Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma.

Abstract

Conventional high-grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis-free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti-apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G2 cell-cycle arrest; Chk1 protein levels were attenuated and ATR-Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven-depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven-controlled ATR-Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix-embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR-Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy.

• Authors: Zuzanna Baranski, Tijmen H Booij, Anne-Marie Cleton-Jansen, Leo S Price, Bob van de Water, Judith V M G Bovée, Pancras C W Hogendoorn, Erik H J Danen
• Journal: The Journal of pathology (J Pathol) Vol. 236 Issue 3 Pg. 348-59 (Jul 2015) ISSN: 1096-9896 [Electronic] England
• PMID: 25757065 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
• AVEN protein, human
• Adaptor Proteins, Signal Transducing
• Antibiotics, Antineoplastic
• Apoptosis Regulatory Proteins
• Membrane Proteins
• Thiophenes
• Doxorubicin
• Urea
• Protein Kinases
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• Checkpoint Kinase 1

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Ataxia Telangiectasia Mutated Proteins (genetics, metabolism)
• Bone Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Checkpoint Kinase 1
• DNA Damage
• Doxorubicin (pharmacology)
• G2 Phase Cell Cycle Checkpoints
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Proteins (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• Osteosarcoma (drug therapy, genetics, pathology)
• Phosphorylation
• Protein Kinases (genetics, metabolism)
• RNA Interference
• Signal Transduction
• Thiophenes (pharmacology)
• Urea (analogs & derivatives, pharmacology)