Energy metabolism in glioblastoma stem cells: PPARα a metabolic adaptor to intratumoral microenvironment

Glioblastoma (GB), the most-common cancer in the adult brain, despite surgery
and radio/ chemotherapy, is to date almost incurable. Many hypoxic tumors, including
GB, show metabolic reprogramming to sustain uncontrolled proliferation, hypoxic
conditions and angiogenesis. Peroxisome Proliferator-activated Receptors (PPAR),
particularly the α isotype, have been involved in the control of energetic metabolism.
Herein, we characterized patient-derived GB neurospheres focusing on their energetic
metabolism and PPARα expression. Moreover, we used a specific PPARα antagonist
and studied its effects on the energetic metabolism and cell proliferation/survival
of GB stem cells. The results obtained demonstrate that tumor neurospheres are
metabolically reprogrammed up-regulating glucose transporter, glucose uptake
and glycogen and lipid storage, mainly under hypoxic culture conditions. Treatment
with the PPARα antagonist GW6471 resulted in decreased cell proliferation and
neurospheres formation. Therefore, PPARα antagonism arises as a potent new
strategy as adjuvant to gold standard therapies for GB for counteracting recurrences
and opening the way for pre-clinical trials for this class of compounds. When tumor
neurospheres were grown in hypoxic conditions in the presence of different glucose
concentrations, the most diluted one (0.25g/L) mimicking the real concentration
present in the neurosphere core, PPARα increase/PPARγ decrease, increased
proliferation and cholesterol content, decreased glycogen particles and LDs were
observed. All these responses were reverted by the 72 h treatment with the PPARα
antagonist.