Energetic Metabolism in Glioblastoma Stem Cells: Effects of PPARalpha Antagonists

Glioblastoma multiforme (GBM, grade IV astrocytoma) is the most malignant and aggressive of brain tumors with poor prognosis and a median survival of patients of approximately 15 months. Over the past decade there has been an increasing interest in the role of cancer stem cells in the tumorigenesis process, because they are responsible of tumor drug resistance and relapse. It is known that glioblastoma stem cells (GSCs) are a heterogeneous population that resides in the intratumoral perivascular and necrotic/hypoxic niches and that hypoxia exerted a crucial function, maintaining stemness and governing their fate. Particularly, hypoxia inducible factors (HIFs) regulate many aspects of tumor malignant progression such as proliferation, angiogenesis, metastasis and metabolism, whose mechanisms, in GSCs, today are poorly understood. In the brain Peroxisome proliferator activated Receptors (PPARs), ligand-activated transcription factors, belonging to the nuclear hormone receptor superfamily, play a specific role in the energetic metabolism. Three isotypes have been described, the α, β and γ, that have a tissue specific distribution and pleiotropic functions as they are involved in many ways in cell proliferation, differentiation, glucose and lipid metabolism

Hypoxia modulation of peroxisome proliferator-activated receptors (PPARs) in human glioblastoma stem cells. Implications for therapy

Gliobastoma (GB), the most common adult brain tumor, infiltrates normal brain area rendering impossible the complete surgical resection, resulting in a poor median survival (14-15 months), despite the aggressive multimodality treatments post-surgery, such as radiation and chemo-therapy. GB is characterized by hypoxic and necrotic regions due to a poorly organized tumor vascularization, leading to inadequate blood supply and consequently to hypoxic and necrotic areas. We have previously shown that, under hypoxia GB primary cells increased the expression of stemness markers as well as the expression of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and also the crucial role played by PPARs in mouse neural stem cells maintenance and differentiation. Due to the importance of lipid signaling in cell proliferation and differentiation, in this work, we analyzed the expression of PPARs in GB neurospheres both in normoxic and hypoxic conditions. The results obtained suggest a differential regulation of the three PPARs by hypoxia, thus indicating a possible therapeutic strategy to counteract GB recurrencies. J. Cell. Biochem. 113: 3342-3352, 2012. © 2012 Wiley Periodicals, Inc

Hypoxia modulation of Peroxisome-proliferator-activated receptors (PPARs) in human glioblastoma stem cells. Implications for therapy

"Gliobastoma, the most common adult brain tumor, infiltrates normal brain area rendering impossible the complete surgical resection, resulting in a poor median survival (14-15 months), despite the aggressive multimodality treatments post-surgery, such as radiation, and chemo-therapy. GB is characterized by hypoxic and necrotic regions due to a poorly organized tumour vascularisation, leading to inadequate blood supply and consequently to hypoxic and necrotic areas. We have previously shown that, under hypoxia GB primary cells increased the expression of stemness markers as well as the expression of the nuclear receptor PPARα and also the crucial role played by PPARs in mouse neural stem cells maintenance and differentiation. Due to the importance of lipid signaling in cell proliferation and differentiation, in this work we analyzed the expression of PPARs in GB neurospheres both in normoxic and hypoxic conditions. The results obtained suggest a differential regulation of the three PPARs by hypoxia, thus indicating a possible therapeutic strategy to counteract GB recurrencies

Roles of PPAR transcription factors in the energetic metabolic switch occurring during adult neurogenesis

PPARs are a class of ligand-activated transcription factors belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids and vitamin D that control the expression of a large number of genes involved in lipid and carbohydrate metabolism and in the regulation of cell proliferation, differentiation and death. The role of PPARs in the CNS has been primarily associated with lipid and glucose metabolism; however, these receptors are also implicated in neural cell differentiation and death, as well as neuronal maturation. Although it has been demonstrated that PPARs play important roles in determining NSCs fate, less is known about their function in regulating NSCs metabolism during differentiation. In order to identify the metabolic events, controlled by PPARs, occurring during neuronal precursor differentiation, the glucose and lipid metabolism was followed in a recognized model of neuronal differentiation in vitro, the SH-SY5Y neuroblastoma cell line. Moreover, PPARs distribution were also followed in situ in adult mouse brains. The concept of adult neurogenesis becomes relevant especially in view of those disorders in which a loss of neurons is described, such as Alzheimer disease, Parkinson disease, brain injuries and other neurological disorders. Elucidating the crucial steps in energetic metabolism and the involvement of PPARγ in NSC neuronal fate (lineage) may be useful for the future design of preventive and/or therapeutic interventions

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 a isotype, have been involved in the control of energetic metabolism. Herein, we characterized patient-derived GB neurospheres focusing on their energetic metabolism and PPARa expression. Moreover, we used a specific PPARa 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 PPARa antagonist GW6471 resulted in decreased cell proliferation and neurospheres formation. Therefore, PPARa 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, PPARa increase/PPARα 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

Roles of PPAR transcription factors in the energetic metabolic switch occurring during adult neurogenesis

PPARs are a class of ligand-activated transcription factors belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids and vitamin D that control the expression of a large number of genes involved in lipid and carbohydrate metabolism and in the regulation of cell proliferation, differentiation and death. The role of PPARs in the CNS has been primarily associated with lipid and glucose metabolism; however, these receptors are also implicated in neural cell differentiation and death, as well as neuronal maturation. Although it has been demonstrated that PPARs play important roles in determining NSCs fate, less is known about their function in regulating NSCs metabolism during differentiation. In order to identify the metabolic events, controlled by PPARs, occurring during neuronal precursor differentiation, the glucose and lipid metabolism was followed in a recognized model of neuronal differentiation in vitro, the SH-SY5Y neuroblastoma cell line. Moreover, PPARs distribution were also followed in situ in adult mouse brains. The concept of adult neurogenesis becomes relevant especially in view of those disorders in which a loss of neurons is described, such as Alzheimer disease, Parkinson disease, brain injuries and other neurological disorders. Elucidating the crucial steps in energetic metabolism and the involvement of PPARγ in NSC neuronal fate (lineage) may be useful for the future design of preventive and/or therapeutic interventions

Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease: possible role of 4-hydroxynonenal (4-HNE)

Aging and many neurological disorders, such as AD, are linked to oxidative stress, which is considered the common effector of the cascade of degenerative events. In this phenomenon, reactive oxygen species play a fundamental role in the oxidative decomposition of polyunsaturated fatty acids, resulting in the formation of a complex mixture of aldehydic end products, such as malondialdehyde, 4-hydroxynonenal, and other alkenals. Interestingly, 4-HNE has been indicated as an intracellular agonist of peroxisome proliferator-activated receptor β/δ. In this study, we examined, at early and advanced AD stages (3, 9, and 18 months), the pattern of 4-HNE and its catabolic enzyme glutathione S-transferase P1 in relation to the expression of PPARβ/δ, BDNF signaling, as mRNA and protein, as well as on their pathological forms (i.e., precursors or truncated forms). The data obtained indicate a novel detrimental age-dependent role of PPAR β/δ in AD by increasing pro-BDNF and decreasing BDNF/TrkB survival pathways, thus pointing toward the possibility that a specific PPARβ/δ antagonist may be used to counteract the disease progression