Cellular model of warburg effect identifies tumor promoting function of UCP2 in breast cancer and its suppression by genipin

Ayyasamy, Vanniarajan ; Owens, Kjerstin M. ; Desouki, Mohamed Mokhtar ; Liang, Ping ; Bakin, Andrei ; Thangaraj, Kumarasamy ; Buchsbaum, Donald J. ; LoBuglio, Albert F. ; Singh, Keshav K. (2011) Cellular model of warburg effect identifies tumor promoting function of UCP2 in breast cancer and its suppression by genipin PLoS One, 6 (9). Article ID e24792, 13 pages. ISSN 1932-6203

[img]
Preview
PDF
978kB

Official URL: http://journals.plos.org/plosone/article?id=10.137...

Related URL: http://dx.doi.org/10.1371/journal.pone.0024792

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 (rho0) 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 rho0 derivative, breast cancer cell lines and primary breast tumors. Among several genes, our study revealed that over-expression of mitochondrial uncoupling protein UCP2 in rho0 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.

Item Type:Article
Source:Copyright of this article belongs to Public Library of Science.
ID Code:107399
Deposited On:23 Jul 2017 16:58
Last Modified:23 Jul 2017 16:58

Repository Staff Only: item control page