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

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. © the japanese pharmacological society.