TY - JOUR AB - Cisplatin (CDDP) and doxorubicin (DOX) are chemotherapeutic drugs that trigger apoptosis by inducing DNA‑damage. A previous study using breast cancer cells demonstrated the negative feedback modulation of the epidermal growth factor receptor (EGFR) and receptor tyrosine‑protein kinase erbB‑2 (ErbB2) via extracellular signal‑regulated kinase (ERK)‑mediated phosphorylation of conserved Thr‑669 and Thr‑677 residues, respectively, in the juxtamembrane domain. In addition, CDDP has been identified to cause negative feedback inhibition of activated EGFR in lung cancer cells. In the present study, the role of phosphorylation in the feedback control of the ErbB2/ErbB3 heterodimer in human breast and gastric cancer cells was investigated. Phosphorylation of ErbB2 at Thr‑677 was induced by CDDP and DOX, which in turn reduced tyrosine autophosphorylation of ErbB2 and ErbB3. Treatment with trametinib, a mitogen‑activated protein kinase inhibitor that blocks ERK‑mediated Thr‑677 phosphorylation, and substitution of Thr‑677 to alanine, blocked the feedback inhibition of ErbB2 and ErbB3. In addition, these agents caused the degradation of ErbB proteins through the activation of p38 mitogen‑activated protein kinase (p38) and ERK. These results demonstrate that chemotherapeutic agents trigger ERK‑ and p38‑mediated post‑translational downregulation of ErbB receptors. AD - Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930‑0194, Japan AU - Park,Chul,Min AU - Kawasaki,Yuki AU - Refaat,Alaa AU - Sakurai,Hiroaki DA - 2018/02/01 DO - 10.3892/ol.2017.7532 EP - 1762 IS - 2 JO - Oncol Lett KW - receptor tyrosine‑protein kinase erbB‑2 receptor tyrosine‑protein kinase erbB‑3 cisplatin doxorubicin extracellular signal‑regulated kinase breast cancer PY - 2018 SN - 1792-1074 1792-1082 SP - 1758 ST - Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways T2 - Oncology Letters TI - Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways UR - https://doi.org/10.3892/ol.2017.7532 VL - 15 ER -