Oncotarget

Research Papers:

Overexpression of transient receptor potential mucolipin-2 ion channels in gliomas: role in tumor growth and progression

Maria Beatrice Morelli, Massimo Nabissi, Consuelo Amantini, Daniele Tomassoni, Francesco Rossi, Claudio Cardinali, Matteo Santoni, Antonietta Arcella, Maria Antonietta Oliva, Angela Santoni, Carlo Polidori, Maria Paola Mariani and Giorgio Santoni _

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Oncotarget. 2016; 7:43654-43668. https://doi.org/10.18632/oncotarget.9661

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Abstract

Maria Beatrice Morelli1,2, Massimo Nabissi1, Consuelo Amantini3, Daniele Tomassoni3, Francesco Rossi1, Claudio Cardinali1,2, Matteo Santoni4, Antonietta Arcella5, Maria Antonietta Oliva5, Angela Santoni2,5, Carlo Polidori1, Maria Paola Mariani6, Giorgio Santoni1

1School of Pharmacy, University of Camerino, Camerino, Italy

2Department of Molecular Medicine, Sapienza University, Rome, Italy

3School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy

4Department of Medical Oncology, Polytechnic University of Marche, Ancona, Italy

5I.N.M. Neuromed, Pozzilli, Isernia, Italy

6Anatomo-Pathology Operative Unit, AV3 Macerata, Italy

Correspondence to:

Giorgio Santoni, email: giorgio.santoni@unicam.it

Keywords: TRP channels, mucolipin-2, gliomas, proliferation, apoptosis

Received: March 09, 2016     Accepted: May 01, 2016     Published: May 27, 2016

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.


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