Metabolic reprogramming is associated with flavopiridol resistance in prostate cancer DU145 cells

Area of Science:

• Oncology
• Cancer Biology
• Metabolic Research

Background:

• Flavopiridol (FP) is a potent cyclin-dependent kinase inhibitor effective against cancer cells in vitro.
• Clinical trials show limited efficacy of FP in aggressive cancers, with resistance mechanisms largely unknown.
• Prostate cancer exhibits significant heterogeneity and therapeutic challenges.

Purpose of the Study:

• To investigate the molecular mechanisms underlying resistance to Flavopiridol in human prostate cancer cells.
• To characterize the phenotypic and metabolic alterations in FP-resistant prostate cancer cells.
• To explore the relationship between metabolic plasticity, stemness, and FP resistance.

Main Methods:

• Long-term treatment of DU145 prostate cancer cells with Flavopiridol to generate resistant cell lines (DU145^FP).
• Comparative analysis of mitochondrial function, glycolytic activity, cell cycle, migration, and apoptosis.
• Assessment of sensitivity to other chemotherapeutic agents (cisplatin, docetaxel).
• Evaluation of stem cell marker expression.

Main Results:

• FP-resistant DU145^FP cells developed accumulated mitochondrial lesions and enhanced glycolytic features.
• Resistant cells exhibited slow proliferation, high migration, and strong anti-apoptotic potential.
• DU145^FP cells showed reduced sensitivity to cisplatin and docetaxel.
• Over-expression of multiple stem cell-associated biomarkers was observed in resistant cells.

Conclusions:

• FP-resistant prostate cancer cells undergo significant metabolic remodeling, shifting towards glycolysis.
• Metabolic plasticity is a key factor contributing to acquired resistance to FP.
• Metabolic alterations are linked to enhanced cancer cell stemness and reduced chemosensitivity, presenting a novel therapeutic target.