Phosphoproteome profiling provides insight into the mechanism of action for carvedilol‐mediated cancer prevention

摘要

Recent studies suggest that the β‐blocker drug carvedilol prevents skin carcinogenesis but the mechanism is unknown. Carvedilol is one of a few β‐blockers identified as biased agonist based on an ability to promote β‐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 P70S6?K 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 β‐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 β‐blockers such as carvedilol.