Abstract
Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial malignancy, causing 3–4% of all cancer-related death [1,2,3]
Gamma Secretase Inhibitor (GSI) and AG490 were provided by Sigma Aldrich (Milan, Italy); human anti-β-Actin, anti-ObR, and anti-Ob antibodies from Santa Cruz Biotechnology (Santa Cruz, CA, USA); human anti-Janus-activated kinase (JAK)2, anti-signal transducer and activator of transcription 3 (STAT3), anti-pJAK2Tyr1007/1008, and anti-pSTAT3Tyr705 from Cell Signaling Technology (Beverly, MA, USA); and human anti-Prominin-1 (CD133) from Proteintech (Rosemont, IL, USA)
We found that tumor spheres from GBM cells exhibited increased levels of the leptin receptor and treatment with leptin induced an increase in the neurosphere forming efficiency and self-renewal capacity, in the clonogenic potential and stem cell frequency, along with an enrichment of the CD133+ cell population
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial malignancy, causing 3–4% of all cancer-related death [1,2,3]. The standard treatments for GBM include surgical resection in combination with radiotherapy and chemotherapy with Temozolomide [4]. Despite enormous efforts in multimodal treatment approaches, the prognosis of glioblastoma remains very poor, with a median overall survival of less than 15 months after diagnosis [5]. GBM is characterized by extensive phenotypic, morphological, and cellular heterogeneity that is thought to be maintained by a population of transformed stem-like cells referred to as glioma stem cells (GSCs). It has been reported that GSCs contribute to tumor initiation, invasion, recurrence, and resistance to therapy due to their self-renewal ability and multi-lineage differentiation potential [6,7]. The identification of novel molecular mechanisms that sustain the stem-like properties of glioblastoma cells will be important for therapeutic purpose
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