Abstract 2000: The regulatory role of endothelial nitric oxide synthase signaling in the growth of prostate cancer stem-like cells

Abstract

Abstract Cumulative studies indicate that there is a small subpopulation of cancer cells present in cancers or solid tumors referred as cancer stem-like cells (CSCs) as they share some common characteristics with stem cells, particularly self-renewal and multipotency, and these CSCs may contribute to the tumor initiation, treatment resistance and relapse. Recent advances also indicate that prostate cancer stem-like cells (PCSCs) may play a critical role in the development of castration-resistant prostate cancer (CRPC) and also its metastasis. Here, we demonstrated using an established CRPC xenograft model (VCaP-CRPC) that both the xenograft tumors and a xenograft-derived cell line contained more PCSC population, which showed higher expression levels of endothelial nitric oxide synthase (eNOS) and elevated intracellular NO production. PCSCs, isolated from prostaspheres derived from prostate cancer cell lines (DU145, LNCaP and VCaP) using a newly developed agar-based non-attachment 3D-culture method, exhibited up-regulation of eNOS and increased intracellular NO levels. Interruption of eNOS signaling by NOS inhibitors and shRNA-knockdown could significantly suppress the sphere formation capability of prostate cancer cells. Exogenous overexpression of eNOS could promote the tumor growth capacity of prostate cancer cells and their metastasis in vivo, while knockdown of eNOS could prevent the tumor growth and metastasis. Combined transcriptome-sequencing analysis and qPCR validation of prostaspheres upon eNOS-knockdown identified some potential targets of eNOS/NO signaling in the PCSC-enriched prostaspheres. In summary, our results suggest that eNOS/NO signaling may play a positive role in the growth regulation of PCSCs and eNOS might be a potential target for advanced prostate cancer. This study is supported by a General Research Fund from the Research Grants Council of Hong Kong (project code 14107617) and an Innovation and Technology Fund (GHP/003/16GD) from the Innovation and Technology Commission of Hong Kong. Citation Format: Weijie Gao, Dinglan Wu, Yuliang Wang, Zhu Wang, Taiyang Ma, Franky Leung Chan. The regulatory role of endothelial nitric oxide synthase signaling in the growth of prostate cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2000.