Targeting SERT promotes tryptophan metabolism: mechanisms and implications in colon cancer treatment

Abstract

Background Serotonin signaling has been associated with tumorigenesis and tumor progression. Targeting the serotonin transporter to block serotonin cellular uptake confers antineoplastic effects in various tumors, including colon cancer. However, the antineoplastic mechanism of serotonin transporter inhibition and serotonin metabolism alterations in the absence of serotonin transporter have not been elucidated, especially in colon cancer, which might limit anti-tumor effects associating with targeting serotonin transporter. Methods The promotion in the uptake and catabolism of extracellular tryptophan and targeting serotonin transporter was detected by using quantitative reverse-transcription polymerase chain reaction, western blotting and liquid chromatography tandem mass spectrometry. Western blotting Immunoprecipitation and immunofluorescence was utilized to research the serotonylation of mTOR by serotonin and serotonin transporter inhibition. The primary mouse model, homograft model and tissue microarry was used to explore the tryptophan pathway in colon cancer. The cell viability assay, western blotting, xenograft and primary colon cancer mouse model were used to identify whether the combination of sertraline and tryptophan restriction had a synergistic effect. Results Targeting serotonin transporter through genetic ablation or pharmacological inhibition in vitro and in vivo induced a compensatory effect by promoting the uptake and catabolism of extracellular tryptophan in colon cancer. Mechanistically, targeting serotonin transporter suppressed mTOR serotonylation, leading to mTOR inactivation and increased tryptophan uptake. In turn, this process promoted serotonin biosynthesis and oncogenic metabolite kynurenine production through enhanced tryptophan catabolism. Tryptophan deprivation, or blocking its uptake by using trametinib, a MEK inhibitor, can sensitize colon cancer to selective serotonin reuptake inhibitors. Conclusions The present study elucidated a novel feedback mechanism involved in the regulation of serotonin homeostasis and suggested innovative strategies for selective serotonin reuptake inhibitors-based treatment of colon cancer.

Sertraline inhibits stress-induced tumor growth through regulating CD8+ T cell-mediated anti-tumor immunity

“…Consistently, SSRIs can reduce the cell viability of cancer cells, including colon cancer cells and prostate cancer cells in basic studies [15,16]. In our previous study, we also found that sertraline inhibited the proliferation of HCT116 and SW480 colon cancer cells [17]. Overall, these studies indicate that SSRIs might exert an antitumor effect.…”

Disruption of autophagy by increased 5-HT alters gut microbiota and enhances susceptibility to experimental colitis and Crohn’s disease

“…In addition to receptor sensing, 5-HT can alter gene expression through serotonylation of histone H3 ( 51 ). While little is known on the direct evidence of autophagy regulation via serotonylation, recently, it has been demonstrated that 5-HT treatment of human colon cancer cells activates mTORC1 through serotonylation ( 52 ). Exploring the role of serotonylation in autophagy in gut inflammation will further enhance our understanding on the interaction between 5-HT signaling and autophagy.…”

Action Mechanism of Zhuang Medicine Jin-mu Granules Against Chronic Pelvic Inflammatory Disease Explored Using Comprehensive Network Pharmacology and Metabolomics

“…Studies have shown that Bifidobacteria and Lactobacilli improve the survival rate of intestinal epithelial cells by inhibiting the apoptosis pathway activated by pathogenic bacteria. [51][52][53] Indole derivatives produced by tryptophan metabolism are important signaling molecules produced by probiotics to maintain the intestinal epithelial barrier and inhibit inflammation.…”