Inhibition of c-Met promoted apoptosis, autophagy and loss of the mitochondrial transmembrane potential in oridonin-induced A549 lung cancer cells.

Herein, inhibition of hepatocyte growth factor receptor, c-Met, significantly increased cytochrome c release and Bax/Bcl-2 ratio, indicating that c-Met played an anti-apoptotic role. The following experiments are to elucidate this anti-apoptotic mechanism, then the effect of c-Met on autophagy has also been discussed. Investigated was the influence of c-Met on apoptosis, autophagy and loss of mitochondrial transmembrane potential (Δψm), and the relevant proteins were examined. First, we found that activation of extracellular signal-regulated kinase (ERK), p53 was promoted by c-Met interference. Subsequent studies indicated that ERK was the upstream effector of p53, and this ERK-p53 pathway mediated release of cytochrome c and up-regulation of Bax/Bcl-2 ratio. Secondly, the inhibition of c-Met augmented oridonin-induced loss of mitochondrial transmembrane potential (Δψm), resulting apoptosis. Finally, the inhibition of c-Met increased oridonin-induced A549 cell autophagy accompanied by Beclin-1 activation and conversion from microtubule-associated protein light chain 3 (LC3)-I to LC3-II. Activation of ERK-p53 was also detected in autophagy process and could be augmented by inhibition of c-Met. Moreover, suppression of autophagy by 3-methyladenine (3-MA) or small interfering RNA against Beclin-1 or Atg5 decreased oridonin-induced apoptosis. Inhibition of apoptosis by pan-caspase inhibitor (z-VAD-fmk) decreased oridonin-induced autophagy as well and Loss of Δψm also occurred during autophagic process. Thus, inhibiting c-Met enhanced oridonin-induced apoptosis, autophagy and loss of Δψm in A549 cells.

Liu Y ，Liu JH ，Chai K ，Tashiro S ，Onodera S ，Ikejima T ... -  《-》

Inactivation of ras and changes of mitochondrial membrane potential contribute to oridonin-induced autophagy in a431 cells.

Li D ，Cui Q ，Chen SG ，Wu LJ ，Tashiro S ，Onodera S ，Ikejima T ... -  《JOURNAL OF PHARMACOLOGICAL SCIENCES》

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.

Liu Y ，Yang Y ，Ye YC ，Shi QF ，Chai K ，Tashiro S ，Onodera S ，Ikejima T ... -  《-》

Oridonin induced autophagy in human cervical carcinoma HeLa cells through Ras, JNK, and P38 regulation.

Cui Q ，Tashiro S ，Onodera S ，Minami M ，Ikejima T ... -  《JOURNAL OF PHARMACOLOGICAL SCIENCES》

P53-mediated cell cycle arrest and apoptosis through a caspase-3- independent, but caspase-9-dependent pathway in oridonin-treated MCF-7 human breast cancer cells.

Cui Q ，Yu JH ，Wu JN ，Tashiro S ，Onodera S ，Minami M ，Ikejima T ... -  《ACTA PHARMACOLOGICA SINICA》