Nuclear localized p70S6K maintain cancer stem-like properties by modulating RPA3 activity in osteosarcoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• Cancer stem-like cells (CSCs) drive therapeutic failure and chemoresistance in osteosarcoma.
• Nuclear p70 ribosomal protein S6 kinase (p70S6K) is linked to poor prognosis, but its role in cancer development is understudied.
• Replication protein A3 (RPA3) is highly expressed in osteosarcoma CSCs.

Purpose of the Study:

• To investigate the novel nuclear function of p70S6K in osteosarcoma development.
• To elucidate the mechanism by which nuclear p70S6K promotes CSC properties.
• To evaluate the therapeutic potential of targeting the nuclear p70S6K-RPA3 axis.

Main Methods:

• Single-cell transcriptomics to identify RPA3 expression in osteosarcoma CSCs.
• Biochemical assays to study the interaction between p70S6K and RPA3.
• Pharmacological inhibition of the p70S6K-RPA axis in osteosarcoma models.

Main Results:

• Nuclear p70S6K physically interacts with RPA3, modulating its single-strand DNA-binding activity.
• This interaction drives the acquisition and maintenance of CSC properties in osteosarcoma.
• Pharmacological inhibition of the p70S6K-RPA axis significantly suppresses osteosarcoma tumor growth.

Conclusions:

• This study reveals a novel nuclear function of p70S6K in promoting CSC maintenance via RPA3.
• The nuclear p70S6K-RPA3 pathway is a critical driver of osteosarcoma progression.
• Targeting the nuclear p70S6K-RPA3 axis presents a promising CSC-based therapeutic strategy for osteosarcoma.