Neurostatin blocks glioma cell cycle progression by inhibiting EGFR activation.
The high frequency and malignancy of human glioblastomas has stimulated the search for potential therapeutic approaches. The control of the glioma cell proliferation in response to mitogenic signals is one of the most promising antitumoral strategies, and the main target of several therapies. Neurostatin, an O-acetylated derivative of the ganglioside GD1b, has potent antiproliferative activity over the in vitro and in vivo growth of glioma cells. The mechanism of its antitumoral action is the focus of the present study. Using a combined in vitro-in vivo approach, we observed that neurostatin arrested glioma proliferation by inhibiting the expression of cell cycle promoters (i.e. cyclins and CDKs) and promoting the expression of cell cycle inhibitors (i.e. p21 and p27). Neurostatin inhibits epidermal growth factor receptor (EGFR) signaling pathways, blocking the activation of the main promitogenic MAPKs and PI3K pathways. Neurostatin action not only interferes in the cell cycle progression, but also in the protection from apoptosis, and the generation of angiogenic and invasive responses. The antitumoral actions described here point to neurostatin as a novel and promising chemotherapeutic agent for glioma treatment.
Valle-Argos
Beatriz
B
Neural Plasticity Group, Functional and Systems Neurobiology Department, Cajal Institute, CSIC, 28002 Madrid, Spain.
Gómez-Nicola
Diego
D
Nieto-Sampedro
Manuel
M
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D006028:Glycosphingolipids / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006028:Glycosphingolipids; C116059:neurostatin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors; D018844:Cyclin-Dependent Kinases