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Src Kinase Activation by beta-Adrenergic Signaling in Cancer Cells – Key Trigger for Cancer Metastasis

Src Kinase signaling beta-Adrenergic Signaling Cancer Cells
Src kinase signaling and cancer metastasis

Update at BrainImmuneIn 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.

This study reinforces the pivotal role of stress in cancer progression and suggests that readily available therapeutic modalities may be greatly efficacious as an adjunctive cancer treatment.

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.

Source: Nat Commun, 2013; 4:1403. doi: 10.1038/ncomms2413.
Read More: National Library of Medicine