Autophagy, induced by metabolic stress and radiation, mediates the transition to senescence in glioblastome multiforme cells

Glioblastoma multiforme (GBM) is the most commonly diagnosed and most aggressive type of malignant brain tumor in humans. Established hallmarks of GBM include, intense resistance to apoptosis and pronounced predisposition to necrosis. These hallmarks contribute to the poor prognosis of GBM patients. Therefore, there is an urgent need for the development of advanced therapies or even better, a cure. Subtypes of GBM, defined by genomic profiling, can contribute to the development of better therapies that are specific to the genomic defects of each subtype of GBM. Clinical trials with caloric restriction are underway at Duke University and Thomas Jefferson. The radiation response data of the combination of gamma-radiation with nutrient deprivation by starvation Hank's balanced saline solution (HBSS) provides translational data for GBM therapy, as a combination of fractionated radiotherapy combined with restricted caloric intake prior to the delivery of radiation. Mechanistically, starvation HBSS induces metabolic stress thereby activating autophagy, an effector mechanism of senescence. Presently, senescence is acknowledged as an anti-proliferative response with potential roles in tumor suppression. Therefore, results presented here showing induction of senescence via autophagy may provide a mechanistic basis for tumor suppression or "cure" after radiation therapy and metabolic stress.