Low-Dose MLN4924 Enhances SH-SY5Y Cell Viability and Migration by Targeting SOCS3 Signaling
Zelin Lai1, Simin Yang2, Xia Liu2
1Neurosurgery Center, National Key Clinical Specialty, Engineering Research Center of Diagnostic and Therapeutic Technology and Devices for Cerebrovascular Diseases in Ministry of Education, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China. laizelin@smu.edu.cn.
Abstract:
MLN4924 (pevonedistat), a selective inhibitor of the NEDD8-activating enzyme, has inhibitory effects on various tumors by blockade of the neddylation pathway. Conversely, recent studies show that low-dose MLN4924 exerts pro-survival effects in both cancer cells and neurons, however, its actions on SH-SY5Y cells remain unclear. In this study, the effects of low-dose MLN4924 in SH-SY5Y cells were assessed by CCK-8 and Transwell assay, respectively. SH-SY5Y cells were transfected with enhanced green fluorescent protein plasmid to further observe neurite changes. The expression of SOCS3, p-JAK2 and p-STAT3 were analyzed by Western blot, and the potential interaction between MLN4924 and SOCS3 was explored via in silico molecular docking. Our results showed that 0.1 μM MLN4924 significantly enhanced SH-SY5Y cell viability and migration while concurrently reducing neurite outgrowth. The expression level of SOCS3 was significantly increased in the MLN4924 treatment group compared with the control group, but the phosphorylation levels of JAK2 and STAT3 showed no changes. Molecular docking further predicted that Glu63 of SOCS3 serves as a key residue for MLN4924 binding. Together, low-dose MLN4924 enhances SH-SY5Y cell viability and migration by targeting SOCS3 signaling, independent of JAK2/STAT3 signaling.
Insights
Low-dose MLN4924 (pevonedistat) boosts SH-SY5Y cell survival and migration by increasing SOCS3 expression, independent of JAK2/STAT3 signaling. This finding clarifies its complex role in neuronal cells.
Area of Science:
- Neuroscience
- Molecular Biology
- Cancer Research
Background:
- MLN4924 (pevonedistat) inhibits the NEDD8-activating enzyme, impacting tumor growth via the neddylation pathway.
- Low-dose MLN4924 shows pro-survival effects in cancer cells and neurons, but its impact on SH-SY5Y cells is not well understood.
Purpose of the Study:
- To investigate the effects of low-dose MLN4924 on SH-SY5Y cell viability, migration, and neurite outgrowth.
- To elucidate the underlying molecular mechanisms, including the role of SOCS3, JAK2, and STAT3 signaling.
Main Methods:
- Cell viability and migration assessed using CCK-8 and Transwell assays.
- Neurite outgrowth observed in cells transfected with enhanced green fluorescent protein plasmid.
- Protein expression and phosphorylation analyzed by Western blot; molecular docking used to explore drug-target interactions.
Main Results:
- 0.1 μM MLN4924 significantly increased SH-SY5Y cell viability and migration.
- MLN4924 treatment led to reduced neurite outgrowth.
- SOCS3 expression was significantly upregulated, while JAK2 and STAT3 phosphorylation remained unchanged.
- Molecular docking identified Glu63 of SOCS3 as a key binding residue for MLN4924.
Conclusions:
- Low-dose MLN4924 enhances SH-SY5Y cell viability and migration through SOCS3 targeting.
- The observed effects are independent of the JAK2/STAT3 signaling pathway.
- MLN4924 exhibits a complex, dose-dependent effect on neuronal cells, influencing survival and morphology.
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