Interruption of hepatocyte growth factor signaling augmented oridonin-induced death in human non-small cell lung cancer A549 cells via c-met-nuclear factor-κB-cyclooxygenase-2 and c-Met-Bcl-2-caspase-3 pathways.
The aim of this study was to elucidate the molecular mechanisms mediating hepatocyte growth factor (HGF)-induced protection against oridonin-induced apoptosis in A549 cells. Oridonin induced decrease in Bcl-2/Bax ratio and activation of caspase-3, while these processes were reversed by HGF, suggesting that HGF played an anti-apoptotic role in oridonin-induced A549 cell death. HGF-induced protective effect was partially attributed to the activation of nuclear factor (NF)-κB and cyclooxygenase 2 (COX-2), since the protective effect was abolished by inhibition of NF-κB or interruption of COX-2. Then the activated COX-2 could prevent cells from initiating the apoptotic response by promoting prostaglandin E₂ (PGE₂) release. Activation of NF-κB-COX-2 by HGF-treatment triggered the increase in Bcl-2/Bax ratio, inhibition of procaspase-3 cleavage, promotion of Ca²⁺-independent intracellular phospholipase A2 (iPLA2) expression and augmentation of PGE₂ release, leading to antagonizing oridonin-induced cell death in A549 cells. HGF-induced cell survival in response to oridonin administration was associated with the activation of c-Met-NF-κB-COX-2 and c-Met-Bcl-2-caspase-3 signaling pathways. iPLA2, downstream effector of caspase-3, also participated in these processes.
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
Ying
Y
Liu
Qi-Feng
QF
Shi
Min
M
Qi
Shin-Ichi
S
Tashiro
Satoshi
S
Onodera
Takashi
T
Ikejima
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D045786:Diterpenes, Kaurane; D054522:Group VI Phospholipases A2 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D045786:Diterpenes, Kaurane; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C011959:oridonin; D017228:Hepatocyte Growth Factor; D007770:L-Lactate Dehydrogenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051550:I-kappa B Kinase; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human; D053148:Caspase 3; D015232:Dinoprostone