Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells

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.

Stromal‐induced downregulation of miR‐1247 promotes prostate cancer malignancy

“…These phenomena are at least in part dependent on microRNA (miRNA) deregulation upon CAF contact as revealed by a global analysis of miRNAs expression. The most downregulated miRNA involved in CAF‐induced EMT of PCa cells is miR‐205, which acts as a tumor suppressor by downregulating EMT as previously shown in our studies (Gandellini et al, ; Giannoni et al, ; Ippolito et al, ). We now focused our attention on miR‐1247, the second most downregulated miRNA in PC3 cells upon CAF contact.…”

Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism

“…Here, we propose that metabolic flexibility as well as mitochondrial dependency are two crucial requirements of AraC resistance of AML cells in vivo . An OXPHOS-dependent energetic flexibility may be responsible for resistance to oncogene ablation or induced senescence, oxidative stress, radiation and chemotherapeutics (35,36,57–60), suggesting that resistance in cancer is associated with a shift toward a HIGH OXPHOS status. Of note, this model may explain several recent studies inducing chemosensitivity in AML cells through modulation of mitochondrial metabolism.…”

Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

“…Decreased expression of miR-205 is associated with drug resistance and EMT in PC3-DR cells. Induced re-expression of miR-205 was demonstrated to shift mitochondrial oxidative phosphorylation to Warburg metabolism and resulted in increased sensitivity to docetaxel (Ippolito et al, 2016).…”