Abstract
Chronic stress has been shown to facilitate progression of epithelial ovarian cancer (EOC), however, the neuro-endocranial mechanism participating in this process still remains unclear. Here, we reported that chronic restraint stress (CRS) promoted the abdominal implantation metastasis of EOC cells and the expression of epithelial–mesenchymal transition-related markers in tumor-bearing mouse model, including TWIST, SLUG, SNAIL, and β-catenin. We observed that β-catenin co-expressed with SLUG and norepinephrine (NE) in tumor tissues obtained from nude mice. Further ex vivo experiments revealed that NE promoted migration and invasion of ovarian cancer cells and SLUG expression through upregulating expression and improving transcriptional function of β-catenin in vitro. A human phosphor-kinase array suggested that NE activated various kinases in ovarian cancer cells, and we further confirmed that AKT inhibitor reduced NE-mediated pro-metastatic impacts and activation of the β-catenin/SLUG axis. Furthermore, the expression levels of NE and β-catenin were examined in ovarian tumor tissues by using tumor tissue arrays. Results showed that the expression levels of both NE and β-catenin were associated with poor clinical stage of serous EOC. Moreover, we found that melatonin (MLT) effectively reduced the abdominal tumor burden of ovarian cancer induced by CRS, which was partially related to the inhibition of the NE/AKT/β-catenin/SLUG axis. Collectively, these findings suggest a novel mechanism for CRS-mediated ovarian cancer metastasis and MLT has a potential therapeutic efficacy against ovarian cancer.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer worldwide
The H&E staining showed that the tumor tissues obtained from control and chronic restraint stress (CRS) groups were characterized as serous adenocarcinoma
Our results demonstrate that CRS promoted the abdominal metastasis of EOC, and activated the expression of Epithelial–mesenchymal transition (EMT)-related molecules
Summary
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer worldwide. various forms of therapy have been created, more than 70% of patients will relapse within 18 months[1]. Depression is reported to be related to a modestly risk of ovarian cancer[2] and shorter survival in patients with ovarian cancer[3]. As is known to all, cancer patients usually live under chronic mental stress due to diagnosis-associated strong emotions, depression, and inquietude. Catecholamines are hormones released during a stress response, especially by chronic stress, including norepinephrine (NE) and epinephrine (Epi)[4]. Stressrelated NE and Epi are considered to worsen progression and prognosis of ovarian cancer through promoting angiogenesis[5,6], aggressiveness[7], chemo-resistance[8]. NE and Epi are widely reported to facilitate ovarian cancer progression via binding to β2 adrenergic receptor, which results in activation of cyclic AMP/Protein Kinase A axis and phosphorylation of several pro-tumoral proteins (reviewed in[9]).
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