5‑HT serotonin receptors modulate mitogenic signaling and impact tumor cell viability

Abstract

Symptoms of depression are present in over half of all cancer patients, and selective serotonin reuptake inhibitor (SSRI) anti-depressant medications are prescribed to nearly a quarter of these individuals in order to cope with their disease. Previous studies have provided evidence that elevated serotonin (5-HT) and serotonin receptor levels may contribute to oncogenic progression, yet little is known regarding the mechanism by which this occurs. The data demonstrated that serotonin receptor mRNAs and proteins are expressed across diverse cancer types, and that serotonin stimulation of tumor cells activates oncogenic signaling mediators including components of the AKT, CREB, GSK3, and MAPK pathways. Selective pharmacological inhibition of the seven known classes of 5-HT receptors in sarcoma and breast cancer cells resulted in dose dependent decreases in tumor cell viability, activation of the p53 DNA damage pathway, suppression of MAPK activity, and significantly reduced tumor volume in an in ovo model. Based on a retrospective clinical analysis of 419 patients diagnosed with breast cancer, we discovered that use of SSRIs was associated with a 2.3-fold increase in tumor proliferation rates for late stage patients based on their Ki-67 index (P=0.03). These data provide evidence that serotonin signaling pathways, which treating oncologists often pharmacologically target to assist cancer patients to psychologically cope with their illness, activate signaling pathways known to promote tumor growth and survival.

A Systems Biology Approach to Investigating the Interaction between Serotonin Synthesis by Tryptophan Hydroxylase and the Metabolic Homeostasis

“…This suggests that high serotonin levels in the gut may act as a cancer driver. Some studies have reported the role of serotonin in colon cancer [ 52 , 53 , 54 ]. Tutton et al reported that serotonin supplementation promoted the proliferation of colon cancer cells [ 53 ].…”

Biopotential of Bersama abyssinica Fresen Stem Bark Extracts: UHPLC Profiles, Antioxidant, Enzyme Inhibitory, and Antiproliferative Propensities

“…In this regard, the human colon cancer HCT116 cell line was selected and treated with the extract. The effect of water extract was evaluated on both basal and 5-HT-induced cell viability; 5-HT has long been described as a proinflammatory factor, particularly in the gut [10], with in vitro studies substantiating a mitogen role, mediated by different receptor types towards multiple cell lines [9]. According to these findings, a preliminary study was carried out in order to optimize the experimental conditions that could demonstrate a cell viability-stimulating effect of 5-HT, in a wide range of concentrations (0.1 pg/mL to 1 µg/mL).…”

“…In this study, the enzyme inhibitory properties and antioxidant activity of the ethyl acetate, methanol, and water extracts of B. abyssinica stem bark were determined. Considering the traditional antitumoral use [4], antiproliferative effects were investigated against the human colon cancer HCT116 cell line challenged with serotonin (5-HT), a well-known central neurotransmitter, that acts in the periphery and, particularly in the gut, as a proinflammatory and mitogen factor [8][9][10]. It is expected that data generated from this study could provide further scientific information on B. abyssinica for future works.…”

Effect of SSRI exposure on the proliferation rate and glucose uptake in breast and ovary cancer cell lines

“…In line with the reported worse outcome of cancer patients receiving SSRI treatment, it was recently reported that SSRI treatment was associated with increased tumor cell proliferation rates in breast cancer tissues from late stage patients 23 . In this context, SSRIs amitriptyline and fluoxetine were found to potentiate tumor growth in a rat model of 7,12-Dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis 24 .…”