Novel regulatory program for norepinephrine‐induced epithelial–mesenchymal transition in gastric adenocarcinoma cell lines

Abstract

Norepinephrine and epinephrine, catecholamine hormones that are major mediators for chronic stress-induced cancers, are implicated in the progression of a number of cancer cells, including gastric adenocarcinoma. However, the underlying mechanisms of these hormones have not been well elucidated. Epithelial–mesenchymal transition (EMT) is a crucial event responsible for cancer cell invasion and metastasis. The hypothesis regarding whether the promotive effects of norepinephrine (NE) on cancer are in part due to its ability to induce an EMT program has not been proven. In this study, we show that NE does not only obviously induce EMT alterations in the morphological characteristics of gastric adenocarcinoma cells, but also increases the markers of EMT, including vimentin expression, and decreases E-cadherin expression, further resulting in cell motility and invasiveness. We also reveal that these actions are mainly mediated through the activation of β2-AR–HIF-1α–Snail signaling pathways. In summary, this study implies that NE induces EMT in gastric adenocarcinoma through the regulation of β2-AR–HIF-1α–Snail activity. The data provide a new perspective on chronic stress in a negative social and psychological state, which may be a risk factor for cancer development and progression.EMT: a novel regulatory program for stress hormone norepinephrine. EMT and gastric adenocarcinoma.

The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo

“…In the present study, we demonstrated that stress activates the release of several substances different from catecholamines leading to an increase of migration of tumor cells from primary tumor to lymph nodes without affecting tumor growth (6). Additionally, we demonstrated that norepinephrine increased the expression of CK, MMP-2 and MMP-9 paralleled by EMT effects (E-cadherin loss and vimentin augmentation) (9)(10)(11)16), that are indispensable for metastasis formation. The combination of our results delivers good perspectives for the development of non-heart active and β2-specific blockers for the inhibition of metastasis development.…”

“…The differential remodeling of E-cadherin and vimentin has been characterized in cells that have undergone EMT. The loss of E-cadherin occurs in most epithelial cancers, and can be correlated to higher mobility and invasiveness of tumor cells (9,10). On the other hand, the increased vimentin expression is usually associated with increased in vitro motility of cancer cell lines (9,10).…”

β 2 -Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer

“…It will be important to characterize if β 2 AR agonism induces similar behavior in other tumor cell lines and in vivo . Notably, several recent in vitro studies suggest that βAR signaling induces an epithelial-mesenchymal transition in gastric, colon and lung cancer cell lines (Lu et al, 2015; Shan et al, 2014; Zhang et al, 2016). To better understand βAR regulation of epithelial-mesenchymal transition it will be necessary to clarify the molecular mechanisms.…”

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

“…Shan et al showed that the human gastric cancer cell lines BGC-823 and SGC-7901 underwent morphological changes typical of EMT, and showed increased invasiveness, in response to co-culture with norepinephrine via a beta2-adrenergic signalling pathway [113]. Zhang et al showed a similar association between increased catecholamine signalling and initiation of EMT in HT-29 and A549 colorectal cancer cell lines [114].…”