title: Cellular model of Warburg effect identifies tumor promoting function of UCP2 in breast cancer and its suppression by genipin.
abstract: The Warburg Effect is characterized by an irreversible injury to mitochondrial oxidative phosphorylation (OXPHOS) and an increased rate of aerobic glycolysis. In this study, we utilized a breast epithelial cell line lacking mitochondrial DNA (rho(0)) that exhibits the Warburg Effect associated with breast cancer. We developed a MitoExpress array for rapid analysis of all known nuclear genes encoding the mitochondrial proteome. The gene-expression pattern was compared among a normal breast epithelial cell line, its rho(0) derivative, breast cancer cell lines and primary breast tumors. Among several genes, our study revealed that over-expression of mitochondrial uncoupling protein UCP2 in rho(0) breast epithelial cells reflects gene expression changes in breast cancer cell lines and in primary breast tumors. Furthermore, over-expression of UCP2 was also found in leukemia, ovarian, bladder, esophagus, testicular, colorectal, kidney, pancreatic, lung and prostate tumors. Ectopic expression of UCP2 in MCF7 breast cancer cells led to a decreased mitochondrial membrane potential and increased tumorigenic properties as measured by cell migration, in vitro invasion and anchorage independent growth. Consistent with in vitro studies, we demonstrate that UCP2 over-expression leads to development of tumors in vivo in an orthotopic model of breast cancer. Genipin, a plant derived small molecule, suppressed the UCP2 led tumorigenic properties, which were mediated by decreased reactive oxygen species and down-regulation of UCP2. However, UCP1, 3, 4 and 5 gene expression was unaffected. UCP2 transcription was controlled by SMAD4. Together, these studies suggest a tumor-promoting function of UCP2 in breast cancer. In summary, our studies demonstrate that i) the Warburg Effect is mediated by UCP2; ii) UCP2 is over-expressed in breast and many other cancers; iii) UCP2 promotes tumorigenic properties in vitro and in vivo and iv) genipin suppresses the tumor promoting function of UCP2.
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Vanniarajan
authors.initials: V
authors.lastname: Ayyasamy
authors.forename: Kjerstin M
authors.initials: KM
authors.lastname: Owens
authors.forename: Mohamed Mokhtar
authors.initials: MM
authors.lastname: Desouki
authors.forename: Ping
authors.initials: P
authors.lastname: Liang
authors.forename: Andrei
authors.initials: A
authors.lastname: Bakin
authors.forename: Kumarasamy
authors.initials: K
authors.lastname: Thangaraj
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
authors.forename: Albert F
authors.initials: AF
authors.lastname: LoBuglio
authors.forename: Keshav K
authors.initials: KK
authors.lastname: Singh
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D057889:Iridoid Glycosides / Q000494:pharmacology*; D039823:Iridoids; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D057889:Iridoid Glycosides; D039823:Iridoids; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D051901:Smad4 Protein; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; C007834:genipin