The Evaualtion of MACF1 as a Novel Onco-Protein Within Glioblastoma that when Inhibited Enhances the Efficacy of DNA Damaging Agents Radiation and BCNU
Glioblastoma Multiforme (GBM) is an aggressive cancer of the central nervous system. The poor prognosis of GBM patients can be accredited to the malignancies extensive cellular and genetic heterogeneity. There are an excess of novel unevaluated proteins whose functions participate in glioblastoma progression. One such protein is the cytoskeletal cross-linker, Microtubule Actin Crosslinking Factor 1 (MACF1), which our lab has shown to be expressed at high levels in glioblastoma tissue as compared to its absence in normal brain tissue and low grade gliomas. MACF1’s implication in GBM biology has received minimal evaluation, in this study we have demonstrated the synergistic and anti-tumorigenic effects that MACF1 inhibition has on glioblastoma cell lines A172 and U251 in combination with DNA damaging agents. The combinatorial experimental studies from our lab demonstrated that MACF1 inhibition enhanced the efficacy of DNA damaging agents BCNU, TMZ, and radiation. The combinatorial approach produced the cellular response of decreased proliferation and migration within GBM cell lines. Mechanistically we were able to demonstrate MACF1’s function within the WNT signaling pathway. Our study revealed that MACF1inhibition in decreased the expression of scaffolding protein Axin1 and the transcriptional activator β-catenin. Furthermore we were able to show that the combinatorial approach of radiation and MACF1 inhibition enhanced GBM cell sensitivity through the modulation of ribosomal protein S6, thus establishing MACF1 as a novel radiosensitizer. The anti-tumorigenic effects of MACF1 silencing have been examined, to our knowledge there are no data evaluating MACF1’s function as an onco-protein within glioblastoma. Our data demonstrated that MACF1 when overexpressed in normal human astrocytes produced tumorigenic characteristics such as increased proliferation, migration, and cellular transformation. To this end our lab has established that MACF1 is a novel onco-protein within GBM. Taken together MACF1 has been identified as a novel onco-protein that when inhibited enhances the efficacy of DNA damaging agents radiation and BCNU within glioblastoma cell lines
"The Evaualtion of MACF1 as a Novel Onco-Protein Within Glioblastoma that when Inhibited Enhances the Efficacy of DNA Damaging Agents Radiation and BCNU"
ETD Collection for Tennessee State University.