Long noncoding RNA lncARSR confers resistance to Adriamycin and promotes osteosarcoma progression

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Chemotherapy resistance, particularly to Adriamycin (ADM), is a major obstacle in osteosarcoma treatment.
• Mechanisms driving ADM resistance in osteosarcoma progression are not fully understood.

Purpose of the Study:

• To investigate the role of long noncoding RNA ARSR (lncARSR) in the development of adaptive ADM resistance in osteosarcoma.
• To elucidate the molecular mechanisms by which lncARSR contributes to ADM resistance.

Main Methods:

• Comparative analysis of lncARSR expression in ADM-resistant versus sensitive osteosarcoma cell lines.
• Functional studies involving overexpression and depletion of lncARSR to assess effects on drug resistance, cell survival, migration, and apoptosis.
• Investigation of downstream targets, including multidrug resistance-associated protein-1 (MRP1), Survivin, matrix metalloproteinase-2 (MMP2), and AKT signaling.
• Validation in an U2OS/ADM mouse model.

Main Results:

• lncARSR was significantly overexpressed in ADM-resistant osteosarcoma cells (U2OS/ADM, MG63/ADM), correlating with resistance to paclitaxel and cisplatin.
• Overexpression of lncARSR increased rhodamine 123 efflux, cell survival, and migration, while its depletion enhanced apoptosis and reduced motility.
• lncARSR upregulation activated AKT signaling, leading to increased expression of MRP1, Survivin, and MMP2.
• Reduction of lncARSR effectively overcame ADM resistance in a preclinical mouse model.

Conclusions:

• lncARSR plays a critical role in the adaptive resistance to Adriamycin in osteosarcoma.
• The lncARSR/AKT/MRP1/Survivin/MMP2 pathway is a key mechanism driving chemoresistance and progression in osteosarcoma.
• Targeting lncARSR presents a potential therapeutic strategy to improve outcomes for patients with refractory osteosarcoma.