https://scholars.lib.ntu.edu.tw/handle/123456789/458625
Title: | Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway | Authors: | Chang M.-C. CHI-AN CHEN CHANG-YAO HSIEH CHIEN-NAN LEE Su Y.-N. Hu Y.-H. WEN-FANG CHENG |
Issue Date: | 2009 | Journal Volume: | 424 | Journal Issue: | 3 | Start page/Pages: | 449-458 | Source: | Biochemical Journal | Abstract: | Mesothelin, a secreted protein, is overexpressed in some cancers, but its exact function remains unclear. The aim of the present study was to evaluate the possible function of mesothelin. Real-time PCR, RT (reverse transcription)-PCR, cytotoxicity assays, proliferative assays, apoptotic assays by Hoechst staining, detection of active caspases 3 and 7 by flow cytometric analysis, and immunoprecipitation and immunoblotting were performed. Cancer tissues in paclitaxel-resistant ovarian cancer patients expressed higher levels of mesothelin as assessed using real-time PCR than paclitaxel-sensitive ovarian cancer patients (the mean crossing point value change of mesothelin was 26.9±0.4 in the resistant group and 34.3±0.7 for the sensitive group; P<0.001). Mesothelin also protected cells from paclitaxel-induced apoptosis. The protein expression of Bcl-2 family members, such as Bcl-2 and Mcl-1, was significantly increased regardless of whether cells were treated with exogenous mesothelin or were mesothelin-transfectants. Furthermore, mesothelin-treated cells revealed rapid tyrosine phosphorylation of the p85 subunit of PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) 1/2 for enhancing MAPK (mitogen-activated protein kinase) activity. The anti-apoptotic ability was suppressed and the expression of Bcl-2 family in response to mesothelin was altered by inhibiting PI3K activity, but not by inhibiting MAPK activity. Thus mesothelin can inhibit paclitaxel-induced cell death mainly by involving PI3K signalling in the regulation of Bcl-2 family expression. Mesothelin is a potential target in reducing resistance to cytotoxic drugs. ? The Authors Journal compilation ? 2009 Biochemical Society. |
URI: | 2-s2.0-73149108613 https://scholars.lib.ntu.edu.tw/handle/123456789/458625 |
ISSN: | 0264-6021 | DOI: | 10.1042/BJ20082196 | SDG/Keyword: | Apoptosis; Apoptotic; Bcl-2 family; Cancer tissues; Caspases; Crossing point; Cytotoxic drugs; Cytotoxicity assays; Extracellular signal-regulated kinase; Flow-cytometric analysis; Hoechst; Immunoblotting; Immunoprecipitations; Induced apoptosis; Mitogen activated protein kinase; Ovarian cancers; Paclitaxel; Phosphoinositide 3-kinase; Protein expressions; Real-time PCR; Reverse transcription; Secreted protein; Transfectants; Tyrosine phosphorylation; Amino acids; Enzyme activity; Phosphatases; Phosphorylation; Proteins; Cell death; caspase 3; caspase 7; mesothelin; mitogen activated protein kinase; paclitaxel; phosphatidylinositol 3 kinase; protein bcl 2; protein mcl 1; animal cell; apoptosis; article; cell proliferation; cell protection; cell survival; clinical article; concentration response; controlled study; cytotoxicity test; drug targeting; enzyme activity; enzyme inhibition; flow cytometry; human; nonhuman; ovary cancer; priority journal; protein expression; protein function; protein phosphorylation; real time polymerase chain reaction; regulatory mechanism; reverse transcription polymerase chain reaction; 1-Phosphatidylinositol 3-Kinase; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Culture Media, Serum-Free; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Membrane Glycoproteins; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Ovarian Neoplasms; Paclitaxel; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Transfection |
Appears in Collections: | 醫學系 |
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