Transcriptomic changes associated with the antiproliferative effects of indole-3-acetic acid in SH-SY5Y neuroblastoma cells: an exploratory study.
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BACKGROUND: Neuroblastoma is a highly heterogeneous paediatric malignancy characterized by dysregulated oncogenic pathways that promote tumor progression and therapeutic resistance. We previously demonstrated that indole-3-acetic acid (IAA), a naturally occurring indole derivative, exerts antiproliferative effects in SH-SY5Y and SK-N-BE(2) neuroblastoma cells by reducing cell viability, downregulating ALK expression, inducing G1 cell-cycle arrest, promoting autophagy, and suppressing clonogenicity and migration. METHODS AND RESULTS: To explore molecular correlates of these effects, we analysed the transcriptomic response of SH-SY5Y neuroblastoma cells to IAA treatment by RNA sequencing (RNA-seq), followed by differential expression analysis and Gene Ontology (GO)-based Gene Set Enrichment Analysis (GSEA). RNA-seq identified concentration-dependent transcriptional responses to IAA treatment, with the most pronounced changes observed at 1 mM concentration. GSEA identified neuronal migration as a significantly enriched biological process, suggesting modulation of developmental programs associated with the neural origin of neuroblastoma cells. Among the differentially expressed genes, ERBB4 and GPM6A showed reduced expression and MAMDC2 displayed increased expression following IAA treatment, changes that were confirmed by qRT-PCR in independent biological samples. ADGRG1, FER1L4 and DCDC2 were not confirmed by qRT-PCR and are reported as RNA-seq observations only. ALK transcript levels remained unaffected, raising the hypothesis that reduced ALK protein levels may involve post-transcriptional regulation, although this was not directly tested in the present study. ERBB4, MAMDC2 and GPM6A are involved in cancer-related signalling and cellular behaviour, and their modulation by IAA has not been previously described. CONCLUSION: These findings show that IAA induces extensive transcriptional changes in SH-SY5Y cells and identify candidate molecular correlates of its antiproliferative activity. This exploratory, hypothesis-generating study is limited to transcript-level data from a single cell line. It provides a dataset and candidate genes for future validation and mechanistic studies in neuroblastoma models with different molecular backgrounds.