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<p>Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid proliferation, therapy resistance, and extensive invasion, largely driven by epithelial-mesenchymal transition (EMT). Longikaurin A (LK-A), a natural kaurane diterpenoid, has demonstrated promising anti-cancer properties, yet its role in EMT regulation within GBM remains unclear. This study aimed to systematically investigate the inhibitory effects of LK-A on TGF-β1-induced EMT and to elucidate the underlying molecular mechanisms contributing to its anti-invasive potential in GBM. LK-A inhibited EMT-associated phenotypic changes, including reduced expression of mesenchymal markers (N-cadherin, Vimentin) and increased expression of epithelial markers (ZO-1, Occludin), alongside suppression of key EMT transcription factors (Snail, Twist1). Functionally, LK-A impaired EMT-induced cell migration, invasion, and glioma stem cell-like traits, evidenced by decreased gliosphere formation and downregulation of stemness markers such as Sox2 and Oct4. Mechanistic analyses revealed that LK-A triggered reactive oxygen species (ROS) accumulation, leading to the activation of the JNK/p38 MAPK signaling cascade. Pharmacological inhibition of JNK or ROS scavenging reversed the anti-EMT effects of LK-A, confirming that EMT suppression is mediated through ROS-dependent JNK activation. In vivo, LK-A significantly suppressed tumor growth, EMT marker expression, and stemness in xenograft models. Collectively, these findings identify LK-A as a potent regulator of EMT and glioma stemness via ROS/JNK signaling. This work provides new mechanistic insight into the anti-tumor effects of LK-A and highlights its potential as a promising therapeutic strategy for combating GBM aggressiveness.</p>

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Longikaurin A - Mediated Regulation of ROS/JNK Signaling Counteracts Epithelial-Mesenchymal Transition in Glioblastoma

  • 期刊论文

  • 发表日期：

    2025年11月20日

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  • Hua Chen,
  • Yangming Mao,
  • Xiang Chen,
  • Xia Zhao

摘要

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid proliferation, therapy resistance, and extensive invasion, largely driven by epithelial-mesenchymal transition (EMT). Longikaurin A (LK-A), a natural kaurane diterpenoid, has demonstrated promising anti-cancer properties, yet its role in EMT regulation within GBM remains unclear. This study aimed to systematically investigate the inhibitory effects of LK-A on TGF-β1-induced EMT and to elucidate the underlying molecular mechanisms contributing to its anti-invasive potential in GBM. LK-A inhibited EMT-associated phenotypic changes, including reduced expression of mesenchymal markers (N-cadherin, Vimentin) and increased expression of epithelial markers (ZO-1, Occludin), alongside suppression of key EMT transcription factors (Snail, Twist1). Functionally, LK-A impaired EMT-induced cell migration, invasion, and glioma stem cell-like traits, evidenced by decreased gliosphere formation and downregulation of stemness markers such as Sox2 and Oct4. Mechanistic analyses revealed that LK-A triggered reactive oxygen species (ROS) accumulation, leading to the activation of the JNK/p38 MAPK signaling cascade. Pharmacological inhibition of JNK or ROS scavenging reversed the anti-EMT effects of LK-A, confirming that EMT suppression is mediated through ROS-dependent JNK activation. In vivo, LK-A significantly suppressed tumor growth, EMT marker expression, and stemness in xenograft models. Collectively, these findings identify LK-A as a potent regulator of EMT and glioma stemness via ROS/JNK signaling. This work provides new mechanistic insight into the anti-tumor effects of LK-A and highlights its potential as a promising therapeutic strategy for combating GBM aggressiveness.