Microtubule actin crosslinking factor 1 (MACF1) is a spectraplakin cytoskeletal crosslinking protein whose function and role in cancer biology has lacked investigation. Recent studies have identified MACF1 as a novel target in glioblastomas expressed in tissue from tumor patient explants but not normal brain tissue and when silenced has an antitumorigenic impact on these tumors. Radiation as a single agent therapy to treat glioblastomas has been used for decades and has done little to improve survival of individuals diagnosed with this disease. However, contemporary clinical radiotherapy protocols have provided evidence that combinatorial radiotherapy approaches confer a therapeutic benefit in glioblastoma patients. In this study MACF1 was investigated as a radiosensitization target in glioblastomas. Methods
To provide context of MACF1 in glioblastomas, The Cancer Genome Atlas expression analyses were performed in conjunction with genes associated with glioblastoma evolution, while a genetic inhibitory approach, cell migratory assays, and immunofluorescence procedures were used to evaluate responses to MACF1 suppression with radiation. Additionally, expression analyses were conducted to assess co-expression of mTOR signaling pathway regulators and MACF1 in glioblastoma patient samples. Results
Our amalgamation approach demonstrated that negative regulation of MACF1, which was positively correlated with epidermal growth factor receptor and p70s6k expression, enhanced the sensitivity of glioblastoma cells to radiation as a consequence of reducing glioblastoma cell viability and migration. Mechanistically, the antitumorigenic effects on glioblastoma cell behaviors after radiation and impairing MACF1 function were associated with decreased expression of ribosomal protein S6, a downstream effector of p70s6k. Conclusion
MACF1 represents a diagnostic marker with target specificity in glioblastomas that can enhance the efficacy of radiation while minimizing normal tissue toxicity. This approach could potentially expand combinatorial radiation strategies for glioblastoma treatments via impairment of translational regulatory processes that contribute to poor patient survival.
Bonner K, Borlay D, Kutten O, Quick QA. Inhibition of the Spectraplakin Protein Microtubule Actin Crosslinking Factor 1 Sensitizes Glioblastomas to Radiation. Brain Tumor Res Treat. 2020 Apr;8(1):43-52. https://doi.org/10.14791/btrt.2020.8.e1