Rsk2 inhibition induces an aneuploid post-mitotic arrest of cell cycle progression in osteosarcoma cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Osteosarcoma is the most common primary bone cancer with high mortality.
• The c-Fos transgenic mouse model develops spontaneous osteosarcoma.
• Ribosomal S6 kinase 2 (Rsk2) is crucial for c-Fos-induced osteosarcoma in mice.

Purpose of the Study:

• To investigate the role of Rsk2 in osteosarcoma formation and proliferation.
• To explore Rsk2 and Aurora kinase B as potential therapeutic targets for osteosarcoma.

Main Methods:

• Osteosarcoma cell lines were derived from FosTg and FosTg;Rsk2^-/y mice.
• Pharmacological inhibitors of Rsk (BI-D1870) and Aurora kinase B (Hesperadin) were used.
• Cell proliferation, cytokinesis, and nuclear status were analyzed in mouse and human osteosarcoma cell lines.

Main Results:

• Rsk2 deficiency reduced the growth advantage of FosTg osteosarcoma cells.
• Impaired Rsk2 function led to aberrant nuclear numbers due to failed cytokinesis and mitotic catastrophe.
• BI-D1870 mimicked genetic Rsk2 inactivation, reducing osteosarcoma cell proliferation and Aurora kinase B expression.
• Hesperadin also impaired cytokinesis, causing polynuclear cell accumulation in both mouse and human osteosarcoma cells.

Conclusions:

• Rsk2 plays a significant role in promoting osteosarcoma cell proliferation.
• Rsk2 inhibition leads to mitotic catastrophe via impaired cytokinesis.
• Aurora kinase B is involved in Rsk2-mediated osteosarcoma progression.
• Targeting Rsk2 and/or Aurora kinase B presents a promising therapeutic strategy for osteosarcoma.