Creatine Kinase Blockade Disrupts Energy Metabolism and Redox Homeostasis to Suppress Osteosarcoma Progression

Area of Science:

• Oncology
• Biochemistry
• Metabolic Pathways

Background:

• Osteosarcoma is a prevalent bone cancer in young individuals with stagnant survival rates.
• The creatine kinase (CK) system fuels cancer cell energy demands via the phosphocreatine (pCr) shuttle.
• Novel therapeutic targets are crucial for improving osteosarcoma treatment outcomes.

Purpose of the Study:

• To investigate the therapeutic potential of pharmacologically inhibiting CK in osteosarcoma.
• To evaluate the impact of CK blockade on tumor cell proliferation, apoptosis, mitochondrial function, stemness, and motility.
• To assess the efficacy of CK inhibition in preclinical osteosarcoma models.

Main Methods:

• Pharmacological inhibition of creatine kinase (CK) activity in osteosarcoma cell and mouse models.
• Assessment of cell proliferation, apoptosis, mitochondrial respiration, and stemness markers.
• Evaluation of tumor growth, metastasis, and dissemination in vivo.

Main Results:

• CK inhibition significantly suppressed osteosarcoma cell growth and clonogenicity.
• Apoptosis was identified as the primary cell death mechanism following CK blockade.
• Mitochondrial function, ATP buffering, stemness, migration, and invasion were impaired.
• Tumor progression and dissemination were significantly reduced in mouse models.

Conclusions:

• Targeting the CK-pCr energy system represents a viable metabolic vulnerability in osteosarcoma.
• CK inhibition effectively reduces tumor aggressiveness and metastatic potential.
• Disabling CK offers a promising therapeutic strategy and a potential partner for existing cytotoxic regimens.