Aldolase A: the broker of glycolysis
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Targeting aldolase A in hepatocellular carcinoma leads to imbalanced glycolysis and energy stress due to uncontrolled FBP accumulation
Increased glycolytic flux is a hallmark of cancer; however, an increasing body of evidence indicates that glycolytic ATP production may be dispensable in cancer, as metabolic plasticity allows cancer cells to readily adapt to disruption of glycolysis by increasing ATP production via oxidative phosphorylation. Using functional genomic screening, we show here that liver cancer cells show a unique sensitivity toward aldolase A (ALDOA) depletion. Targeting glycolysis by disrupting the catalytic activity of ALDOA led to severe energy stress and cell cycle arrest in murine and human hepatocellular carcinoma cell lines. With a combination of metabolic flux analysis, metabolomics, stable-isotope tracing and mathematical modelling, we demonstrate that inhibiting ALDOA induced a state of imbalanced glycolysis in which the investment phase outpaced the payoff phase. Targeting ALDOA effectively converted glycolysis from an energy producing into an energy-consuming process. Moreover, we found that depletion of ALDOA extended survival and reduced cancer cell proliferation in an animal model of hepatocellular carcinoma. Thus, our findings indicate that induction of imbalanced glycolysis by targeting ALDOA presents a unique opportunity to overcome the inherent metabolic plasticity of cancer cells.
Exploring metabolic reprogramming in esophageal cancer: the role of key enzymes in glucose, amino acid, and nucleotide pathways and targeted therapies
Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.
Matrix stiffness regulates nucleus pulposus cell glycolysis by MRTF-A-dependent mechanotransduction
Increased matrix stiffness of nucleus pulposus (NP) tissue is a main feature of intervertebral disc degeneration (IVDD) and affects various functions of nucleus pulposus cells (NPCs). Glycolysis is the main energy source for NPC survival, but the effects and underlying mechanisms of increased extracellular matrix (ECM) stiffness on NPC glycolysis remain unknown. In this study, hydrogels with different stiffness were established to mimic the mechanical environment of NPCs. Notably, increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis, and NPCs cultured on rigid substrates exhibited a reduction in glycolysis. Meanwhile, RNA sequencing analysis showed altered cytoskeleton-related gene expression in NPCs on rigid substrates. Myocardin-related transcription factor A (MRTF-A) is a transcriptional coactivator in mechanotransduction mainly responding to cytoskeleton remodeling, which was activated and translocated to the nucleus under rigid substrate and was upregulated during IVDD progression. Furthermore, gas chromatography-mass spectrometry (GC-MS) analysis revealed that MRTF-A overexpression reduced NPC glycolytic metabolite abundance and identified a correlation with AMPK pathway. Mechanistically, rigid substrates and MRTF-A overexpression inhibited Kidins220 expression and AMPK phosphorylation in NPCs, whereas MRTF-A inhibition, treated with the MRTF-A inhibitor CCG, partially rescued NP tissue degeneration and glycolytic enzyme expression. Our data demonstrate that MRTF-A is a critical regulator that responds to increased matrix stiffness in IVDD, and MRTF-A activation reduces NPC glycolysis by down-regulating Kidins220 and inhibiting AMPK phosphorylation.
TPM4 condensates glycolytic enzymes and facilitates actin reorganization under hyperosmotic stress
Actin homeostasis is fundamental for cell structure and consumes a large portion of cellular ATP. It has been documented in the literature that certain glycolytic enzymes can interact with actin, indicating an intricate interplay between the cytoskeleton and cellular metabolism. Here we report that hyperosmotic stress triggers actin severing and subsequent phase separation of the actin-binding protein tropomyosin 4 (TPM4). TPM4 condensates recruit glycolytic enzymes such as HK2, PFKM, and PKM2, while wetting actin filaments. Notably, the condensates of TPM4 and glycolytic enzymes are enriched of NADH and ATP, suggestive of their functional importance in cell metabolism. At cellular level, actin filament assembly is enhanced upon hyperosmotic stress and TPM4 condensation, while depletion of TPM4 impairs osmolarity-induced actin reorganization. At tissue level, colocalized condensates of TPM4 and glycolytic enzymes are observed in renal tissues subjected to hyperosmotic stress. Together, our findings suggest that stress-induced actin perturbation may act on TPM4 to organize glycolytic hubs that tether energy production to cytoskeletal reorganization.
Transcription factor ONECUT3 regulates HDAC6/HIF-1α activity to promote the Warburg effect and tumor growth in colorectal cancer
The Warburg effect, also known as aerobic glycolysis, plays a crucial role in the onset and progression of colorectal cancer (CRC), although its mechanism remains unclear. In this study, bioinformatics analysis of public databases combined with validation using clinical specimens identified the transcription factor ONECUT3 as a key regulator related to the Warburg effect in CRC. Functionally, silencing ONECUT3 reverses the Warburg effect and suppresses tumor growth. Importantly, ONECUT3 promotes tumor growth in a glycolysis-dependent manner through hypoxia-inducible factor 1α (HIF-1α). Mechanistically, ONECUT3 does not directly regulate the expression of HIF-1α but instead inhibits its acetylation via histone deacetylase 6 (HDAC6). This deacetylation enhances the transcriptional activity of HIF-1α, ultimately upregulating multiple glycolysis-related genes downstream of HIF-1α, thereby driving the Warburg effect and facilitating tumor growth in CRC. These findings reveal a novel mechanism by which ONECUT3 regulates the Warburg effect in CRC and suggest that targeting ONECUT3 may offer a promising therapeutic strategy for CRC.
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