In the July 2013 issue of Nature Communications, Armaiz-Pena et al. demonstrate that stress is able through activation of beta-adrenergic signaling in tumor cells to trigger a critical phosphorylation event, resulting in Src kinase activation, which in turn, can affect tumor growth and metastasis.
Building on previous work showing that sympathetic nervous system activity can promote tumor cell invasion and associated angiogenesis in ovarian carcinoma, the authors sought to further define the signaling pathway involved.
Signaling resulting from activation of beta-adrenergic receptors (ADRB) by norepinephrine affects a broad array of processes involved in the progression of various cancer types. Here, the authors determined key regulators of the cellular phosphoproteome following norepinephrine-stimulation of ADRB in cancer cells.
Increased serine phosphorylation at Src amino terminus following cAMP treatment was demonstrated 30 years ago, and a consensus PKA site at SrcS17 was subsequently identified. However, no physiological role for phosphorylation at SrcS17 had been established.
In the Nature Communications, study Armaiz-Pena et al. identify Src as a key regulator of phosphoproteomic signaling networks activated in response to beta-adrenergic signaling in cancer cells. In this work, Src activation in human ovarian cancer cells increased with norepinephrine exposure in the presence of beta-adrenergic receptors.
These results also identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumor cell migration, invasion and growth.
Thus, Src activation led to enhanced induction of genes associated with tumor migration and invasion. Of note, norepinephrine (NE, also known as noradrenaline) is the most abundant stress mediator in the ovary, and in this study, in human ovarian cancer samples, high tumoral NE levels were correlated with high pSrcY419 levels.
Furthermore, in a mouse stress model, stressed animals exhibited greater tumor growth, but propranolol treatment limited this effect, further highlighting the role of beta-adrenergic receptors.
The results have identified a new functional role for SrcS17 as a key molecular switch that links a serine kinase to downstream tyrosine kinase signaling and disease progression. Specifically, the results indicate that the neuroendocrine stress response can directly affect tumor growth and malignant progression through receptors expressed on tumor cells that lead to a critical phosphorylation event, resulting in Src activation.
Norepinephrine is the most abundant stress hormone in the ovary and its levels are much higher in the ovary than in the plasma. To the extent that biobehavioral states can modulate catecholamine levels in the tumor microenvironment, these findings offer new opportunities for designing interventions to protect individuals from the harmful effects of chronic adrenergic stimulation.
As a clinical correlation, the authors used adverse events data to demonstrate that beta-blocker treatment in cancer patients was associated with a decreased in mortality.
The authors suggest that the beta-antagonists can abrogate many of the deleterious effects of increased adrenergic signaling. For example, among prostate cancer patients taking anti-hypertensive medication, only beta blockers were associated with a reduction of cancer risk while others have shown a reduction in overall cancer risk.
Moreover, the findings described here support the use of Src family kinase inhibitors as tools to block the deleterious effects of increased sympathetic activity. Thus, overall, the data represent a new understanding of Src regulation in response to adrenergic signaling in cancer cells and provide a biologically plausible and potent way of inhibiting tumor progression among cancer patients.
A 2014 study investigated the effects of carvedilol(CAR) on migration and invasion of breast cancer cells and its corresponding signal pathways. The invasive potential of breast cancer cells was investigated after incubation with CAR and/or norepinephrine (NE). Membrane invasion culture system chamber was used to measure the invasive and migratory potential of breast cancer cells. cAMP-Glo and PKCδ kinase activity assay kits were used to measure cAMP and PKCδ activity, respectively.
The beta-blocker carvedilol significantly decreased the potential of migration and invasion of breast cancer cells. Carvedilol inhibited Src activation in MDA-MB-231 and MCF-7 cells through blocking beta or alpha adrenergic receptor (ADR), respectively. Furthermore, CAR suppressed the Src activation through different signaling pathways. Under treatment of CAR, cAMP/PKA-Src pathway was inhibited in MDA-MB-231 cells; but in MCF-7 cells, CAR mainly inhibited the PKCδ-Src pathway. The authors concluded that carvedilol was an anti-metastatic agent, which targets Src involving cAMP/PKA or PKCδ pathway in malignant breast cells.
A 2015 article summarized the known molecular interactions between the potent oncogene Src and a variety of metastasis suppressors. In this process the role of Src in cancer metastasis can be multifaceted, with this latter oncogene being able to negatively regulate a number of metastasis suppressors, while itself being a target for these proteins. This further indicates the complex relationship between Src and metastasis suppressors, which participate in a delicate balance that ultimately determines a cell’s ability to invade and metastasize.
Of note, metastasis suppressors, by definition, inhibit metastasis at any step of the metastatic cascade. Notably, Src is a non-receptor, cytoplasmic, tyrosine kinase, which becomes aberrantly activated in many cancer-types following stimulation of plasma membrane receptors.
A 2022 study investigated the molecular mechanism by which beta2-adrenergic receptors (β2-AR) exert a pro-metastatic function in hepatocarcinoma (HCC) cells and breast cancer (BC) cells. The authors explored the underlying mechanism by which adrenergic agonists promoted migration and invasion in HCC cells and BC cells. They found that norepinephrine (NE) and epinephrine (E) increased the migratory and invasive abilities of HCC cells and BC cells.
Norepinephrine (NE) and epinephrine-induced Src activation was responsible for the increased migration and invasion and was blocked by ADRB2 knockdown. This is perhaps the first study suggesting the crucial role of the β2-AR/Src axis in the metastatic ability of HCC cells and BC cells. In conclusion, the study indicated that the β2-AR/Src axis is critically involved in adrenergic agonist-induced migration and invasion in human HCC cells and BC cells. Thus, the β2-AR/Src axis could be an attractive target to manage the chronic stress-induced progression of HCC and BC.