Glycolytic Reprogramming Emerges as Key Therapeutic Target in Gastric Cancer
核心洞察
Recent research reveals that gastric cancer (搜索) cells exhibit extensive glycolytic reprogramming through the Warburg effect, where cancer (搜索) cells preferentially rely on glycolysis for energy production even under oxygen-rich conditions, supporting tumor proliferation and therapeutic resistance.
Key regulatory mechanisms include non-coding RNAs (lncRNAs, circRNAs, miRNAs) that modulate glycolytic enzyme expression, with proteins like CENPU (搜索), HMGB2 (搜索), and CD73 (搜索) enhancing glycolysis through various signaling pathways including PI3K/Akt (搜索)/mTOR and HIF-1α (搜索) activation.
Glycolytic enzymes such as hexokinase 2 (HK2 (搜索)), pyruvate kinase M2 (PKM2 (搜索)), and lactate dehydrogenase A (LDHA (搜索)) serve dual roles as metabolic catalysts and oncogenic drivers, with PKM2 functioning as a transcriptional coactivator when translocated to the nucleus.
Glycolytic Reprogramming Emerges as Key Therapeutic Target in Gastric Cancer
Gastric cancer (搜索) remains a formidable global health challenge, ranking as the fifth most common malignancy (搜索) and third leading cause of cancer (搜索)-related deaths worldwide. Despite advances in treatment approaches, the persistently high mortality rate underscores the urgent need for novel therapeutic strategies. Recent comprehensive research has illuminated the critical role of metabolic reprogramming, particularly glycolytic rewiring, in gastric cancer progression and therapeutic resistance.
The Warburg Effect: A Metabolic Hallmark of Gastric Cancer
Cancer (搜索) cells exhibit a distinctive metabolic phenotype known as the Warburg effect, characterized by preferential reliance on glycolysis for energy production even under oxygen-rich conditions. This metabolic shift represents a fundamental departure from normal cellular energy metabolism, where cells typically utilize more efficient oxidative phosphorylation in the presence of oxygen.
In gastric cancer (搜索), this glycolytic reprogramming serves multiple functions beyond energy production. The process generates metabolic intermediates essential for rapid cell division while creating an acidic, lactate-enriched tumor microenvironment that promotes immune evasion, angiogenesis, and metastatic potential. Research demonstrates that even under normoxic conditions, gastric cancer cells preferentially utilize glycolysis, supporting tumor proliferation, invasion, and therapeutic resistance.
Molecular Orchestrators of Glycolytic Reprogramming
Key Regulatory Proteins
Several critical proteins have emerged as master regulators of glycolytic flux in gastric cancer (搜索). Centromere Protein U (CENPU (搜索)) enhances glycolysis and proliferation by upregulating High Mobility Group Box 2 (HMGB2 (搜索)) through activation of the PI3K/Akt (搜索) signaling pathway. This mechanism enables cancer (搜索) cells to rapidly obtain energy through anaerobic glycolysis, even under hypoxic conditions.
HMGB2 (搜索) itself functions as a pivotal regulator, driving glycolysis through dual mechanisms. First, it enhances the transcriptional activity of hypoxia-inducible factor-1α (HIF-1α (搜索)), leading to upregulation of glycolytic enzymes including lactate dehydrogenase A (LDHA (搜索)), pyruvate kinase M2 (PKM2 (搜索)), and hexokinase 2 (HK2 (搜索)). Second, HMGB2 activates NF-κB signaling, which increases glycolytic efficiency and provides energy for tumor cell proliferation and survival.
CD73 (搜索), an enzyme that converts adenosine monophosphate to adenosine, represents another crucial player. The adenosine produced binds to A2A and A2B receptors, activating the cAMP/PKA pathway and regulating glycolytic enzyme expression. This dual mechanism not only enhances glucose uptake and lactate production but also suppresses immune cell function, promoting immune evasion.
Glycolytic Enzymes as Multifunctional Oncogenic Drivers
Beyond their metabolic roles, glycolytic enzymes exhibit pleiotropic control over malignant phenotypes. HK2 (搜索), frequently overexpressed in advanced tumors (搜索), binds mitochondrial voltage-dependent anion channels to evade apoptosis while enhancing glucose phosphorylation. The enzyme also interacts with PDLIM1 (搜索), activating the Wnt/β-catenin pathway and forming a positive feedback loop that sustains elevated glycolytic flux.
PKM2 (搜索) serves as a particularly versatile metabolic rheostat, coordinating both glycolytic metabolism and malignant phenotypes through multiple downstream pathways. As a rate-limiting enzyme, PKM2 catalyzes the conversion of phosphoenolpyruvate to pyruvate while promoting transcription of LDHA (搜索) and GLUT1 (搜索). Notably, PKM2 can translocate to the nucleus, where it phosphorylates STAT3 and forms complexes with c-Myc, upregulating HIF-1α (搜索) and EMT-related genes such as Snail and Twist.
Non-Coding RNA Regulatory Networks
The regulation of glycolysis in gastric cancer (搜索) involves complex networks of non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). These regulatory elements interact through competitive endogenous RNA (ceRNA) networks to modulate glycolytic enzyme expression.
Long non-coding RNA SNHG7 (搜索) modulates glycolysis-related chemoresistance (搜索) by repressing miR-34a, thereby regulating LDHA (搜索) expression. SNHG7 is significantly upregulated in gastric cancer (搜索) and associated with cisplatin resistance, with its knockdown markedly increasing sensitivity to cisplatin treatment.
Circular RNAs contribute to metabolic rewiring primarily through miRNA sequestration. For example, circBFAR promotes glycolysis by sponging miR-513a-3p, thereby lifting its repression of HK2 (搜索). Similarly, circRPS19 enhances HK2 enzymatic activity by stabilizing the protein via the miR-125a-5p/USP7 axis.
Therapeutic Implications and Resistance Mechanisms
Glycolysis and Chemoresistance
Glycolytic reprogramming significantly contributes to chemoresistance (搜索) in gastric cancer (搜索). Research reveals that Helicobacter pylori virulence factor CagA induces resistance to 5-fluorouracil by activating the Akt pathway and upregulating glycolysis. CagA expression is significantly elevated in 5-FU-resistant gastric cancer cells, along with increased expression of glycolytic enzymes such as HK2 (搜索) and LDHA (搜索).
The SNHG7 (搜索)-miR-34a-LDHA (搜索) axis has been implicated in cisplatin resistance, while MALAT1 delivered via exosomes from M2-type tumor-associated macrophages contributes to resistance by modulating HIF-1α (搜索) and β-catenin expression, thereby enhancing glycolytic activity.
Emerging Therapeutic Strategies
Multiple therapeutic approaches targeting glycolytic pathways show promise in preclinical studies. Plant-derived compounds demonstrate significant potential, with salidroside from Rhodiola rosea inhibiting glycolysis by downregulating ENO1, PKM2 (搜索), and GLUT1 (搜索) expression, leading to apoptosis induction in gastric cancer (搜索) cells.
Small molecule inhibitors represent another promising avenue. CD73 (搜索) inhibition by APCP (搜索) significantly suppresses tumor growth, while 2-deoxy-D-glucose (2-DG) and other glycolytic inhibitors show synergistic anti-tumor effects when combined with conventional therapies.
Advanced therapeutic strategies include dual inhibition of oxidative phosphorylation and glycolysis, which results in synergistic antitumor effects. Real-time metabolic monitoring using 13C-MRSI technology demonstrates that this combined approach induces energy depletion and metabolic imbalance, boosting tumor suppression.
Future Directions and Clinical Translation
The study of glycolysis in gastric cancer (搜索) has provided significant insights into metabolic reprogramming and its role in tumor progression and therapeutic resistance. However, substantial challenges remain for clinical translation, including the development of more selective inhibitors, innovative drug delivery systems, and combination therapies that incorporate glycolytic inhibitors with traditional treatments.
Precision medicine approaches utilizing genetic profiling and multi-omics technologies enable identification of glycolytic signatures for personalized treatment development. The integration of artificial intelligence and machine learning to analyze large-scale genomic and clinical datasets offers potential for identifying novel glycolytic biomarkers and predicting treatment responses.
Targeting glycolysis in gastric cancer (搜索) represents a promising therapeutic strategy that could enhance treatment outcomes and help overcome resistance to conventional therapies. Future research should focus on developing more effective glycolytic inhibitors, exploring combination therapies, and utilizing precision medicine approaches to personalize treatment based on individual tumor metabolic profiles.