The Long-Lasting Protective Effect of HGF in Cardiomyoblasts Exposed to Doxorubicin Requires a Positive Feed-Forward Loop Mediated by Erk1,2-Timp1-Stat3
Open Access
- 24 July 2020
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (15), 5258
- https://doi.org/10.3390/ijms21155258
Abstract
Previous studies showed that the hepatocyte growth factor (HGF)–Met receptor axis plays long-lasting cardioprotection against doxorubicin anti-cancer therapy. Here, we explored the mechanism(s) underlying the HGF protective effect. DNA damage was monitored by histone H2AX phosphorylation and apoptosis by proteolytic cleavage of caspase 3. In doxorubicin-treated H9c2 cardiomyoblasts, the long-lasting cardioprotection is mediated by activation of the Ras/Raf/Mek/Erk (extracellular signal-regulated kinase 1,2) signaling pathway and requires Stat3 (signal transducer and activator of transcription 3) activation. The HGF protection was abrogated by the Erk1,2 inhibitor, PD98059. This translated into reduced Y705 phosphorylation and impaired nuclear translocation of Stat3, showing crosstalk between Erk1,2 and Stat3 signaling. An array of 29 cytokines, known to activate Stat3, was interrogated to identify the molecule(s) linking the two pathways. The analysis showed a selective increase in expression of the tissue inhibitor of metalloproteinases-1 (Timp1). Consistently, inhibition in cardiomyoblasts of Timp1 translation by siRNAs blunted both Stat3 activation and the cardioprotective effect of HGF. Thus, Timp1 is responsible for the generation of a feed-forward loop of Stat3 activation and helps cardiomyocytes to survive during the genotoxic stress induced by anthracyclines.Funding Information
- Italian Association for Cancer Research (AIRC 5 xmille Program n°21052)
This publication has 31 references indexed in Scilit:
- ERK1/2 Signaling Plays an Important Role in Topoisomerase II Poison-Induced G2/M Checkpoint ActivationPLOS ONE, 2012
- Identification of the molecular basis of doxorubicin-induced cardiotoxicityNature Medicine, 2012
- Inhibition of Rac1 signaling by lovastatin protects against anthracycline-induced cardiac toxicityCell Death & Disease, 2011
- MET signalling: principles and functions in development, organ regeneration and cancerNature Reviews Molecular Cell Biology, 2010
- A Disintegrin and Metalloproteinase-10 (ADAM-10) Mediates DN30 Antibody-induced Shedding of the Met Surface ReceptorOnline Journal of Public Health Informatics, 2010
- Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: Does it go beyond the RISK pathway?Journal of Molecular and Cellular Cardiology, 2009
- Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulationThe Journal of cell biology, 2008
- Superoxide Anions Are Involved in Doxorubicin-Induced ERK Activation in Hepatocyte CulturesAnnals of the New York Academy of Sciences, 2006
- Repression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase-1 by Anthracyclines Contributes to Their Antiapoptotic Activation of p44/42-MAPKThe Journal of pharmacology and experimental therapeutics, 2003
- Properties of a clonal muscle cell line from rat heartExperimental Cell Research, 1976