In a recent article published in the journal Cell Death & Differentiation, researchers explored the role of HKDC1 (hexokinase domain containing 1) in cancer metabolism, particularly its influence on glycolysis and fatty acid oxidation in the context of glucose availability.
Study: A novel glucose sensor fuelling cancer growth. Image Credit: Sebastian Kaulitzki/Shutterstock.com
The research investigates how HKDC1 contributes to the metabolic reprogramming of cancer cells, enabling them to adapt to varying nutrient conditions, especially within the tumor microenvironment where glucose levels may be limited. This study highlights the potential of targeting HKDC1 and its associated pathways for innovative therapeutic interventions in cancer treatment.
Background
The Warburg effect, first described by Otto Warburg in the 1920s, is a hallmark of cancer characterized by the preference of cancer cells to convert glucose to lactate even in the presence of oxygen. This phenomenon, known as aerobic glycolysis, allows cancer cells to meet their heightened energy and biosynthetic demands.
Advancements in analytical chemistry and mathematical modeling have deepened our understanding of glucose metabolism in cancer, revealing its complex roles beyond mere energy production. Glucose not only serves as a primary energy source but also participates in various cellular processes, including epigenetic modifications and signaling pathways that influence oncogenic processes.
Recent studies have identified glucose sensors, such as the methyltransferase NSUN2, which are activated by glucose and maintain RNA stability and regulate immune responses. However, the specific functions of glycolytic enzymes like HKDC1 in signaling networks remain less understood, prompting further investigation into their roles in cancer biology.
The Current Study
This study employed a multifaceted approach to investigate HKDC1's role in cancer metabolism. Researchers utilized structural modeling techniques to analyze HKDC1's three-dimensional conformation, focusing on key amino acid residues that influence its stability and function. Site-specific mutagenesis was performed to substitute critical residues—particularly Lys620 and Ser896—to assess their roles in ubiquitination and structural integrity.
To evaluate the metabolic impact of HKDC1, human lung cancer cell lines were genetically modified to either overexpress or knock out HKDC1. Glycolytic activity was measured using a Seahorse XF Analyzer for real-time assessment of extracellular acidification rates (ECAR) and oxygen consumption rates (OCR) under varying glucose conditions.
Additionally, pharmacological inhibitors like etomoxir were employed to assess the reliance of HKDC1-deficient cells on fatty acid oxidation for ATP production. In vivo experiments were conducted using immunocompromised mice implanted with HKDC1-ablated and control lung cancer cells to evaluate tumor growth and proliferation rates.
Western blot analysis quantified protein levels of HKDC1, PHB2 (prohibitin 2), and Sp1, providing insights into the interactions and regulatory mechanisms at play. These combined methodologies enabled a comprehensive understanding of HKDC1's role in metabolic adaptation and its implications for tumor growth amid challenges posed by glucose availability.
Results and Discussion
The findings revealed that HKDC1 plays a crucial role in regulating the glycolytic rate of cancer cells. Deletion of HKDC1 resulted in a significant decrease in glycolysis but was compensated by an increase in fatty acid oxidation, allowing cells to maintain stable ATP levels despite reduced glucose availability. This metabolic adaptation suggests that HKDC1 degradation may facilitate cancer cells' ability to thrive in low-glucose environments by promoting fatty acid utilization as an alternative energy source.
Moreover, HKDC1-deficient lung cancer cells exhibited heightened sensitivity to etomoxir, indicating that increased fatty acid oxidation could represent a vulnerability in the absence of HKDC1. The authors demonstrated that HKDC1 interacts with PHB2, influencing tumor growth. In glucose-rich conditions, HKDC1 binds to PHB2, preventing its interaction with Sp1—a transcription factor responsible for activating pro-tumorigenic genes.
Conversely, during glucose deprivation, degradation of HKDC1 releases PHB2, allowing it to translocate to the nucleus and inhibit Sp1 activity, thereby suppressing tumor proliferation. These findings underscore the intricate relationship between glucose metabolism, HKDC1, and tumor growth, emphasizing the potential for targeting these pathways in cancer therapy.
Conclusion
This study provides valuable insights into the metabolic adaptations of cancer cells mediated by HKDC1, highlighting its dual role in regulating glycolysis and fatty acid oxidation. The research suggests that targeting HKDC1 and its associated pathways could offer new therapeutic strategies for cancer treatment—particularly in tumors characterized by metabolic reprogramming.
The potential repurposing of existing fatty acid oxidation inhibitors such as Trimetazidine and Ranolazine—when combined with glucose uptake inhibitors—presents an exciting avenue for future clinical applications. Overall, this work significantly enhances our understanding of cancer metabolism and the complex interplay between nutrient availability and tumor growth, paving the way for innovative approaches to combat cancer.
Journal Reference
Ricci L., Cardaci S. (2024). A novel glucose sensor fuelling cancer growth. Cell Death & Differentiation. DOI: 10.1038/s41418-024-01400-8, https://www.nature.com/articles/s41418-024-01400-8