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<p>Neuroblastoma (NB) is the most typical malignant extracranial solid tumor in the pediatric population. The advent of drug resistance is an essential deterrent in treating high-risk NB patients despite a multi-modality remedy. Inflammation-induced early neuronal degeneration plays a leading part in the pathogenesis of NB via necroptosis; however, the mechanisms remained cryptic. Our current investigation determines the anti-inflammatory and neuroprotective effect of necroptosis inhibitor necrostatin-1 (Nec-1) in receptor-interacting proteins 1 and 3 (RIP1/3)-induced cell death pathway and inflammation caused by hypoxia mimetic agent cobalt chloride (CoCl<sub>2</sub>). Our biomolecular study illustrates that necroptosis marker RIP1/3 and mixed-lineage kinase domain-like pseudokinase (MLKL) protein expression was increased after treatment with CoCl<sub>2</sub> in SH-SY5Y cells. Subsequently, elevated expression levels of RIP1/3 and MLKL further contributed to the inflammation by activating transcription factors extracellular signal-regulated protein kinase (ERK1/2), nuclear factor kappa-B (NF-κB), and releasing high levels of proinflammatory cytokines, such as vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1/CCL2). At the same time, Nec-1 treatment reduced the RIP1/3 and MLKL, phospho-ERK1/2, p65 subunit of NF-κB expression, and VEGF and MCP-1 levels. Molecular docking analysis of RIP1/3—necrostatin-1 complex highlights a significant interaction between necrostatin-1 and specific amino acid residues within the protein. Based on our promising results, necrostatin-1 could be exploited as a therapeutic agent during neuroblastoma’s pathogenesis and its molecular therapy.</p>

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Suppression of necroptosis-driven cell death and inflammation in hypoxic neuroblastoma (SH-SY5Y) cells by necrostatin-1

  • 期刊论文

  • 发表日期：

    2025年3月17日

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  • Amal Majed H. Alenad,
  • Mohd Shahnawaz Khan,
  • Nojood Al-twaijry,
  • Majed S. Alokail,
  • Leon Bernet Shano,
  • Subramani Karthikeyan,
  • Huma Naz,
  • Bigyan Ranjan Jali

摘要

Neuroblastoma (NB) is the most typical malignant extracranial solid tumor in the pediatric population. The advent of drug resistance is an essential deterrent in treating high-risk NB patients despite a multi-modality remedy. Inflammation-induced early neuronal degeneration plays a leading part in the pathogenesis of NB via necroptosis; however, the mechanisms remained cryptic. Our current investigation determines the anti-inflammatory and neuroprotective effect of necroptosis inhibitor necrostatin-1 (Nec-1) in receptor-interacting proteins 1 and 3 (RIP1/3)-induced cell death pathway and inflammation caused by hypoxia mimetic agent cobalt chloride (CoCl2). Our biomolecular study illustrates that necroptosis marker RIP1/3 and mixed-lineage kinase domain-like pseudokinase (MLKL) protein expression was increased after treatment with CoCl2 in SH-SY5Y cells. Subsequently, elevated expression levels of RIP1/3 and MLKL further contributed to the inflammation by activating transcription factors extracellular signal-regulated protein kinase (ERK1/2), nuclear factor kappa-B (NF-κB), and releasing high levels of proinflammatory cytokines, such as vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1/CCL2). At the same time, Nec-1 treatment reduced the RIP1/3 and MLKL, phospho-ERK1/2, p65 subunit of NF-κB expression, and VEGF and MCP-1 levels. Molecular docking analysis of RIP1/3—necrostatin-1 complex highlights a significant interaction between necrostatin-1 and specific amino acid residues within the protein. Based on our promising results, necrostatin-1 could be exploited as a therapeutic agent during neuroblastoma’s pathogenesis and its molecular therapy.