Nitric oxide represses the proliferation of Caco-2 cells by inducing S-G2/M cell cycle arrest

Satoru Sakuma; Yukino Ikeda; Itsumi Inoue; Kanna Yamaguchi; Shohko Honkawa; Tetsuya Kohda; Saaya Minamino; Yohko Fujimoto

Nitric oxide represses the proliferation of Caco-2 cells by inducing S-G₂/M cell cycle arrest

Int J Physiol Pathophysiol Pharmacol. 2019 Oct 15;11(5):205-211. eCollection 2019.

Authors

Satoru Sakuma¹, Yukino Ikeda¹, Itsumi Inoue¹, Kanna Yamaguchi¹, Shohko Honkawa¹, Tetsuya Kohda¹, Saaya Minamino¹, Yohko Fujimoto¹

Affiliation

¹ Department of Physiological Chemistry, Osaka University of Pharmaceutical Sciences 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan.

PMID: 31777644
PMCID: PMC6872484

Abstract

There is conflicting data regarding the ability of nitric oxide (NO) to promote or inhibit colorectal cancer cell proliferation. Furthermore, NO reacts rapidly with endogenous superoxide at a diffusion-controlled rate to give peroxynitrite (ONOO^-), a strong oxidant and nitrating agent. The aim of this study was to assess the effects of exogenous NO and ONOO^- on the proliferation of the colorectal cancer cell line Caco-2. NOR5 and SIN-1 were used as NO and ONOO^- donors, respectively. Both NOR5 and SIN-1 inhibited the proliferation of the Caco-2 cells; however, the effect of NOR5 was slightly stronger than that of SIN-1. The results also indicated that NO plays a major role in the inhibition of SIN-1-induced proliferation of Caco-2 cells. The results of a terminal deoxynucleotidyl transferase dUTP nick end labeling assay, cell cycle analysis, and p21 protein expression measurement further indicated that NO induced S-G₂/M phase arrest, but not apoptosis, in the Caco-2 cells. The results suggest that NO, rather than ONOO^-, has the potential to repress the proliferation of Caco-2 cells by inducing S-G₂/M cell cycle arrest.

Keywords: NOR5; Nitric oxide; SIN-1; colon cancer proliferation; peroxynitrite; reactive nitrogen species.