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.
Highlights
Osteosarcoma is the most common bone malignancy that affects primarily children and young adults
To evaluate cytoplasmic p27 expression in osteosarcoma patient tumors, we performed immunofluorescence staining of tumor specimens on a previously described tissue microarray (TMA)[16] using anti-p27 antibody
Using a human osteosarcoma tissue microarray, we demonstrated that the expression of p27 was elevated in metastatic tumors, in comparison to biopsy and definitive surgery specimens and was highly expressed in the cytoplasm
Summary
Osteosarcoma is the most common bone malignancy that affects primarily children and young adults. Over the past decade many studies have characterized roles of p27 in signaling pathways that affect cell proliferation, survival, differentiation and migration[4]. These are often described as non-canonical p27 functions since they are independent of CDK/cyclin regulation. Cytoplasmic p27 participates in cellular processes including cytoskeleton dynamics, cell migration and metastasis[5,6] This is consistent with reports that cytoplasmic p27 plays a role in processes that are associated with tumor development and disease progression. This work provides insight into mechanisms involving p27 that may predict sensitivity of osteosarcoma tumors to drugs and guide treatment with targeted therapies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
