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Updated: Mar 16, 2026
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells
Luigi Ippolito1, Alberto Marini2, Lorenzo Cavallini1
1Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Abstract:
Drug resistance of cancer cells is recognized as the primary cause of failure of chemotherapeutic treatment in most human cancers. Growing evidences support the idea that deregulated cellular metabolism is linked to such resistance. Indeed, both components of the glycolytic and mitochondrial pathways are involved in altered metabolism linked to chemoresistance of several cancers. Here we investigated the drug-induced metabolic adaptations able to confer advantages to docetaxel resistant prostate cancer (PCa) cells. We found that docetaxel-resistant PC3 cells (PC3-DR) acquire a pro-invasive behavior undergoing epithelial-to-mesenchymal-transition (EMT) and a decrease of both intracellular ROS and cell growth. Metabolic analyses revealed that PC3-DR cells have a more efficient respiratory phenotype than sensitive cells, involving utilization of glucose, glutamine and lactate by the mitochondrial oxidative phosphorylation (OXPHOS). Consequently, targeting mitochondrial complex I by metformin administration, impairs proliferation and invasiveness of PC3-DR cells without effects on parental cells. Furthermore, stromal fibroblasts, which cause a "reverse Warburg" phenotype in PCa cells, reduce docetaxel toxicity in both sensitive and resistant PCa cells. However, re-expression of miR-205, a microRNA strongly down-regulated in EMT and associated to docetaxel resistance, is able to shift OXPHOS to a Warburg metabolism, thereby resulting in an elevated docetaxel toxicity in PCa cells. Taken together, these findings suggest that resistance to docetaxel induces a shift from Warburg to OXPHOS, mandatory for conferring a survival advantage to resistant cells, suggesting that impairing such metabolic reprogramming could be a successful therapeutic approach.
Insights
Drug resistance in prostate cancer (PCa) cells is linked to metabolic changes. Targeting mitochondrial oxidative phosphorylation (OXPHOS) with metformin can reduce docetaxel resistance and invasiveness.
Area of Science:
- Oncology
- Cancer Metabolism
- Cellular Respiration
Background:
- Drug resistance is a major challenge in cancer chemotherapy.
- Altered cellular metabolism, particularly in glycolytic and mitochondrial pathways, is increasingly linked to chemoresistance.
- Prostate cancer (PCa) cells exhibit drug resistance, necessitating investigation into underlying metabolic adaptations.
Purpose of the Study:
- To investigate drug-induced metabolic adaptations conferring advantages to docetaxel-resistant prostate cancer (PCa) cells.
- To explore the role of mitochondrial oxidative phosphorylation (OXPHOS) and epithelial-to-mesenchymal-transition (EMT) in chemoresistance.
- To evaluate potential therapeutic strategies targeting metabolic reprogramming in resistant PCa.
Main Methods:
- Comparative metabolic analysis of docetaxel-sensitive and docetaxel-resistant PC3 cells (PC3-DR).
- Assessment of cellular phenotypes including invasiveness, proliferation, and reactive oxygen species (ROS) levels.
- Pharmacological intervention using metformin to target mitochondrial complex I.
- Investigation of stromal fibroblast influence and the role of miR-205 in metabolic reprogramming.
Main Results:
- Docetaxel-resistant PC3-DR cells exhibit a pro-invasive phenotype, decreased ROS, and reduced cell growth, with a shift towards enhanced OXPHOS utilizing glucose, glutamine, and lactate.
- Metformin administration impairs proliferation and invasiveness of PC3-DR cells by targeting mitochondrial complex I.
- Stromal fibroblasts induce a "reverse Warburg" phenotype, reducing docetaxel toxicity.
- Re-expression of miR-205 shifts metabolism from OXPHOS to Warburg, increasing docetaxel toxicity in PCa cells.
Conclusions:
- Docetaxel resistance in PCa cells is associated with a metabolic shift from Warburg to OXPHOS, conferring a survival advantage.
- Targeting mitochondrial complex I with metformin represents a potential therapeutic strategy to overcome docetaxel resistance.
- Modulating microRNA expression, such as miR-205, can reverse metabolic adaptations and enhance chemotherapy efficacy.
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