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Novel PP2A-Activating Compounds in Neuroblastoma
Nazia Nazam1, Laura V Bownes1, Janet R Julson1
1Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Background:
Neuroblastoma (NB) remains one of the deadliest pediatric solid tumors. Recent advancements aimed at improving outcomes have been insufficient, and patients with high-risk NB continue to have a poor prognosis. Protein phosphatase 2A (PP2A) is a tumor suppressor protein downregulated in many cancers, including NB. PP2A activation has been shown to affect the malignant phenotype in other solid tumors. The present studies aim to investigate the effects of two novel PP2A activators as a NB therapeutic.
Methods:
Four established NB cell lines and a patient-derived xenoline were utilized to study the effect on cell viability, proliferation, motility, and in vivo tumor growth using two novel tricyclic sulfonamide PP2A activators, ATUX-3364 and ATUX-8385.
Results:
ATUX-3364 and ATUX-8385 increased PP2A activity. These PP2A activators led to decreased viability, proliferation, and motility of NB cells. Treatment of animals bearing NB tumors with ATUX-3364 or ATUX-8385 resulted in decreased tumor growth in MYCN-amplified SK-N-BE(2) tumors. At the molecular level, PP2A-based reactivation led to dephosphorylation of MYCN-S62 and decreased MYCN protein expression.
Conclusions:
PP2A activators decreased NB cell viability, proliferation, and motility. In vivo experiments show that PP2A activators have more significant effects on tumorigenesis in MYCN-amplified tumors. Finally, phosphorylation of MYCN protein was decreased following treatment with novel sulfonamide PP2A activators. These data and mechanistic insights may be useful for developing new PP2A-based therapies that target MYCN for the treatment of NB.
Insights
Novel protein phosphatase 2A (PP2A) activators show promise in treating neuroblastoma (NB). These compounds reduced NB cell growth and tumor development, particularly in MYCN-amplified tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pediatric Medicine
Background:
- Neuroblastoma (NB) is a deadly pediatric cancer with poor prognosis for high-risk patients.
- Protein phosphatase 2A (PP2A), a tumor suppressor, is downregulated in NB.
- Targeting PP2A is a potential therapeutic strategy for NB.
Purpose of the Study:
- To investigate the therapeutic potential of two novel PP2A activators, ATUX-3364 and ATUX-8385, for neuroblastoma treatment.
- To explore the effects of PP2A activation on NB cell behavior and tumor growth.
Main Methods:
- Utilized four NB cell lines and a patient-derived xenograft model.
- Assessed effects on cell viability, proliferation, and motility.
- Evaluated in vivo tumor growth and molecular mechanisms.
Main Results:
- ATUX-3364 and ATUX-8385 enhanced PP2A activity, decreasing NB cell viability, proliferation, and motility.
- In vivo studies showed reduced tumor growth in MYCN-amplified NB xenografts.
- Treatment led to decreased MYCN protein expression via dephosphorylation of MYCN-S62.
Conclusions:
- PP2A activators demonstrate efficacy in reducing NB cell growth and motility.
- Significant anti-tumor effects were observed in MYCN-amplified NB models.
- PP2A activation targets MYCN, offering a potential therapeutic avenue for NB treatment.
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