Abstract:
: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.
journal_name
J Pharmacol Scijournal_title
Journal of pharmacological sciencesauthors
Liu Y,Yang Y,Ye YC,Shi QF,Chai K,Tashiro S,Onodera S,Ikejima Tdoi
10.1254/jphs.11181fpsubject
Has Abstractpub_date
2012-01-01 00:00:00pages
423-32issue
4eissn
1347-8613issn
1347-8648pii
JST.JSTAGE/jphs/11181FPjournal_volume
118pub_type
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