Chronic
inflammation is a key driver for
colitis-associated colorectal cancer.
5-hydroxytryptamine (5-HT), a
neurotransmitter, has been reported to promote
inflammation in the gastrointestinal tract. However, the mechanism behind this remains unclear. In this study, we found that
5-HT levels, as well as the expression of
tryptophan hydroxylase 1 (TPH1), the
5-HT biosynthesis rate-limiting
enzyme, were significantly upregulated in
colorectal tumor tissues from patients with
colorectal cancer,
colorectal cancer mouse models, and
colorectal cancer cell lines when compared with normal colorectal tissues or epithelial cell lines.
Colorectal cancer cell-originated
5-HT enhanced NLRP3
inflammasome activation in THP-1 cells and immortalized bone marrow-derived macrophages (iBMDM) via its
ion channel receptor, HTR3A. Mechanistically, HTR3A activation led to Ca2+ influx, followed by CaMKIIα phosphorylation (Thr286) and activation, which then induced NLRP3 phosphorylation at Ser198 (mouse: Ser194) and
inflammasome assembling. The NLRP3
inflammasome mediated IL1β maturation, and release upregulated
5-HT biosynthesis in
colorectal cancer cells by inducing TPH1 transcription, revealing a positive feedback loop between
5-HT and NLRP3 signaling. Silencing TPH1 or HTR3A by
short hairpin RNA slowed down
tumor growth in an established CT26 and iBMDM coimplanted subcutaneous allograft
colorectal cancer mouse model, whereas treatment with TPH1 inhibitor 4-chloro-DL-phenylalanine or HTR3A antagonist
tropisetron alleviated
tumor progression in an
azoxymethane/
dextran sodium sulfate-induced
colorectal cancer mouse model. Addressing the positive feedback loop between
5-HT and NLRP3 signaling could provide potential therapeutic targets for
colorectal cancer.