Rodrigues 2014 Abstract MiP2014
|Bioenergetics’ traits of tongue cancer metastatic cells.|
Buccal cancer affects 3% of all cases of cancer in the world. The most common malignant tumors of the oral cavity are of the spinocellular type and are characterized by invasive growth, frequently perineural. Although the main etiological factors, tobacco and alcohol, are known, at this point the biochemical features associated with the progression of the disease are largely fragmentary.
We investigated the bioenergetics of oral tongue squamous cell carcinoma (OTSCC) metastatic spread. An orthotopic model was developed by the implantation of SCC-9 ZsGreen cells into the tongue of BALB/c nude mice. The animals were sacrificed 60 days later and the axillary lymph nodes collected. Fragments of positive lymph nodes were used for explants cultures, from which the LN-1 ZsGreen cell line was isolated. The retransplantation generated LN-2 ZsGreen cell lines. LN1 and LN2 present degrees of aggressiveness as measured by their metastatic behavior .
When compared for ATP content, SCC9, LN1 and LN2 cells displayed similar profiles. All three were strongly sensitive to glycolytic inhibitors as 2-DOG and iodocetamide, but were quasi-insensitive to respiratory the inhibitors rotenone and antimycin A. These results indicate that SCC9, LN1 and LN2 primarily depend on glycolysis for ATP synthesis, although their mitochondria were not dysfunctional. Our results with high-resolution respirometry (HRR) show that mitochondrial function is similar in all three cell lines. Interestingly, oxygen consumption of digitonin permeabilized cells displayed a decreased activity of Complex I- but not of Complex II-linked respiration. Furthermore, mitochondrial content was decreased. Interestingly, the content of Complex III increased linearly with the metastatic behavior of the cells. Since many types of cancer involve defects in respiratory complexes, it is possible that the observed reduced activity of Complex I is compensated by an enhanced activity of Complex III. Alternatively, in the more aggressive cells electrons bypassing Complex I may increase the speed of the entire electron transfer-pathway, therefore facilitating ROS production, migration and invasion. To investigate whether tongue cancer cells used specific energy substrates in a differential manner, palmitoyl CoA was added to the incubation medium. Stimulation of OXPHOS capacity by SCC9 and LN1 cells, and, less so, by the more aggressive LN2 cells was observed only with palmitoyl CoA+malate. Additionally, inhibition of beta-oxidation using etomoxir induced a decrease in ATP levels in LN1 and LN2 cells. These results suggest that mitochondria of tongue metastatic cells can select specific energy substrates such as amino acids and/or fatty acids to maintain redox balance and ATP balance during invasion.
Labels: MiParea: Respiration, mt-Biogenesis;mt-density Pathology: Cancer
Organism: Mouse Tissue;cell: Lymphocyte Preparation: Permeabilized cells Enzyme: Complex III
Pathway: F, N, S HRR: Oxygraph-2k Event: B3, Poster MiP2014
1-Inst Bioquímica Médica Leopoldo De Meis, UFRJ, Rio de Janeiro, Brazil; 2-Fac Odontologia, UFRJ, Rio de Janeiro, Brazi; 3-Maladies Rares: Génétique ET Métabolisme, Univ Bordeaux Segalen, France. - [email protected]
- Agostini M, Almeida LY, Bastos DC, Ortega RM, Moreira FS, Seguin F, Zecchin KG, Raposo HF, Oliveira HC, Amoedo ND, Salo T, Coletta RD, Graner E (2014) The fatty acid synthase inhibitor orlistat reduces the growth and metastasis of orthotopic tongue oral squamous cell carcinomas. Mol Cancer Ther 13: 585-95.