| Summary: | 博士 === 國立中興大學 === 生物化學研究所 === 99 === Whether Hispidulin, a flavone from traditional Chinese medicine, can modulate the anticancer effects of TRAIL, the cytokine that is currently in clinical trial, was investigated. In the present study, we found that Hispidulin potentiated the TRAIL-induced apoptosis in human ovarian cancer cells, and converted TRAIL-resistant cells to TRAIL-sensitive cells. When examined for its mechanism, we found that Hispidulin was highly effective in activation of caspases 8 and caspase 3 and consequent PARP cleavage. Moreover, we found that Hispidulin down-regulated the expression of Mcl-1, Bcl-2, and Bcl-xL. Whereas the down-regulation of Bcl-2, and Bcl-xL was less pronounced, the down-regulation of Mcl-1 was quite dramatic and was time-dependent. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. Interestingly, we determined that AMPK is activated upon Hispidulin treatment resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease. Therefore, our results show a novel mechanism for the sensitization to TRAIL-induced apoptosis linking Hispidulin treatment to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of death receptor (DR) ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.
Epithelial-mesenchymal transition is thought to play a crucial role in malignant process; it has been implicated not only in cell surface changes, but also in multiple complex signal transduction changes, as well as protein expression changes. Especially, the changes of between E-cadherin (epithelial marker) and Vimentin (interstitial marker) should also be considered. In this study, the protein expression changes were determined by proteomics techniques may serve as markers to provide the information of therapeutic responses and may provide an accelerated path toward clinical drug development.
The goal of this study was to investigate the differences in signal transduction between MCF-7 breast cancer cells exposed to anti-cancer drug (CHM-1) and that of non-stimulated cells. The experimental group was then exposed to anti-cancer drug, while the control group had no adjuvant treatment. Proteins were extracted from intact cell pellets, identified by two-dimensional gel electrophoresis and MALDI-TOF peptide mass fingerprinting. Validation of data obtained from 2-DE was confirmed by Western blot analysis. It revealed that breast cancer cells MCF-7, MDA-MB-231 and MDA-MB-435, after exposing to CHM-1, E-cadherin was upregulated, whereas Vimentin was downregulated. The expression of E-cadherin in MCF-7 (epithelial phenotype) was markedly higher than those in MDA-MB-231 and MDA-MB-435 (mesenchymal phenotype). In contrast, a markedly decreased expression of Vimentin was observed in MDA-MB-231 and MDA-MB-435 than that in MCF-7.
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