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

Abstract

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.

Keywords: CPI-613; TCA cycle; cancer metabolism; colorectal cancer; mitochondria; oncogenic signaling; targeted therapy; tumor microenvironment.

Figure 1

Comparison of the metabolism in non-malignant cells (A) and cancer cells (B) In most non-malignant cells, the absence of growth factor signaling, the limited supply of nutrients and the activity of tumor suppressors promotes oxidative phosphorylation (OXPHOS) in order to maximize the energetic yield. In cancer cells, growth factor signaling and oncogenes facilitate the transporter-mediated uptake of nutrients (e.g., glucose, glutamate) to supply a metabolic shift towards the biosynthesis of lipids, nucleotides and proteins. The TCA cycle serves as the main hub, connecting anabolic and catabolic processes by generating and providing intermediates. Metabolites and oncometabolites of the TCA cycle act as signaling molecules.

Figure 2

Oncogenic signaling and tumor suppressor activity in CRC cell metabolism. The metabolic pathways, centered around the TCA cycle, are indicated by continuous lines and include catabolic (glycolysis, OXPHOS), anabolic (lipid synthesis) and anaplerotic (glutaminolysis) reactions. Tumor suppressors (e.g., p53), oncogenes (e.g., RAS, MYC) and transcription factors (e.g., HIF1) regulate metabolic reprogramming by controlling the expression and activity of metabolic enzymes (e.g., HK, PDK, GLS) and transporters (e.g., GLUT1, SN2). Modulators of the TCA cycle (denoted in red), which are currently tested as chemotherapeutics in clinical trials, target different enzymes of the tumor cell metabolism (see chapter 3 for further details).