Targeting JNK-interacting-protein-1 (JIP1) sensitises osteosarcoma to doxorubicin
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Jantine Posthuma De Boer1, Pim W. van Egmond2, Marco N. Helder1,3, Renée X. de Menezes4, Anne-Marie Cleton-Jansen5, Jeroen A.M. Beliën6, Henk M. W. Verheul7, Barend J. van Royen1,3, Gert-Jan J.L. Kaspers8, Victor W. van Beusechem7
1 Department of Orthopaedic Surgery, VU University Medical Center, Amsterdam, the Netherlands
2 Department of Surgery, Medisch Centrum Alkmaar (MCA), the Netherlands
3 Research Institute MOVE/Skeletal Tissue Engineering Group Amsterdam (STEGA), the Netherlands
4 Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
5 Department of Pathology, Leiden University Medical Center (LUMC), the Netherlands
6 Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands
7 RNA Interference Functional Oncogenomics Laboratory (RIFOL), Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands
8 Paediatric Oncology/Haematology, VU University Medical Center, Amsterdam, the Netherlands
V.W. van Beusechem, email:
Keywords: osteosarcoma, functional genomics, siRNA, chemosensitisation, JIP1
Received: August 09, 2012, Accepted: September 25, 2012, Published: September 28, 2012
Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. Despite aggressive therapy, survival outcomes remain unsatisfactory, especially for patients with metastatic disease or patients with a poor chemotherapy response. Chemoresistance contributes to treatment failure. To increase the efficacy of conventional chemotherapy, essential survival pathways should be targeted concomitantly. Here, we performed a loss-of-function siRNA screen of the human kinome in SaOS-2 cells to identify critical survival kinases after doxorubicin treatment. Gene silencing of JNK-interacting-protein-1 (JIP1) elicited the most potent sensitisation to doxorubicin. This candidate was further explored as potential target for chemosensitisation in OS. A panel of OS cell lines and human primary osteoblasts was examined for sensitisation to doxorubicin using small molecule JIP1-inhibitor BI-78D3. JIP1 expression and JIP1-inhibitor effects on JNK-signalling were investigated by Western blot analysis. JIP1 expression in human OS tumours was assessed by immunohistochemistry on tissue micro arrays. BI-78D3 blocked JNK-signalling and sensitised three out of four tested OS cell lines, but not healthy osteoblasts, to treatment with doxorubicin. Combination treatment increased the induction of apoptosis. JIP1 was found to be expressed in two-thirds of human primary OS tissue samples. Patients with JIP1 positive tumours showed a trend to inferior overall survival. Collectively, JIP1 appears a clinically relevant novel target in OS to enhance the efficacy of doxorubicin treatment by means of RNA interference or pharmacological inhibition.
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