ABSTRACT
Parkin (PARK2) deficiency is frequently observed in various cancers and potentially promotes tumor progression. Here, we showed that Parkin expression is downregulated in liver cancer tissues, which correlates with poor patient survival. Parkin deficiency in liver cancer cells promotes migration and metastasis as well as changes in EMT and metastasis markers. A negative correlation exists between TMEFF1 and Parkin expression in liver cancer cells and tumor tissues. Parkin deficiency leads to upregulation of TMEFF1 which promotes migration and metastasis. TMEFF1 transcription is activated by Parkin-induced endogenous TGF-ß production and subsequent phosphorylation of Smad2/3 and its binding to TMEFF1 promotor. TGF-ß inhibitor and TMEFF1 knockdown can reverse shParkin-induced cell migration and changes of EMT markers. Parkin interacts with and promotes the ubiquitin-dependent degradation of HIF-1α/HIF-1ß and p53, which accounts for the suppression of TGF-ß production. Our data have revealed that Parkin deficiency in cancer leads to the activation of the TGF-ß/Smad2/3 pathway, resulting in the expression of TMEFF1 which promotes cell migration, EMT, and metastasis in liver cancer cells.
Subject(s)
Cell Movement , Liver Neoplasms , Smad2 Protein , Smad3 Protein , Transforming Growth Factor beta , Ubiquitin-Protein Ligases , Humans , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Transforming Growth Factor beta/metabolism , Cell Line, Tumor , Signal Transduction , Transcriptional Activation , Animals , Epithelial-Mesenchymal Transition , Membrane Proteins/metabolism , Membrane Proteins/genetics , Neoplasm Metastasis , Neoplasm Proteins/metabolism , Neoplasm Proteins/genetics , Mice, Nude , MiceABSTRACT
Fructus Psoraleae (FP) is an edible Chinese herbal which is widely used in Asia for the treatment of various diseases including asthma, diarrhea, and osteoporosis. This study aimed to investigate the inhibitory effects of the crude ethanol extract from FP on human carboxylesterase 2 (hCE2), as well as to identity and characterize the naturally occurring inhibitors of hCE2 in FP. Our results demonstrated that the ethanol extract of FP displayed potent inhibitory effects towards hCE2, while five major bioactive constitutes in FP were efficiently identified by LC-DAD-ESI-MS/MS, with the aid of LC-based activity profiling. The identified bioactive compounds including neobavaisoflavone, isobavachalcone, bavachinin, corylifol A and bakuchiol were found to be naturally occurring potent inhibitors of hCE2, with low Ki values ranging from 0.62µM to 3.89µM. This is the first report of the chemical constitutes in FP as potent inhibitors of hCE2.