Inhibition of G-protein-coupled receptor kinase 2 (GRK2) triggers the growth-promoting mitogen-activated protein kinase (MAPK) pathway.
Inhibition of G-protein-coupled receptor kinase 2 (GRK2) is an emerging treatment option for heart failure. Because GRK2 is also indispensable for growth and development, we analyzed the impact of GRK2 inhibition on cell growth and proliferation. Inhibition of GRK2 by the dominant-negative GRK2-K220R did not affect the proliferation of cultured cells. In contrast, upon xenograft transplantation of cells into immunodeficient mice, the dominant-negative GRK2-K220R or a GRK2-specific peptide inhibitor increased tumor mass. The enhanced tumor growth upon GRK2 inhibition was attributed to the growth-promoting MAPK pathway because dual inhibition of the GRK2 and RAF-MAPK axis by the Raf kinase inhibitor protein (RKIP) did not increase tumor mass. The MAPK cascade contributed to the cardioprotective profile of GRK2 inhibition by preventing cardiomyocyte death, whereas dual inhibition of RAF/MAPK and GRK2 by RKIP induced cardiomyocyte apoptosis, cardiac dysfunction, and signs of heart failure. Thus, cardioprotective signaling induced by GRK2 inhibition is overlapping with tumor growth promotion.
Department of Chemistry and Applied Biosciences, Molecular Pharmacology Unit, Swiss Federal Institute of Technology (ETH) Zuerich, CH-8057 Zuerich, Switzerland.
Xuebin
X
Fu
Department of Chemistry and Applied Biosciences, Molecular Pharmacology Unit, Swiss Federal Institute of Technology (ETH) Zuerich, CH-8057 Zuerich, Switzerland.
Samuel
S
Koller
Department of Chemistry and Applied Biosciences, Molecular Pharmacology Unit, Swiss Federal Institute of Technology (ETH) Zuerich, CH-8057 Zuerich, Switzerland.
Joshua
J
Abd Alla
Department of Chemistry and Applied Biosciences, Molecular Pharmacology Unit, Swiss Federal Institute of Technology (ETH) Zuerich, CH-8057 Zuerich, Switzerland; Department of Medicine, Institute of Pharmacology and Toxicology, University of Zuerich, CH-8057 Zuerich, Switzerland. Electronic address: ursula.quitterer@pharma.ethz.ch.
Ursula
U
Quitterer
D000818:Animals; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid / Q000379:methods; D003587:Cytomegalovirus / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006333:Heart Failure / Q000628:therapy; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods; D019076:Transgenes
D054769:G-Protein-Coupled Receptor Kinase 2