title: Overexpression of transient receptor potential mucolipin-2 ion channels in gliomas: role in tumor growth and progression.
abstract: The Transient Receptor Potential (TRP) superfamily consists of cation-selective and non-selective ion channels playing an important role both in sensory physiology and in physiopathology in several complex diseases including cancers. Among TRP family, the mucolipin (TRPML1, -2, and -3) channels represent a distinct subfamily of endosome/lysosome Ca2+ channel proteins. Loss-of-function mutations in human TRPML-1 gene cause a neurodegenerative disease, Mucolipidosis Type IV, whereas at present no pathology has been associated to human TRPML-2 channels. Herein we found that human TRPML-2 is expressed both in normal astrocytes and neural stem/progenitor cells. By quantitative RT-PCR, western blot, cytofluorimetric and immunohistochemistry analysis we also demonstrated that TRPML-2 mRNA and protein are expressed at different levels in glioma tissues and high-grade glioma cell lines of astrocytic origin. TRPML-2 mRNA and protein levels increased with the pathological grade, starting from pylocitic astrocytoma (grade I) to glioblastoma (grade IV). Moreover, by RNA interference, we demonstrated a role played by TRPML-2 in survival and proliferation of glioma cell lines. In fact, knock-down of TRPML-2 inhibited the viability, altered the cell cycle, reduced the proliferation and induced apoptotic cell death in glioma cell lines. The DNA damage and apoptosis induced by TRPML-2 loss increased Ser139 H2AX phosphorylation and induced caspase-3 activation; furthermore, knock-down of TRPML-2 in T98 and U251 glioma cell lines completely abrogated Akt and Erk1/2 phosphorylation, as compared to untreated cells. Overall, the high TRPML-2 expression in glioma cells resulted in increased survival and proliferation signaling, suggesting a pro-tumorigenic role played by TRPML-2 in glioma progression.
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.|Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Morelli
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Nabissi
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Tomassoni
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.|Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cardinali
authors.affiliation: Department of Medical Oncology, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Santoni
authors.affiliation: I.N.M. Neuromed, Pozzilli, Isernia, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Arcella
authors.affiliation: I.N.M. Neuromed, Pozzilli, Isernia, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Oliva
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.|I.N.M. Neuromed, Pozzilli, Isernia, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Polidori
authors.affiliation: Anatomo-Pathology Operative Unit, AV3 Macerata, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Mariani
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
mesh_terms: D017209:Apoptosis; D001706:Biopsy; D001932:Brain Neoplasms / Q000473:pathology*; D063646:Carcinogenesis / Q000473:pathology; D053148:Caspase 3; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D005910:Glioma / Q000473:pathology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D060787:Neoplasm Grading; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: C468783:H2AX protein, human; D006657:Histones; C510641:Mcoln2 protein, human; D034741:RNA, Small Interfering; D050051:Transient Receptor Potential Channels; D051058:Oncogene Protein v-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: TRP channels; apoptosis; gliomas; mucolipin-2; proliferation