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Targeting gastrin-releasing peptide as a new approach to treat aggressive refractory neuroblastomas
Pritha Paul1, Lauren A Gillory, JungHee Kang
1Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Background:
The overall survival for neuroblastoma remains dismal, in part due to the emergence of resistance to chemotherapeutic drugs. We have demonstrated that gastrin-releasing peptide (GRP), a gut peptide secreted by neuroblastoma, acts as an autocrine growth factor. We hypothesized that knockdown of GRP will induce apoptosis in neuroblastoma cells and potentiate the cytotoxic effects of chemotherapeutic agents.
Methods:
The human neuroblastoma cell lines (JF, SK-N-SH) were transfected with small interfering (si) RNA targeted at GRP. Apoptosis was assessed by DNA fragmentation assay. Immunoblotting was used to confirm molecular markers of apoptosis, and flow cytometry was performed to determine cell cycle arrest after GRP knockdown.
Results:
siGRP resulted in an increase in apoptosis in the absence of chemotherapeutic interventions. A combination of GRP silencing and chemotherapeutic drugs resulted in enhanced apoptosis when compared to either of the treatments alone. GRP silencing led to increased expression of proapoptotic proteins, p53 and p21.
Conclusion:
Silencing of GRP induces apoptosis in neuroblastoma cells; it acts synergistically with chemotherapeutic effects of etoposide and vincristine. GRP knockdown-mediated apoptosis appears to be associated with upregulation of p53 in neuroblastoma cells. Targeting GRP may be postulated as a potential novel agent for combinational treatment to treat aggressive neuroblastomas.
Insights
Targeting gastrin-releasing peptide (GRP) induces programmed cell death (apoptosis) in neuroblastoma cells. Silencing GRP enhances chemotherapy effectiveness, offering a potential new treatment strategy for aggressive neuroblastomas.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Neuroblastoma exhibits poor survival rates, often linked to chemotherapy resistance.
- Gastrin-releasing peptide (GRP) functions as an autocrine growth factor in neuroblastoma.
- GRP secretion by neuroblastoma cells suggests a potential therapeutic target.
Purpose of the Study:
- To investigate the role of GRP knockdown in inducing apoptosis in neuroblastoma cells.
- To evaluate if GRP silencing potentiates the cytotoxic effects of chemotherapy.
- To explore GRP as a novel therapeutic target for neuroblastoma.
Main Methods:
- Utilized small interfering RNA (siRNA) to silence GRP in human neuroblastoma cell lines (JF, SK-N-SH).
- Assessed apoptosis via DNA fragmentation assays and confirmed molecular markers through immunoblotting.
- Determined cell cycle arrest using flow cytometry following GRP knockdown.
Main Results:
- GRP silencing significantly increased apoptosis, even without chemotherapy.
- Combined GRP silencing and chemotherapy demonstrated synergistic enhancement of apoptosis.
- GRP knockdown upregulated pro-apoptotic proteins p53 and p21.
Conclusions:
- GRP silencing effectively induces apoptosis in neuroblastoma cells.
- GRP knockdown synergizes with etoposide and vincristine chemotherapy.
- Upregulation of p53 is associated with GRP knockdown-induced apoptosis, suggesting a novel therapeutic approach for aggressive neuroblastomas.
