Targeting JNK-interacting-protein-1 (JIP1) sensitises osteosarcoma to doxorubicin

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Osteosarcoma (OS) is a primary bone cancer in children and adolescents with poor survival rates, particularly for metastatic or chemoresistant cases.
• Chemoresistance is a major cause of treatment failure in OS, necessitating novel therapeutic strategies.
• Targeting essential survival pathways concurrently with chemotherapy can enhance treatment efficacy.

Purpose of the Study:

• To identify critical survival kinases in osteosarcoma cells resistant to doxorubicin.
• To evaluate JNK-interacting-protein-1 (JIP1) as a potential target for chemosensitization in OS.
• To assess the efficacy of JIP1 inhibition in combination with doxorubicin in OS models.

Main Methods:

• Loss-of-function siRNA screen of the human kinome in SaOS-2 cells to identify survival kinases.
• Treatment of OS cell lines and primary osteoblasts with doxorubicin and a small molecule JIP1-inhibitor (BI-78D3).
• Western blot analysis to assess JNK-signalling and immunohistochemistry on tissue microarrays to evaluate JIP1 expression in OS tumors.

Main Results:

• Gene silencing of JIP1 significantly sensitized SaOS-2 cells to doxorubicin.
• The JIP1-inhibitor BI-78D3 blocked JNK-signalling and sensitized three out of four OS cell lines to doxorubicin, without affecting healthy osteoblasts.
• Combination treatment with BI-78D3 and doxorubicin increased apoptosis induction.
• JIP1 was expressed in two-thirds of primary OS tissue samples, with a trend towards inferior overall survival in JIP1-positive tumors.

Conclusions:

• JIP1 is a critical survival kinase in osteosarcoma.
• Pharmacological inhibition of JIP1, in combination with doxorubicin, represents a promising therapeutic strategy to overcome chemoresistance in OS.
• JIP1 is a clinically relevant target for enhancing doxorubicin efficacy in osteosarcoma.