Truu 2017 MiP2017
Bioenergetics is a fast growing field in cancer research, where many promising outcomes could provide targeted cancer treatment . Energy metabolism specific literature is characterized by many contradictions, concluding that cancer cells metabolize their increased glucose uptake via glycolysis rather than more energy efficient oxidative phosphorylation (OXPHOS). Furthermore, the majority of these conclusions are the outcome of only in vitro studies on cell culture models, without taking into consideration the factors arising from the tumor microenvironment giving significant effects in vivo [2-3].
We have analyzed quantitatively the mitochondrial respiration in human post-operational tissue samples in colorectal cancer (HCC), normal colon tissues, colon polyps and in breast cancer (HBC). We also included MDA-MB 231 and MCF-7 cultures. In this work the technique of permeabilized fibers is used, which takes into account the complex structural and functional organization of tissue and its importance for metabolic regulation. The flux was measured as the rate of oxygen consumption, using High-Resolution FluoRespiromety (Oroboros Instruments, Austria). Mitomed medium was used for measurement, containing 5mM glutamate, 2mM malate and 10mM of succinate as substrates.
Our results show that HCC is not fully glycolytic tumor and OXPHOS system might be the main source of ATP. Kinetic parameters displayed remarkable differences between cell cultures and clinical HBC samples. Comparing healthy colon, HCC tissue and colon polyps, we found that colon polyps (52,5 ± 12,7; µM ± SEM) show similar Km values to healthy mucosal colon tissue (42 ± 14; µM ± SEM) rather than HCC (69 ± 10; µM ± SEM). We identified that the development of colon polyps results in reduced VGlut/VSucc ratio which indicates relative suppression of complex I dependent respiration, which is the hallmark of multiple mitochondrial diseases and is generally considered to be an essential property of some cancers. However, relative Complex I functional deficiency was characteristic for HCC, but not for HBC. HCC was characterized with higher mitochondrial biogenesis compared with normal colon tissue.
Further research is in progress to generate a full cancer development model consisting of cell cultures, clinical polyps and malignant versus healthy tissue samples.
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Patients Pathology: Cancer
Preparation: Permeabilized tissue
Pathway: N, NS HRR: Oxygraph-2k
- Truu L(1), Koit A(1), Chekulayev V(1), Tepp K(1), Puurand M(1), Ounpuu L(1), Klepinin A(1), Shevchuk I(1), Kaambre T(1,2)
- Lab Bioenergetics, Nat Inst Chemical Physics Biophysics
- School Natural Sciences Health, Tallinn Univ; Tallinn, Estonia. - [email protected]
- Rodríguez-Enríquez S, Hernández-Esquivel L, Marín-Hernández A, El Hafidi M, Gallardo-Pérez JC, Hernández-Reséndiz I, Rodríguez-Zavala JS, Pacheco-Velázquez SC, Moreno-Sánchez R (2015) Mitochondrial free fatty acid beta-oxidation supports oxidative phosphorylation and proliferation in cancer cells. Int J Biochem Cell Biol 65:209-21.
- McGranahan N, Swanton C (2015) Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27:15-26.
- Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH, Yull FE, Coussens LM, DeClerck YA (2012) Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Research 72:2473-80.