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Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ
| Content Provider | Scilit |
|---|---|
| Author | Whitaker-Menezes, Diana Martinez-Outschoorn, Ubaldo E. Flomenberg, Neal Birbe, Ruth Witkiewicz, Agnieszka K. Howell, Anthony Pavlides, Stephanos Tsirigos, Aristotelis Ertel, Adam Pestell, Richard G. Broda, Paolo Minetti, Carlo Lisanti, Michael P. Sotgia, Federica |
| Copyright Year | 2011 |
| Abstract | We have recently proposed a new mechanism for explaining energy transfer in cancer metabolism. In this scenario, cancer cells behave as metabolic parasites, by extracting nutrients from normal host cells, such as fibroblasts, via the secretion of hydrogen peroxide as the initial trigger. Oxidative stress in the tumor microenvironment then leads to autophagy-driven catabolism, mitochondrial dys-function, and aerobic glycolysis. This, in turn, produces high-energy nutrients (such as L-lactate, ketones, and glutamine) that drive the anabolic growth of tumor cells, via oxidative mitochondrial metabolism. A logical prediction of this new “parasitic” cancer model is that tumor-associated fibroblasts should show evidence of mitochondrial dys-function (mitophagy and aerobic glycolysis). In contrast, epithelial cancer cells should increase their oxidative mitochondrial capacity. To further test this hypothesis, here we subjected frozen sections from human breast tumors to a staining procedure that only detects functional mitochondria. This method detects the in situ enzymatic activity of cytochrome C oxidase (COX), also known as Complex IV. Remarkably, cancer cells show an over-abundance of COX activity, while adjacent stromal cells remain essentially negative. Adjacent normal ductal epithelial cells also show little or no COX activity, relative to epithelial cancer cells. Thus, oxidative mitochondrial activity is selectively amplified in cancer cells. Although COX activity staining has never been applied to cancer tissues, it could now be used routinely to distinguish cancer cells from normal cells, and to establish negative margins during cancer surgery. Similar results were obtained with NADH activity staining, which measures Complex I activity, and succinate dehydrogenase (SDH) activity staining, which measures Complex II activity. COX and NADH activities were blocked by electron transport inhibitors, such as Metformin. This has mechanistic and clinical implications for using Metformin as an anti-cancer drug, both for cancer therapy and chemo-prevention. We also immuno-stained human breast cancers for a series of well-established protein biomarkers of metabolism. More specifically, we now show that cancer-associated fibroblasts over-express markers of autophagy (cathepsin B), mitophagy (BNIP3L), and aerobic glycolysis (MCT4). Conversely, epithelial cancer cells show the over-expression of a mitochondrial membrane marker (TOMM20), as well as key components of Complex IV (MT-CO1) and Complex II (SDH-B). We also validated our observations using a bioinformatics approach with data from >2,000 breast cancer patients, which showed the transcriptional upregulation of mitochondrial oxidative phosphorylation (OXPHOS) in human breast tumors (p < $10^{-20}$), and a specific association with metastasis. Therefore, upregulation of OXPHOS in epithelial tumor cells is a common feature of human breast cancers. In summary, our data provide the first functional in vivo evidence that epithelial cancer cells perform enhanced mitochondrial oxidative phosphorylation, allowing them to produce high amounts of ATP. Thus, we believe that mitochondria are both the “powerhouse” and “Achilles’ heel” of cancer cells. |
| Related Links | https://www.tandfonline.com/doi/pdf/10.4161/cc.10.23.18151?needAccess=true https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272287/pdf |
| Ending Page | 4064 |
| Page Count | 18 |
| Starting Page | 4047 |
| ISSN | 15384101 |
| e-ISSN | 15514005 |
| DOI | 10.4161/cc.10.23.18151 |
| Journal | Cell Cycle |
| Issue Number | 23 |
| Volume Number | 10 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2011-12-01 |
| Access Restriction | Open |
| Subject Keyword | Pathology Mitochondria Oxidative Phosphorylation (oxphos) Complex I Complex Iv Electron Transport Respiratory Chain Metformin Warburg Effect Autophagy Mitophagy Aerobic Glycolysis Cytochrome C Oxidase (cox) Warburg Respiratory Enzyme Nadh Dehydrogenase Cancer Metabolism |
| Content Type | Text |
| Subject | Cell Biology Developmental Biology Medicine Molecular Biology |
