Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells.
The human EGF receptor (HER) 2 receptor tyrosine kinase is a survival factor for human cardiomyocytes, and its inhibition may explain the increased incidence of cardiomyopathy associated with the anti-HER2 monoclonal antibody trastuzumab (Genentech, South San Francisco, CA), particularly in patients with prior exposure to cardiotoxic chemotherapies e.g., anthracyclines. Here, we show that GW2974 (HER2/EGF receptor tyrosine kinase inhibitor), but not trastuzumab, activates AMP-activated protein kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNFalpha-induced cell death. GW2974 stimulates calcium dependent fatty acid oxidation in vitro and in the myocardium of GW2974-treated rodents. Calcium chelation or siRNA-targeted AMPK knockdown blocks GW2974 induced fatty acid oxidation. In addition, inhibition of AMPK by a specific inhibitor resulted in increased killing of cardiomyocytes. Elucidating the effects of HER2-targeted therapies on AMPK may predict for risk of cardiomyopathy and provide a novel HER2-targeted strategy designed to protect myocardium from the pro-apoptotic effects of pro-inflammatory cytokines released in response to cardiac injury by chemotherapy or acute ischemia.
Spector
Neil L
NL
Duke Comprehensive Cancer Center, Duke University Medical Center, Medical Science Research Building II, Durham, NC 27710, USA.
Yarden
Yosef
Y
Smith
Bradley
B
Lyass
Ljuba
L
Trusk
Patricia
P
Pry
Karen
K
Hill
Jason E
JE
Xia
Wenle
W
Seger
Rony
R
Bacus
Sarah S
SS
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000032:analysis / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate; D002118:Calcium; D066246:ErbB Receptors; D005227:Fatty Acids; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C506645:GW2974