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Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

  • Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation,the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.
Metadaten
Author:Carina Neitzel, Philipp Demuth, Simon Wittmann, Jörg FahrerORCiD
URN (permanent link):urn:nbn:de:hbz:386-kluedo-65666
Parent Title (English):Cancers
Publisher:MDPI
Document Type:Article
Language of publication:English
Publication Date:2020/06/29
Year of Publication:2020
Publishing Institute:Technische Universität Kaiserslautern
Date of the Publication (Server):2021/09/21
Issue:2020, 12, 1731
Number of page:32
Source:doi:10.3390/cancers12071731
Faculties / Organisational entities:Fachbereich Chemie
DDC-Cassification:5 Naturwissenschaften und Mathematik / 540 Chemie
Licence (German):Zweitveröffentlichung