Energy metabolism in glioblastoma stem cells: PPARα a metabolic adaptor to intratumoral microenvironment
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Alessia Fidoamore1,*, Loredana Cristiano1,*, Chiara Laezza2, Renato Galzio1, Elisabetta Benedetti1, Benedetta Cinque1, Andrea Antonosante1, Michele d’Angelo1, Vanessa Castelli1, Maria Grazia Cifone1, Rodolfo Ippoliti1, Antonio Giordano3,5 and Annamaria Cimini1,3,4
1 Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
2 Institute of Endocrinology and Experimental Oncology, IEOS, CNR, Naples, Italy
3 Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Temple University, Philadelphia, Pennsylvania, USA
4 National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy
5 Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
* These authors have equally contributed to the paper
Annamaria Cimini, email:
Keywords: tumor stem cells, metabolism, PPARs
Received: September 18, 2016 Accepted: June 10, 2017 Published: July 07, 2017
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.
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