Abstract
Glioblastoma (GBM) is the most aggressive human brain tumor. The high growth potential and decreased susceptibility to apoptosis of the glioma cells is mainly dependent on genetic amplifications or mutations of oncogenic or pro-apoptotic genes, respectively. We have previously shown that the activation of the M2 acetylcholine muscarinic receptors inhibited cell proliferation and induced apoptosis in two GBM cell lines and cancer stem cells. The aim of this study was to delve into the molecular mechanisms underlying the M2-mediated cell proliferation arrest. Exploiting U87MG and U251MG cell lines as model systems, we evaluated the ability of M2 receptors to interfere with Notch-1 and EGFR pathways, whose activation promotes GBM proliferation. We demonstrated that the activation of M2 receptors, by agonist treatment, counteracted Notch and EGFR signaling, through different regulatory cascades depending, at least in part, on p53 status. Only in U87MG cells, which mimic p53-wild type GBMs, did M2 activation trigger a molecular circuitry involving p53, Notch-1, and the tumor suppressor mir-34a-5p. This regulatory module negatively controls Notch-1, which affects cell proliferation mainly through the Notch-1/EGFR axis. Our data highlighted, for the first time, a molecular circuitry that is deregulated in the p53 wild type GBM, based on the cross-talk between M2 receptor and the Notch-1/EGFR pathways, mediated by mir-34a-5p.
Highlights
Glioblastoma multiforme (GBM) is the most common primary brain tumor and is considered the most aggressive and malignant human cancer [1]
Exploiting U87MG and U251MG cell lines as model systems, we evaluated the ability of M2 receptors to interfere with Notch-1 and epidermal growth factor receptor (EGFR) pathways, whose activation promotes GBM proliferation
While in vitro and in vivo studies have indicated that the activation of M3 receptors enhanced tumor cell proliferation [14,15,16], we have demonstrated that the activation of M2 receptors, by arecaidine propargyl ester (APE) was able to arrest cell proliferation in GBM cell lines (U87MG and U251MG) and GB cancer stem cells [17,18,19]
Summary
Glioblastoma multiforme (GBM) is the most common primary brain tumor and is considered the most aggressive and malignant human cancer [1]. GBM is extremely invasive and shows high ability to infiltrate through the brain parenchima. This tumor shows high chemo- and radio-resistance, making the identification of new molecular targets for cell growth and survival relevant for GBM therapy. The most frequent signaling pathways dysregulated in GBMs are Notch and epidermal growth factor receptor (EGFR) [2]. The Notch proteins (Notch 1–4) are transmembrane receptors produced as long polypeptides that are activated by several proteolytic cleavages. Aberrant expression of proteins involved in the Notch cascade may play relevant roles in glioma development. It has been demonstrated that the knockdown of Notch-1 or the inhibition of its activity in glioma cell lines led to cell cycle arrest, accompanied by decreased cell proliferation and increased cell death [6,7]
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