Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach
| Autor: | Seán M. Kilbride, Maika Dunst, Christian Senft, Markus Rehm, Brona M. Murphy, Jakob Weissenberger, Donat Kögel, Heinrich J. Huber, Jochen H. M. Prehn, Jasmin Schmid, Aine C. Murphy, B Weyhenmeyer, Volker Seifert, Michel Mittelbronn |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Cancer Research 0302 clinical medicine Caspase 0303 health sciences biology Brain Neoplasms Caspase 3 apoptosis Intracellular Signaling Peptides and Proteins Middle Aged Caspase 9 3. Good health XIAP Dacarbazine Caspases 030220 oncology & carcinogenesis Original Article Female Stem cell Algorithms medicine.drug Adult Cell Survival Immunology Brain tumor X-Linked Inhibitor of Apoptosis Protein Disease-Free Survival Mitochondrial Proteins 03 medical and health sciences Cellular and Molecular Neuroscience Temozolomide medicine Humans Progression-free survival systems medicine Antineoplastic Agents Alkylating Aged 030304 developmental biology glioblastoma Cell Biology medicine.disease Apoptotic Protease-Activating Factor 1 Apoptosis biology.protein Cancer research Apoptosis Regulatory Proteins |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting. |
| Databáze: | OpenAIRE |
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