RNA-seq Analysis Reveals Upregulation in ER -Stress-Related Genes Upon LCL-161 Treatment in SH-SY5Y Human Neuroblastoma Cells

Background: SMAC mimetics (SM) are compounds that are developed on secondary mitochondria-derived activators of caspase (SMAC) protein structure and sensitize cancer cells to cell death, either alone or in the presence of death ligands or chemotherapies. However, their efficacy as a single agent or in combination with chemotherapy is highly variable and limited. In this study, we aimed to identify the transcriptomic changes in the SH-SY5Y cells upon induction with SM using RNA sequencing (RNA-seq). Hence, the total gene expression changes to understand the mechanism of action of SM in SH-SY5Y cells were examined. Methods and Results: RNA sequencing was performed on LCL-161 (a monovalent type of SM) treated SH-SY5Y neuroblastoma cells. The significantly upregulated and downregulated genes were studied using Real-time PCR (Q-PCR). In addition to the intrinsic apoptotic pathways, we identified significant upregulation in the endoplasmic reticulum (ER)-stress-related genes upon LCL-161 induction in RNA-seq results. Conclusion: These results demonstrated that ER stress response pathways might play a role in the SM response in addition to previously known apoptotic or necroptotic pathways. Further studies are required to establish whether ER stress pathways act as pro-survival or pro-apoptotic pathways in this response.