Oxytocin involves in chronic stress-evoked melanoma metastasis via β-arrestin 2-mediated ERK signaling pathway

Abstract

Stress is associated with an increased risk of lung metastasis in melanoma. However, the underlying mechanism is elusive. Oxytocin (OXT), a neurohormone produced by the hypothalamus, plays a vital role in laboring induction and lactation. Emerging evidence suggests that OXT also regulates human emotions, social cognition, social behaviors and stress-related disorders. Here, we reported that a significant up-regulation of oxytocin receptors (OXTRs) was observed in malignant melanoma. The activation of OXTRs dramatically promoted migration, invasion and angiogenesis but not the proliferation of melanoma cells in vitro and in vivo via β-arrestin 2-dependent ERK-VEGF/MMP-2 pathway. Next, chronic restraint stress significantly elevated the plasma level of OXT. Notably, 21 days chronic restraint stress facilitated lung metastasis of melanoma and reduced overall survival in mice, which were largely abrogated by knocking down either OXTR or β-arrestin 2. These findings provide evidence that chronic stress hormone-OXT promotes lung metastasis of melanoma via a β-arrestin 2-dependent mechanism and suggest that OXT, a novel pro-metastasis factor, is a potential therapeutic target for melanoma.

Chronic stress promotes EMT-mediated metastasis through activation of STAT3 signaling pathway by miR-337-3p in breast cancer

“…Breast cancer remains the most common cancer in women worldwide and metastasis is widely accepted as the major cause for cancer death 4 , 5 . In breast tumor bearing mice model, psychosocial stress could induce the formation of pre-metastatic niches in distant organs 6 – 9 , while blocking stress-associated hormone factors could reduce the metastasis 10 , 11 . Previous clinical research also indicated that stress-related factors are involved in promoting breast cancer progression 12 .…”

β-arrestin 2 Is a Prognostic Factor for Survival of Ovarian Cancer Patients Upregulating Cell Proliferation

“…The link between GPCR/β-arrestins complexes and cancer is an established concept ( 41 ) and seems to be result of sustained intracellular signaling occurring upon dysregulation of intracellular β-arrestin protein levels ( 42 ). These molecules were associated with drug resistance of breast ( 43 ) and lung cancer cells ( 44 ), cancer cell migration and invasion ( 45 ), tumor progression ( 46 ) and metastasis ( 47 ), as well as a number of other tumors ( 48 ). Thus, β-arrestins were proposed as a target for therapeutic strategies ( 49 ).…”

I8-arachnotocin–an arthropod-derived G protein-biased ligand of the human vasopressin V2 receptor

“…Differentiating between signaling events that occur pre or post β-arrestin recruitment has become an important focus 32–34 for studies looking at understanding the (patho)physiological roles of β-arrestin-mediated receptor internalization, desensitization and trafficking 35,36 . In addition, β-arrestin-dependent signaling has been linked to chronic stress-evoked melanoma metastasis via OTR 37 , increased neonatal rat cardiac fibroblast proliferation via V 1a R 38 , morphine tolerance via V 1b R 39 and sustained non-canonical signaling after receptor internalization via V 2 R, resulting in strong antidiuretic and anti-natriuretic effects 40 . Biased ligands such as I8-arachnotocin discovered in this work are thus important tools to advance our understanding in these areas of interest.…”