ArticleCancer science2026
Decreased Expression by a Chemically Modified siRNA to PTBP1 Seriously Affects Warburg Effect in Colorectal Cancer Cells.
Article in Cancer science, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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20 authors.
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Abstract
Cancer cells preferentially rely on aerobic glycolysis, known as the Warburg effect, to support growth and survival. We previously demonstrated that polypyrimidine tract-binding protein 1 (PTBP1) maintains PKM2 dominance by regulating pyruvate kinase isoform splicing, sustaining the Warburg phenotype. PTBP1 suppression shifts metabolism toward PKM1 dominance, enhancing oxidative phosphorylation, reactive oxygen species (ROS) production, apoptosis, and antitumor immunity. Thirteen chemically modified siR-PTBP1 derivatives targeting either the coding region or the 3'-untranslated region (3'-UTR) of PTBP1 mRNA were synthesized and evaluated in colorectal cancer cell lines. Cytotoxicity, protein expression, oxidative stress, and metabolic alterations were assessed using cell-based assays, immunoblotting, and metabolomic analysis. siRNA stability was evaluated following nuclease exposure and quantified by TaqMan RT-qPCR. siRNAs targeting the 3'-UTR more effectively suppressed PTBP1 expression and increased the PKM1/PKM2 ratio than coding-region-targeting siRNAs. Among them, derivative 2-6 showed the strongest cytotoxicity with oxidative stress and apoptosis. Metabolomic profiling demonstrated altered glycolytic flux and preserved pentose phosphate pathway intermediates with activated redox responses, while adenylate and guanylate energy charges remained viable, indicating metabolic stress without energy collapse. Tricarboxylic acid cycle metabolites were elevated, consistent with enhanced oxidative phosphorylation. Derivative 2-6 showed resistance to nuclease-mediated degradation. Direct PKM2 knockdown did not induce comparable cytotoxicity. Chemically modified siR-PTBP1, particularly derivative 2-6, induces a metabolically vulnerable state characterized by oxidative imbalance, leading to apoptosis. These findings identify PTBP1 as a key regulator of the Warburg effect and support siRNA-based metabolic targeting as a therapeutic strategy.
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