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08:07
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
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p27/Kip1 functions as a tumor suppressor and oncoprotein in osteosarcoma
Arthur W Currier1,2, E A Kolb1, Richard G Gorlick3
1Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
Scientific Reports
|April 18, 2019
Summary
Cytoplasmic p27/kip1 (p27) promotes osteosarcoma metastasis. Targeting p27 stabilization and nuclear export enhances chemotherapy efficacy, offering new treatment strategies for this bone cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The p27/kip1 (p27) protein acts as a tumor suppressor by inhibiting cell cycle progression.
- Emerging evidence suggests p27 may also promote cancer cell invasion and migration, functioning as an oncoprotein.
- Understanding p27's dual role is crucial for developing effective osteosarcoma treatments.
Purpose of the Study:
- To investigate the role of p27 expression and localization in osteosarcoma metastasis.
- To explore the interaction between p27 and stathmin-1 (STMN1) in regulating cell invasion.
- To evaluate the impact of drug sequencing and p27 modulation on osteosarcoma cell apoptosis and growth.
Main Methods:
- Analysis of human osteosarcoma tissue microarrays to correlate p27 expression with metastatic markers.
- Investigation of p27 phosphorylation at T198 and its interaction with STMN1.
- Assessment of gemcitabine and AZD1775 efficacy, including drug sequencing and p27 stabilization.
- Evaluation of the effect of Exportin-1 (XPO1) inhibition on p27 localization and cell growth.
Main Results:
- High cytoplasmic p27 expression correlated with increased metastasis and expression of markers like vimentin and STMN1.
- T198 phosphorylation of p27 regulates its interaction with STMN1, impacting microtubule stabilization and cell invasion.
- Gemcitabine and AZD1775 synergy depended on p27 stabilization; gemcitabine-induced apoptosis involved caspase-mediated p27 cleavage.
- Inhibition of nuclear export of p27 by blocking XPO1 promoted growth arrest.
Conclusions:
- Cytoplasmic p27 plays a significant role in osteosarcoma cell invasion and migration.
- Drug sequencing strategies that stabilize p27 can enhance anti-cancer effects.
- Modulating p27's expression and subcellular localization presents a promising therapeutic avenue for osteosarcoma.
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