Mitochondrial uncoupler DNP induces coexistence of dual-state hyper-energy metabolism leading to tumor growth advantage in human glioma xenografts

IntroductionCancer bioenergetics is an essential hallmark of neoplastic transformation. Warburg postulated that mitochondrial OXPHOS is impaired in cancer cells, leading to aerobic glycolysis as the primary metabolic pathway. However, mitochondrial function is altered but not entirely compromised in most malignancies, and that mitochondrial uncoupling is known to increase the carcinogenic potential and modifies treatment response by altering metabolic reprogramming. Our earlier study showed that transient DNP exposure increases glycolysis in human glioma cells (BMG-1). The current study investigated the persistent effect of DNP on the energy metabolism of BMG-1 cells and its influence on tumor progression in glioma xenografts. MethodsBMG-1 cells were treated with 2,4-dinitrophenol (DNP) in-vitro, to establish the OXPHOS-modified (OPM-BMG) cells. Further cellular metabolic characterization was carried out in both in-vitro cellular model and in-vivo tumor xenografts to dissect the role of metabolic adaptation in these cells and compared them with their parental phenotype. Results and DiscussionChronic exposure to DNP in BMG-1 cells resulted in dual-state hyper-energy metabolism with elevated glycolysis(++) and OXPHOS++ compared to parental BMG-1 cells with low glycolysis(+) and OXPHOS+. Tumor xenograft of OPM-BMG cells showed relatively increased tumor-forming potential and accelerated tumor growth in nude mice. Moreover, compared to BMG-1, OPM-BMG tumor-derived cells also showed enhanced migration and invasion potential. Although mitochondrial uncouplers are proposed as a valuable anti-cancer strategy; however, our findings reveal that prolonged exposure to uncouplers provides tumor growth advantage over the existing glioma phenotype that may lead to poor clinical outcomes.

Automated summary

Cancer cells exhibit altered energy metabolism, with impaired mitochondrial function and increased glycolysis. This study investigated the effect of prolonged exposure to the mitochondrial uncoupler DNP on the energy metabolism of glioma cells and its impact on tumor progression. The results showed that chronic DNP exposure increased glycolysis and OXPHOS in glioma cells, leading to enhanced tumor formation and accelerated tumor growth in an animal model. Furthermore, DNP-treated cells also exhibited increased migration and invasion potential. These findings suggest that prolonged exposure to mitochondrial uncouplers may confer a growth advantage to glioma cells and result in poor clinical outcomes.