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.

HRAS‐driven cancer cells are vulnerable to TRPML1 inhibition

“…B-D Bar graph showing the relative levels of total or free/total cholesterol in HN31 cell extracts exposed to the indicated perturbagens (B-C), or larval brain extracts from animals This study adds to the growing body of knowledge regarding endolysosomal proteins in oncogenesis. A recent study reported that increased expression of a TRPML1 paralog, TRPML2, supports tumorigenesis in glioma [64]. We also found that the gene encoding TRPML2 is slightly elevated in HN31 cells and plays a minor role in cancer cell proliferation.…”

Involvement of the TRPML Mucolipin Channels in Viral Infections and Anti-viral Innate Immune Responses

“…TRPML2 mRNA is mainly detected in lymphocytes and other cells of the immune system (19). In addition, TRPML2 was found to be overexpressed in aggressive human glioblastoma (20). TRPML3 is mainly expressed in cochlear and vestibular sensory hair cells and melanocytes (21).…”

The Role of TRP Channels in the Metastatic Cascade

“…To the best knowledge of the authors, there is no direct evidence linking TRPML channels to cancer invasiveness and metastasis, although the channel has an altered expression in glioblastoma and breast cancer [ 102 ]. This might be due to the subcellular localization of TRPML channels, as they are primarily expressed in endosomes and lysosomes, and they are not as easily investigated as channels residing in the plasma membrane.…”

“…This might be due to the subcellular localization of TRPML channels, as they are primarily expressed in endosomes and lysosomes, and they are not as easily investigated as channels residing in the plasma membrane. Moreover, the literature focuses on the effect of TRPML on autophagy and autophagy-related signaling that is independent of the calcium permeability of the channel [ 102 ]. However, these channels are key regulators of lysosomal calcium release, and moreover, their expression is linked to ERK1/2 and Akt signaling which plays a role in cell migration.…”