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Updated: Jan 26, 2026
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
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.
Abstract:
The p27/kip1 (p27) tumor suppressor inhibits cyclin/cyclin-dependent kinase (CDK) complexes and halts cell cycle progression. p27 further regulates invasion and migration in cancer cells, suggesting p27 also functions as an oncoprotein. Using a human osteosarcoma tissue microarray we identified high expression of cytoplasmic p27 in metastatic tumors. We demonstrated a positive correlation between mRNA and protein expression of p27 and expression of key metastatic markers, vimentin, snail-2, β-catenin and stathmin-1 (STMN1) in patient tumors. Our results show that T198 phosphorylation of p27 controls the interaction between p27 and STMN1 that regulates microtubule stabilization and the invasion and migration of osteosarcoma cells. We found that anti-tumoral activity of gemcitabine and the Wee1 kinase inhibitor AZD1775 in osteosarcoma cells, was dependent on drug sequencing that relied on p27 stabilization. Gemcitabine activated caspase-3 and synergized with AZD1775 through caspase-mediated cleavage of p27, that dissociated from STMN1 and effectively induced apoptosis. Further, blockage of nuclear export of p27 by inhibition of Exportin-1 (XPO1) promoted growth arrest, demonstrating that the biological effects of agents relied on the expression and localization of p27. Together, these data provide a rationale for combining chemotherapy with agents that promote p27 tumor suppressor activity for the treatment of osteosarcoma.
Insights
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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