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Characterizing the impact of the unfolded protein response in glioblastoma via proteomics approaches
Diffuse glioblastoma is one of the most common type of human brain tumors and among the deadliest of all human cancers. Recent studies reveal that the unfolded protein response (UPR) pathway plays an important role in tumor proliferation and therapeutic resistance. Due to this reason, the UPR network has become a potential target for the cancer treatment aiming to induce cancer cell death by activating the UPR apoptosis site. However, little is known about the mechanism how the UPR can affect the outcome of tumor progression as well as tumor resistance against therapeutic treatments. The aim of this study is to perform a comprehensive and system wide investigation of the UPR activation in glioblastoma utilizing state-of-the-art mass spectrometry based proteomics techniques. First, a sensitive and straightforward targeted mass spectrometry method was successfully developed allowing the identification and absolute quantification of low abundant UPR key proteins for the first time. Applying this method, the UPR protein expression level could be quantitatively monitored over the treatment time describing the activation level of UPR under activation. Seconds, together with the research group of Dr. Medenbach at the University of Regensburg, a multi-omics approach in glioblastoma cells describing the mechanism of action of the UPR over time and at multiple biological levels was performed. By combining the transcriptomics and proteomics data, we could detect a group of UPR responsive proteins. Further validation experiments showed alterations in mitochondrial one‐carbon metabolism triggered by UPR activation, too. Moreover, resistance against anti-folate agents interfering directly the mitochondrial one‐carbon metabolism in glioblastoma cells could be observed in UPR activated cells. This finding opens new therapeutic directions and targets in suppressing the development of resistance against cancer therapies. In the final chapter, together with the research group of Dr. Knobbe-Thomsen at the University of Düsseldorf, ...
Characterizing the impact of the unfolded protein response in glioblastoma via proteomics approaches
Diffuse glioblastoma is one of the most common type of human brain tumors and among the deadliest of all human cancers. Recent studies reveal that the unfolded protein response (UPR) pathway plays an important role in tumor proliferation and therapeutic resistance. Due to this reason, the UPR network has become a potential target for the cancer treatment aiming to induce cancer cell death by activating the UPR apoptosis site. However, little is known about the mechanism how the UPR can affect the outcome of tumor progression as well as tumor resistance against therapeutic treatments. The aim of this study is to perform a comprehensive and system wide investigation of the UPR activation in glioblastoma utilizing state-of-the-art mass spectrometry based proteomics techniques. First, a sensitive and straightforward targeted mass spectrometry method was successfully developed allowing the identification and absolute quantification of low abundant UPR key proteins for the first time. Applying this method, the UPR protein expression level could be quantitatively monitored over the treatment time describing the activation level of UPR under activation. Seconds, together with the research group of Dr. Medenbach at the University of Regensburg, a multi-omics approach in glioblastoma cells describing the mechanism of action of the UPR over time and at multiple biological levels was performed. By combining the transcriptomics and proteomics data, we could detect a group of UPR responsive proteins. Further validation experiments showed alterations in mitochondrial one‐carbon metabolism triggered by UPR activation, too. Moreover, resistance against anti-folate agents interfering directly the mitochondrial one‐carbon metabolism in glioblastoma cells could be observed in UPR activated cells. This finding opens new therapeutic directions and targets in suppressing the development of resistance against cancer therapies. In the final chapter, together with the research group of Dr. Knobbe-Thomsen at the University of Düsseldorf, ...
Characterizing the impact of the unfolded protein response in glioblastoma via proteomics approaches
Nguyen, Dinh Lien Chi (Autor:in) / Schmitz, Oliver J.
07.11.2023
Hochschulschrift
Elektronische Ressource
Englisch