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Nimbolide Inhibits SOD2 to Control Pancreatic Ductal Adenocarcinoma Growth and Metastasis
Tugba Mehmetoglu-Gurbuz1, Rajkumar Lakshmanaswamy1,2,3, Karla Perez1
1Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA.
Abstract:
Reactive oxygen species are frequently associated with various cancers including pancreatic ductal adenocarcinomas (PDACs). Superoxide dismutase 2 (SOD2) is an enzyme that plays an important role in reactive oxygen species (ROS) signaling. Investigating the molecular function and biological functions of SOD2 can help us develop new therapeutic options and uncover new biomarkers for PDAC diagnosis and prognosis. Here, we show that nimbolide (NB), a triterpene limonoid, effectively blocks the growth and metastasis of PDACs by suppressing the expression and activity of SOD2. To identify the role of SOD2 in NB-induced anticancer activity, we used RNA interference to silence and plasmid transfection to overexpress it. Silencing SOD2 significantly reduced the growth and metastatic characteristics like epithelial-to-mesenchymal transition, invasion, migration, and colony-forming capabilities of PDACs, and NB treatment further reduced these characteristics. Conversely, the overexpression of SOD2 enhanced these metastatic characteristics. ROS signaling has a strong feedback mechanism with the PI3K/Akt signaling pathway, which could be mediated through SOD2. Finally, NB treatment to SOD2-overexpressing PDAC xenografts resulted in significant inhibition of tumor growth and metastasis. Overall, this work suggests that NB, a natural and safe phytochemical that silences SOD2 to induce high levels of ROS generation, results in increased apoptosis and reduced growth and progression of PDACs. The role of SOD2 in regulating NB-induced ROS generation presents itself as a therapeutic option for PDACs.
Insights
Nimbolide (NB) inhibits pancreatic cancer growth by suppressing Superoxide Dismutase 2 (SOD2). This natural compound reduces metastasis and enhances ROS generation, offering a potential therapeutic strategy for pancreatic ductal adenocarcinomas (PDACs).
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Reactive oxygen species (ROS) are implicated in pancreatic ductal adenocarcinomas (PDACs).
- Superoxide dismutase 2 (SOD2) is a key enzyme in ROS signaling, potentially influencing PDAC progression.
- Understanding SOD2's role is crucial for developing novel PDAC diagnostics and therapeutics.
Purpose of the Study:
- To investigate the role of SOD2 in nimbolide (NB)-induced anticancer activity in PDACs.
- To determine if NB suppresses PDAC growth and metastasis by targeting SOD2.
- To explore the therapeutic potential of NB as a SOD2 inhibitor for PDAC treatment.
Main Methods:
- Utilized RNA interference to silence SOD2 and plasmid transfection to overexpress SOD2 in PDAC cells.
- Assessed the effects of SOD2 manipulation and NB treatment on PDAC cell growth, epithelial-to-mesenchymal transition (EMT), invasion, migration, and colony formation.
- Evaluated NB's efficacy in PDAC xenograft models with varying SOD2 expression levels.
Main Results:
- Silencing SOD2 significantly inhibited PDAC growth and metastatic characteristics, an effect further enhanced by NB treatment.
- Overexpression of SOD2 promoted PDAC metastasis, while NB treatment counteracted this effect.
- NB treatment of SOD2-overexpressing PDAC xenografts led to significant inhibition of tumor growth and metastasis.
Conclusions:
- Nimbolide (NB) effectively blocks PDAC growth and metastasis by suppressing SOD2 expression and activity.
- NB induces ROS generation, leading to increased apoptosis and reduced PDAC progression.
- Targeting SOD2 with NB presents a promising therapeutic strategy for pancreatic ductal adenocarcinomas.
