Activation of ERK–p53 and ERK-Mediated Phosphorylation of Bcl-2 Are Involved in Autophagic Cell Death Induced by the c-Met Inhibitor SU11274 in Human Lung Cancer A549 Cells

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  • Liu Ying
    China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, PR China
  • Yang Ying
    China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, PR China
  • Ye Yuan-Chao
    China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, PR China
  • Shi Qi-Feng
    China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, PR China
  • Chai Kuan
    China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, PR China
  • Tashiro Shin-ichi
    Department of Clinical and Biomedical Science, Showa Pharmaceutical University, Japan
  • Onodera Satoshi
    Department of Clinical and Biomedical Science, Showa Pharmaceutical University, Japan
  • Ikejima Takashi
    China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, PR China

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SU11274, a small molecule inhibitor of c-Met, was reported to induce apoptosis in human non-small-cell lung cancer (NSCLC) cells. However, SU11274-mediated autophagy in NSCLC cells has rarely been reported. The aim of this study was to elucidate the molecular mechanisms mediating SU11274-induced autophagy in NSCLC A549 cells. Here we reported that SU11274-induced autophagy was accompanied with an increase in the conversion of LC3-I to LC3-II and up-regulation of Beclin-1 expression. Subsequently, we also found that small interfering RNA against c-Met induced A549 cell autophagy while promotion of c-Met by hepatocyte growth factor (HGF) suppressed A549 cell autophagy. Inhibition of autophagy by 3-methyladenine (3-MA) suppressed SU11274-induced cell death, suggesting that SU11274-induced autophagy caused cell death. Further study showed that ERK and p53 were activated after SU11274 treatment. Interruption of ERK and p53 activities decreased SU11274-induced autophagy, and blocking of ERK by the specific inhibitor PD98059 suppressed SU11274-induced p53 activation. Moreover, ERK activation upregulated Beclin-1 expression through induction of Bcl-2 phosphorylation, but p53 did not induce Bcl-2 phosphorylation. In conclusion, inhibition of c-Met induced autophagic cell death, which was associated with ERK–p53 activation and ERK-mediated Bcl-2 phosphorylation in A549 cells.

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