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Background <p>Ovarian cancer is a highly aggressive malignancy influenced by complex molecular interactions, including those involving long non-coding RNAs. RBM5-AS1, a nuclear-retained lncRNA, interacts with GCN5 to acetylate PGC-1α, thereby enhancing the Warburg effect. Although fasting is known to exert antitumor effects by modulating lncRNAs and activating PGC-1α, its impact on the RBM5-AS1/GCN5 axis in ovarian cancer remains underexplored. This study evaluates the therapeutic efficacy of RBM5-AS1 knockdown and GCN5 inhibition under fasting-mimicked conditions in SKOV3 cells.</p> Methods and results <p>The findings of cytotoxicity assays revealed a dose-dependent decrease in cell viability, with the fasting + siRNA + MB-3 combination showing the most potent anticancer effect. LDH assays confirmed enhanced membrane damage in this group. Migration assays demonstrated reduced motility, while DAPI and acridine orange/ethidium bromide staining indicated significant apoptotic features present in fasting + siRNA + MB-3-treated ovarian cancer cells. Colony formation was markedly inhibited under the combination treatment, confirming suppression of clonogenic potential. Flow cytometry analysis revealed &gt; 80% late apoptotic/necrotic cells in the fasting + siRNA + MB-3 group. Gene expression analysis further showed downregulation of Warburg-related genes (PDK1/2/3/4, LDH, GLUT1/3/4) and upregulation of PDH and pro-apoptotic markers (Caspase, Bax), alongside reduced PGC-1α acetylation.</p> Conclusion <p>These findings indicate that fasting enhances the therapeutic effect of RBM5-AS1 knockdown and GCN5 inhibition, leading to a significant disruption of glycolytic metabolism and promoting apoptosis. This combinatorial approach highlights a promising metabolic and epigenetic strategy for ovarian cancer treatment.</p>

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Targeting the lncRNA RBM5-AS1/GCN5 axis under fasting conditions reprograms Glycolysis and induces apoptosis in ovarian cancer cells

  • 期刊论文

  • 发表日期：

    2025年7月9日

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  • Gayathiri Gunasangkaran,
  • Saradhadevi Muthukrishnan,
  • Anjali K. Ravi,
  • Vijaya Anand Arumugam,
  • Velayuthaprabhu Shanmugam,
  • Kunnathur Murugesan Sakthivel,
  • Marie Arockianathan Pushpam,
  • Ashokkumar kaliyaperumal

摘要

Background

Ovarian cancer is a highly aggressive malignancy influenced by complex molecular interactions, including those involving long non-coding RNAs. RBM5-AS1, a nuclear-retained lncRNA, interacts with GCN5 to acetylate PGC-1α, thereby enhancing the Warburg effect. Although fasting is known to exert antitumor effects by modulating lncRNAs and activating PGC-1α, its impact on the RBM5-AS1/GCN5 axis in ovarian cancer remains underexplored. This study evaluates the therapeutic efficacy of RBM5-AS1 knockdown and GCN5 inhibition under fasting-mimicked conditions in SKOV3 cells.

Methods and results

The findings of cytotoxicity assays revealed a dose-dependent decrease in cell viability, with the fasting + siRNA + MB-3 combination showing the most potent anticancer effect. LDH assays confirmed enhanced membrane damage in this group. Migration assays demonstrated reduced motility, while DAPI and acridine orange/ethidium bromide staining indicated significant apoptotic features present in fasting + siRNA + MB-3-treated ovarian cancer cells. Colony formation was markedly inhibited under the combination treatment, confirming suppression of clonogenic potential. Flow cytometry analysis revealed > 80% late apoptotic/necrotic cells in the fasting + siRNA + MB-3 group. Gene expression analysis further showed downregulation of Warburg-related genes (PDK1/2/3/4, LDH, GLUT1/3/4) and upregulation of PDH and pro-apoptotic markers (Caspase, Bax), alongside reduced PGC-1α acetylation.

Conclusion

These findings indicate that fasting enhances the therapeutic effect of RBM5-AS1 knockdown and GCN5 inhibition, leading to a significant disruption of glycolytic metabolism and promoting apoptosis. This combinatorial approach highlights a promising metabolic and epigenetic strategy for ovarian cancer treatment.