title: Targeting metabolic plasticity in breast cancer cells via mitochondrial complex I modulation.
abstract: Heterogeneity commonly observed in clinical tumors stems both from the genetic diversity as well as from the differential metabolic adaptation of multiple cancer types during their struggle to maintain uncontrolled proliferation and invasion in vivo. This study aims to identify a potential metabolic window of such adaptation in aggressive human breast cancer cell lines. With a multidisciplinary approach using high-resolution imaging, cell metabolism assays, proteomic profiling and animal models of human tumor xenografts and via clinically-relevant pharmacological approach for modulating mitochondrial complex I function in human breast cancer cell lines, we report a novel route to target metabolic plasticity in human breast cancer cells. By a systematic modulation of mitochondrial function and by mitigating metabolic switch phenotype in aggressive human breast cancer cells, we demonstrate that the resulting metabolic adaptation signatures can predictably decrease tumorigenic potential in vivo. Proteomic profiling of the metabolic adaptation in these cells further revealed novel protein-pathway interactograms highlighting the importance of antioxidant machinery in the observed metabolic adaptation. Improved metabolic adaptation potential in aggressive human breast cancer cells contribute to improving mitochondrial function and reducing metabolic switch phenotype-which may be vital for targeting primary tumor growth in vivo.
authors: Metabolic Photonics Laboratory, Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA, 90048, USA, xuq@cshs.org.
authors: Qijin
authors: Q
authors: Xu
authors: Eva
authors: E
authors: Biener-Ramanujan
authors: Wei
authors: W
authors: Yang
authors: V Krishnan
authors: VK
authors: Ramanujan
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D053858:Metabolic Networks and Pathways; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D020543:Proteome; D040901:Proteomics; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction; D047368:Tumor Burden; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D020543:Proteome; D014475:Uncoupling Agents; D012402:Rotenone; D042967:Electron Transport Complex I