| Autor: |
Iascone DM; Howard Hughes Medical Institute, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Zhang X; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104.; Wistar Institute, Philadelphia, PA, USA.; Present address: Johns Hopkins University, Baltimore, MD, USA., Bafford P; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104.; Wistar Institute, Philadelphia, PA, USA., Mesaros C; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA., Sela Y; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104.; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Hofbauer S; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA., Zhang SL; Howard Hughes Medical Institute, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Present address: Emory University, Atlanta, GA, USA., Cook K; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Pivarshev P; Howard Hughes Medical Institute, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Stanger BZ; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104.; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Anderson S; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Dang CV; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104.; Wistar Institute, Philadelphia, PA, USA.; Present address: Johns Hopkins University, Baltimore, MD, USA., Sehgal A; Howard Hughes Medical Institute, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. |
| Abstrakt: |
Crosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in an in vitro mouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells. |
