Serotonin/HTR1E signaling blocks chronic stress-promoted progression of ovarian cancer

Abstract

Rationale: Psychological stress has been linked to cancer development and resistance to therapy by many epidemiological and clinical studies. Stress-induced immunosuppressive microenvironment by stress hormones, in particular glucocorticoids, has been extensively studied. However, the impacts of other stress-related neurotransmitters, such as serotonin (5-hydroxytryptamine, 5-HT), on cancer development just start to be revealed. Here, we aimed to identify novel neurotransmitters involved in stress-induced growth and dissemination of ovarian cancer (OC) and reveal the major underlying signaling pathway and the therapeutic significance. Methods: Through a genome-wide CRISPR/Cas9 knockout screen in the murine orthotopic model of ovarian carcinoma (OC), we identified candidate genes regulating the peritoneal dissemination of OC. Among them, we picked out HTR1E, one member of 5-HT receptor family specifically expressed in the ovary and endometrium in addition to brain. The correlation of HTR1E expression with OC progression was analyzed in OC patient specimen by quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry (IHC). Gain-of-function and loss-of-function analyses were performed to explore the functions of 5-HT/HTR1E signaling in OC growth and dissemination in vitro and in vivo . In addition, we investigated the therapeutic values of HTR1E specific agonist and small molecular inhibitors against HTR1E downstream factor SRC in a stressed murine OC xenograft model. Results: In OC patients, the HTR1E expression is dramatically decreased in peritoneal disseminated OC cells, which correlates with poor clinical outcome. Silence of HTR1E in OC cells greatly promotes cell proliferation and epithelial mesenchymal transition (EMT) by the activation of SRC-mediated downstream signaling pathways. Furthermore, chronic stress results in significantly decreased serotonin in the ovary and the enhanced OC growth and peritoneal dissemination in mice, which can be strongly inhibited by specific HTR1E agonist or the SRC inhibitor. Conclusions: We discovered the essential role of serotonin/HTR1E signaling in preventing the chronic psychological stress-promoted progression of OC, suggesting the potential therapeutic value of the HTR1E specific agonist and the SRC inhibitor for OC patients who are suffering from psychological stress.

Novel interaction between neurotrophic factor-α1/carboxypeptidase E and serotonin receptor, 5-HTR1E, protects human neurons against oxidative/neuroexcitotoxic stress via β-arrestin/ERK signaling

“…Fig. S1) [ 23 ]. HTLA cells (10,000 cells/well) were plated in a white 96-well plate in DMEM supplemented with 10% FBS.…”

“…Pharmacological and immunocytochemical localization studies in the guinea pig brain indicate that 5-HTR1E is abundant in the hippocampus, frontal cortex, and olfactory bulb, but with no known function in brain [ 21 , 22 ]. Recently, Qin et al [ 23 ] reported that 5-HTR1E signaling may prevent the chronic psychological stress-promoted progression of ovarian cancer and might have potential therapeutic value.…”

Evaluation of the Influence of Biological Factors during the Course of Treatment in Patients with Ovarian Cancer

“…Information about a positive cancer diagnosis is the cause of many negative emotions in patients that relate to anxiety, social isolation, psychological stress, and depression. These factors not only worsen the effectiveness of the therapy but also contribute to faster development of the neoplasm [ 20 , 21 ]. The stress that appears following a positive cancer diagnosis leads to disorders of the control mechanism, impairing the immune system and often leading to disease progression.…”

“…A study by Qin et al demonstrated the important role of serotonin/HTR1E signaling in the prevention of ovarian progression cancer (OC) caused by chronic psychological stress, suggesting the potential therapeutic value of a specific HTR1E agonist and SRC inhibitor for patients with OC (ovarian cancer) suffering from mental stress [ 21 ]. Henriksen et al found that serotonin (5-HT) receptors 5-HTR1A, 5-HTR1B, 5-HTR2B, and 5-HTR4 are expressed in the healthy ovary as well as in malignant tumors of the ovary.…”

Current applications and future perspective of CRISPR/Cas9 gene editing in cancer

“…Qin et al used genome-wide CRISPR/Cas9 gene knockout to screen candidate genes that regulate peritoneal spread of ovarian cancer (OC) in a mouse orthotopic model. Among them, HTR1E —a member of the 5-HT receptor family that is expressed in the ovary, endometrium, and brain—has significantly reduced expression in peritoneal disseminated OC cells, which is related to poor clinical prognosis [ 94 ]. In addition, orthotopic implantation is more suitable for survival analysis because tumor burden and associated symptoms directly lead to the death of tumor-bearing mice.…”