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

Abstract

OBJECTIVE:

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.

METHODS:

Investigated was the influence of c-Met on apoptosis, autophagy and loss of mitochondrial transmembrane potential (Δψm), and the relevant proteins were examined.

KEY FINDINGS:

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.

CONCLUSION:

Thus, inhibiting c-Met enhanced oridonin-induced apoptosis, autophagy and loss of Δψm in A549 cells.

• Authors: Ying Liu, Jian-Hong Liu, Kuan Chai, Shin-Ichi Tashiro, Satoshi Onodera, Takashi Ikejima
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 65 Issue 11 Pg. 1622-42 (Nov 2013) ISSN: 2042-7158 [Electronic] England
• PMID: 24102522 (Publication Type: Journal Article)
• Copyright: © 2013 Royal Pharmaceutical Society.

Chemical References

• ATG5 protein, human
• Amino Acid Chloromethyl Ketones
• Apoptosis Regulatory Proteins
• Autophagy-Related Protein 5
• BECN1 protein, human
• Beclin-1
• Diterpenes, Kaurane
• Membrane Proteins
• Microtubule-Associated Proteins
• Plant Extracts
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• oridonin
• 3-methyladenine
• Cytochromes c
• Proto-Oncogene Proteins c-met
• Extracellular Signal-Regulated MAP Kinases
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Amino Acid Chloromethyl Ketones
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy (drug effects)
• Autophagy-Related Protein 5
• Beclin-1
• Cytochromes c (metabolism)
• Diterpenes, Kaurane (pharmacology, therapeutic use)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Isodon (chemistry)
• Lung Neoplasms (drug therapy, metabolism, physiopathology)
• Membrane Potential, Mitochondrial (drug effects)
• Membrane Proteins (metabolism)
• Microtubule-Associated Proteins (metabolism)
• Mitochondria (drug effects)
• Phytotherapy
• Plant Extracts (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors)
• RNA, Small Interfering (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)
• bcl-2-Associated X Protein (metabolism)