Phosphoproteome profiling provides insight into the mechanism of action for carvedilol-mediated cancer prevention
| Autor: | Ying Huang, Steven Yeung, Kristan H. Cleveland, Kevin M. Huang, Sherry Liang, Bradley T. Andresen |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Cancer Research Proteome Carcinogenesis Proto-Oncogene Proteins c-jun Adrenergic beta-Antagonists Mice SCID Pharmacology Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Western blot Mice Inbred NOD medicine Animals Anticarcinogenic Agents Humans Neoplastic transformation Phosphorylation Melanoma Molecular Biology Carvedilol Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Epidermal Growth Factor medicine.diagnostic_test HEK293 Cells 030104 developmental biology Mechanism of action chemistry 030220 oncology & carcinogenesis Alprenolol medicine.symptom Signal transduction medicine.drug |
| Zdroj: | Molecular Carcinogenesis. 57:997-1007 |
| ISSN: | 0899-1987 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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