOS expression could be co-targeted by nuclear receptor ERRα and transcription factor ERG in prostate cancer cells and PCSCs.

Conclusions: Enhanced eNOS-NO signaling could function to promote the growth of PCSCs and also the development of metastatic CRPC. Besides eNOS-NO as potential targets, targeting its upstream regulators (ERRα and ERG) of eNOS-NO signaling could also be the therapeutic strategy for the management of advanced prostate cancer, particularly the aggressive cancer carrying with the TMPRSS2:ERG fusion gene.

Keywords: Castration resistance; ERG; ERRα; NO; Prostate cancer; Prostate cancer stem-like cells; eNOS.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Humans
Male
Mice
Neoplastic Stem Cells / metabolism
Nitric Oxide / metabolism
Nitric Oxide Synthase Type III / genetics
Nitric Oxide Synthase Type III / metabolism
Prostate / metabolism
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms, Castration-Resistant* / metabolism
Signal Transduction

Substances

Nitric Oxide
Nitric Oxide Synthase Type III