Ascites development in patients with cancer is associated with considerable morbidity and mortality, representing an unmet clinical need. The development of targeted treatment strategies was so far hampered by a lack of pathophysiologic insight. Patients with ascites due to solid tumors (n = 35) and non-malignant ascites due to liver cirrhosis (n = 5) were prospectively enrolled. Patients with peritonitis, defined as an absolute neutrophil count > 0.25 G/l in ascites were excluded from analysis. Metabolomic profiling of ascites samples was performed using the MxP Quant 500 kit (Biocrates) and analyzed with MetaboAnalystR v4 and R. Among patients with solid tumors, 18 (51.4
The mechanisms by which the glycolytic microenvironment orchestrates amino acid metabolic reprogramming via protein lactylation remain a fundamental yet unresolved question in cancer biology. Here, we identify SIRT1 as a pivotal tumor suppressor in hypopharyngeal squamous cell carcinoma (HSCC) that is frequently downregulated to facilitate malignant progression. Mechanistically, SIRT1 functions as a direct delactylase of the RNA methyltransferase NSUN2, specifically targeting the K470 residue. We demonstrate that SIRT1 deficiency leads to NSUN2 hyperlactylation, which uniquely enhances its catalytic activity toward the m5C methylation of ASNS mRNA, thereby driving de novo asparagine biosynthesis to fuel HSCC proliferation. This SIRT1/NSUN2/ASNS axis establishes a previously uncharacterized molecular bridge linking lactate-driven post-translational modifications to RNA epigenetics and amino acid remodeling. Furthermore, pharmacological activation of SIRT1 exhibits potent synergistic anticancer effects when combined with L-asparaginase (ASNase), offering a sophisticated therapeutic strategy to overcome metabolic adaptation in HSCC.
Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy with poor clinical prognosis. While acyl-CoA thioesterases (ACOTs) are recognized as key regulators of lipid metabolism, their contributions to HNSCC pathogenesis are not well understood. ACOT7 is of particular interest as it catalyzes the hydrolysis of arachidonoyl-CoA (AA-CoA) to arachidonic acid (AA), a lipid mediator known to promote tumor growth and signaling. This study aims to define the functional role of ACOT7 in HNSCC and investigate associated metabolic and molecular changes. The functional role of ACOT7 was examined using an integrated approach, combining analysis of clinical datasets (TCGA and GEO) with in vitro and in vivo experiments. ACOT7 expression was manipulated by siRNA-mediated knockdown or lentiviral overexpression. Effects on malignant phenotypes were assessed using MTT, invasion, migration, colony formation and tumor sphere assays, alongside tumor xenograft models. Transcriptomic profiling, bioinformatic analysis, western blotting, chromatin immunoprecipitation (ChIP), and luciferase reporter assays were conducted to explore the downstream pathways and regulatory mechanisms associated with ACOT7. ACOT7 expression was significantly higher in HNSCC tumor tissues than in adjacent normal tissues and in HNSCC cell lines than in normal human oral keratinocytes (NHOK). Elevated ACOT7 expression was associated with poorer survival in HNSCC and several other cancers. ACOT7 knockdown suppressed malignant phenotypes in vitro and tumor growth in vivo, whereas overexpression had the opposite effects. Intracellular AA levels and tumor-tissue AA and prostaglandin E2 (PGE2) levels decreased following ACOT7 knockdown and increased following overexpression. ChIP and inhibitor experiments supported MYC involvement in ACOT7 transcriptional regulation. Exogenous AA enhanced colony formation and migration and increased total AKT abundance, whereas AKT depletion reduced colony formation in the presence of AA. ACOT7 knockdown reduced total AKT and p-MDM2 levels and increased p53 protein abundance, while AKT depletion produced similar changes in p-MDM2 and p53. ACOT7 promotes malignant phenotypes and alters AA abundance in HNSCC. MYC-associated regulation and changes in total AKT and p-MDM2 levels suggest a potential connection between ACOT7 and growth-related signaling. These findings support further evaluation of ACOT7 as a candidate prognostic biomarker and therapeutic target.
Systemic hypoxia induces whole-body metabolic adaptation, but its impact on tumor metabolism and hepatic bile acid (BA) pathways remains poorly defined. We investigated how high-altitude (HA) hypobaric hypoxia at 3,466 m affects tumor growth, tumor lipid metabolism, and liver BA regulation in mice bearing LLC1 lung carcinoma or E0771 mammary carcinoma. Moreover, we tested the contribution of hypoxia/HIF signaling and HNF4A knockdown to BA-related gene regulation in HepG2 cells. HA did not alter primary tumor growth, terminal tumor weight, necrosis, or hemorrhage in either model. However, LLC1 tumors from HA-acclimatized mice displayed a distinct lipid-metabolic profile, characterized by altered sterol and glycerophospholipid species, tendency toward reduced tumor free fatty acid content, and absence of detectable BAs, that were present in most low-altitude tumors. These tumor changes were accompanied by altered expression of lipid-handling genes, including increased Abca1 and Vdr and reduced Ptgs2 after FDR correction. Systemically, tumor-bearing mice at HA exhibited lower plasma BA levels, normalization of tumor-associated hepatomegaly, and reduced circulating IL-6. In the liver, HA and tumor burden produced overlapping, non-additive changes in BA synthesis, conjugation, and transport programs. In HepG2 cells, hypoxia and pharmacologic HIF stabilization reproduced BA-related transcripts, whereas partial HNF4A-knockdown selectively affected CYP7A1 and BAAT expression. These findings identify hepatic BA metabolism as a hypoxia-sensitive host pathway that links HA acclimatization to tumor lipid remodeling without necessarily altering primary tumor growth.
The emergence of chemoresistance remains a major obstacle to effective cancer therapy, driven in part by the survival of drug-tolerant persister cells (DTPs). A previous study from our laboratory demonstrated that pre-sensitization with a histone deacetylase (HDAC) inhibitor followed by cisplatin (CDDP) significantly reduces DTP formation; however, surviving DTP cells may contribute to tumor relapse through additional adaptive mechanisms. In the present study, we investigated the metabolic and mitochondrial adaptations associated with DTP survival in gastric and liver carcinoma cell lines using TEM, immunoblotting, metabolic assays, and in vivo xenograft studies. DTP cells exhibited increased levels of mitochondrial fusion proteins MFN1 and MFN2 along with activation of the PGC-1α/NRF2/TFAM axis, indicating enhanced mitochondrial biogenesis and oxidative phosphorylation. These alterations were associated with increased ATP production and antioxidant survival responses. Furthermore, low-dose pre-sensitization with valproic acid (VPA), a class I HDAC inhibitor, and metformin (MET), a mitochondrial complex I inhibitor, followed by CDDP treatment, significantly enhanced cell death in DTPs. In the NOD-SCID xenograft mouse model, VPA/MET/CDDP treatment resulted in enhanced anti-tumor efficacy, substantial tumor regression at lower doses, and reduced systemic toxicity. Tumor tissue analysis further revealed increased H3K9 acetylation, reduced Ki67 expression, altered AMPK levels, and elevated caspase-3 expression, consistent with metabolic disruption and induction of apoptosis. Collectively, these findings provide initial evidence for a clinically relevant strategy to inhibit or delay tumor relapse.
