title: Agonist antibodies activating the Met receptor protect cardiomyoblasts from cobalt chloride-induced apoptosis and autophagy.
abstract: Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), mainly activates prosurvival pathways, including protection from apoptosis. In this work, we investigated the cardioprotective mechanisms of Met activation by agonist monoclonal antibodies (mAbs). Cobalt chloride (CoCl2), a chemical mimetic of hypoxia, was used to induce cardiac damage in H9c2 cardiomyoblasts, which resulted in reduction of cell viability by (i) caspase-dependent apoptosis and (ii) - surprisingly - autophagy. Blocking either apoptosis with the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone or autophagosome formation with 3-methyladenine prevented loss of cell viability, which suggests that both processes contribute to cardiomyoblast injury. Concomitant treatment with Met-activating antibodies or HGF prevented apoptosis and autophagy. Pro-autophagic Redd1, Bnip3 and phospho-AMPK proteins, which are known to promote autophagy through inactivation of the mTOR pathway, were induced by CoCl2. Mechanistically, Met agonist antibodies or HGF prevented the inhibition of mTOR and reduced the flux of autophagosome formation. Accordingly, their anti-autophagic function was completely blunted by Temsirolimus, a specific mTOR inhibitor. Targeted Met activation was successful also in the setting of low oxygen conditions, in which Met agonist antibodies or HGF demonstrated anti-apoptotic and anti-autophagic effects. Activation of the Met pathway is thus a promising novel therapeutic tool for ischaemic injury.
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Gallo
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Gatti
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Sala
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Albano
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Costelli
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Casanova
authors.affiliation: 1] Department of Oncology, University of Turin, Turin, Italy [2] Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: P M
authors.initials: PM
authors.lastname: Comoglio
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Crepaldi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D003035:Cobalt; D019610:Cytoprotection / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D002316:Cardiotonic Agents; D003035:Cobalt; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases; C018021:cobaltous chloride
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