RT info:eu-repo/semantics/doctoralThesis
T1 Estudio del remodelado iónico en cáncer de colon mediante la transferencia mitocondrial y la inhibición de la síntesis de poliaminas.
A1 Feijóo Salgado, Verónica
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Cáncer
K1 Colorectal cancer
K1 Cáncer colorrectal
K1 intracellular calcium
K1 Mitocondria
K1 polyamines
K1 Poliaminas
K1 mitochondria
K1 TRPC1
K1 2411 Fisiología Humana
AB Ionic homeostasis is essential for cellular functions and its alteration can lead to the development of diseases such as cancer. Cancer is one of the main causes of death in the world. In Spain, colorectal cancer (CRC) is the cancer with the highest incidence. CRC development involves a remodeling of ionic homeostasis and, more specifically, calcium and potassium. In CRC cells, alteration in intracellular Ca2+ homeostasis and, more specifically store-operated calcium entry (SOCE), has been described. SOCE us increased in HT29 tumor cells related to NCM460 normal colonic cells. These changes may be modulated by mitochondria, by Ca2+ transport molecules such as TRPC1 or by excess of polyamines, associated with CRC development. In this thesis we investigate the contribution of mitochondria, TRPC1 and polyamines to intracellular Ca2+ remodeling in CRC cells. Our results indicate that transfer of isolated mitochondria from NCM460 cells can reduce SOCE in HT29 tumor cells. However, transfer of isolated mitochondria from tumor cells increases SOCE in HT29 cells, whereas it has no effect on SOCE in normal NCM460 cells. Genomic edition of TRPC1 in HT29 tumor cells has no clear effect on SOCE. Pharmacological inhibition of TRPC1 using low concentrations of Pico145 also had no effect on SOCE. Increasing the concentration of the inhibitor has no clear effect. On the other hand, inhibition of polyamine biosynthesis using DFMO can reverse the differential tumor expression of genes related to Ca2+ transport in CRC cell lines. Consequently, polyamine depletion partially reverses the intracellular Ca2+ remodeling associated to CRC. Furthermore, there is an under-expression of K+ channels in HT29 tumor cells. Moreover, HT29 cells show a decrease in total K+ current compared to NCM460 cells, which is reversed by polyamine depletion with DFMO. However, the current mediated by Kv10.1 and Kv11.1 channels is enhanced in HT29 tumor cells and this current increases after treatment of tumor cells with DFMO. These results open new research lines focused on mitochondria and polyamines related to CRC. The mitochondrial transfer between cells or polyamine depletion can contribute to reverse the ionic remodeling that occurs in CRC.
YR 2024
FD 2024
LK https://uvadoc.uva.es/handle/10324/67174
UL https://uvadoc.uva.es/handle/10324/67174
LA spa
NO Escuela de Doctorado
DS UVaDOC
RD 17-may-2024