Journal
MOLECULAR CARCINOGENESIS
Volume 57, Issue 8, Pages 997-1007Publisher
WILEY
DOI: 10.1002/mc.22820
Keywords
-blocker; alprenolol; biased -blocker; carcinogenesis; JB6 P+ cells
Categories
Funding
- Western University of Health Sciences
- Master of Pharmaceutical Sciences (MSPS) Program
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Recent studies suggest that the -blocker drug carvedilol prevents skin carcinogenesis but the mechanism is unknown. Carvedilol is one of a few -blockers identified as biased agonist based on an ability to promote -arrestin-mediated processes such as ERK phosphorylation. To understand the role of phosphoproteomic signaling in carvedilol's anticancer activity, the mouse epidermal JB6 P+ cells treated with EGF, carvedilol, or their combination were analyzed using the Phospho Explorer Antibody Array containing 1318 site-specific and phospho-specific antibodies of over 30 signaling pathways. The array data indicated that both EGF and carvedilol increased phosphorylation of ERK's cytosolic target P70S6K while its nuclear target ELK-1 were activated only by EGF; Furthermore, EGF-induced phosphorylation of ELK-1 and c-Jun was attenuated by carvedilol. Subcellular fractionation analysis indicated that ERK nuclear translocation induced by EGF was blocked by co-treatment with carvedilol. Western blot and luciferase reporter assays confirmed that the biased -blockers carvedilol and alprenolol blocked EGF-induced phosphorylation and activation of c-Jun/AP-1 and ELK-1. Consistently, both carvedilol and alprenolol strongly prevented EGF-induced neoplastic transformation of JB6 P+ cells. Remarkably, oral carvedilol treatment significantly inhibited the growth of A375 melanoma xenograft in SCID mice. As nuclear translocation of ERK is a key step in carcinogenesis, inhibition of this event is proposed as a novel anticancer mechanism for biased -blockers such as carvedilol.
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