Abstract
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.
Highlights
Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents
Concurrent treatment with BI78D3 diminished p-JNK in both cell lines to undetectable levels, indicating successful inhibition of the JIP1-JNK interaction and JNK phosphorylation (Fig 4B). These results suggest that inhibition of JIP1 increases the cytotoxicity of doxorubicin in cells that respond to doxorubicin treatment by increased JNK-signalling via assembly of the JIP1-JNK signalling complex
Improving its efficacy could lead to enhanced tumour control or chemotherapy dose reduction in patients
Summary
Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. The gold standard for therapy consists of a combination of multi-agent neoadjuvant chemotherapy, followed by radical surgery and adjuvant chemotherapy. With this aggressive regimen, 5-year survival rates of approximately 65% are obtained in patients with localised disease. Oncotarget 2012; 3: 1169-1181 disease, 5-year survival rates are reduced to only 20% [1-4]. Chemoresistance, both intrinsic and acquired, is a key issue in the failure of current treatment to cure patients with OS [5,6]. The current chemotherapy regimens are demanding for the patients and serious adverse effects, such as severe mucositis, bone-marrow depression and cardiotoxicity are often encountered. The current chemotherapy regimens are demanding for the patients and serious adverse effects, such as severe mucositis, bone-marrow depression and cardiotoxicity are often encountered. [7-10] In order to improve treatment efficacy whilst limiting adverse effects, new treatment strategies for OS are warranted
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