Transient Receptor Potential Mucolipin-1 Channels in Glioblastoma: Role in Patient’s Survival

Abstract

A link between mucolipin channels and tumors has been recently suggested. Herein, we aim to investigate the transient receptor potential mucolipin (TRPML)-1 relevance in glioblastoma. The expression of this channel was evaluated via qRT-PCR and immunohistochemistry in biopsies from 66 glioblastoma patients and two human glioblastoma cell lines and compared to normal human brain, astrocytes, and epileptic tissues. The subcellular distribution of TRPML-1 was examined via confocal microscopy in the glioma cell lines. Then, to assess the role of TRPML-1, cell viability assays have been conducted in T98 and U251 cell lines treated with the specific TRPML-1 agonist, MK6-83. We found that MK6-83 reduced cell viability and induced caspase-3-dependent apoptosis. Indeed, the TRPML-1 silencing or the blockage of TRPML-1 dependent [Ca2+]i release abrogated these effects. In addition, exposure of glioma cells to the reactive oxygen species (ROS) inducer, carbonyl cyanide m-chlorophenylhydrazone (CCCP), stimulated a TRPML-1-dependent autophagic cell death, as demonstrated by the ability of the autophagic inhibitor bafilomycin A, the TRPML-1 inhibitor sphingomyelin, and the TRPML-1 silencing to completely inhibit the CCCP-mediated effects. To test a possible correlation with patient’s survival, Kaplan–Meier, univariate, and multivariate analysis have been performed. Data showed that the loss/reduction of TRPML-1 mRNA expression strongly correlates with short survival in glioblastoma (GBM) patients, suggesting that the reduction of TRPML-1 expression represents a negative prognostic factor in GBM patients.

Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice

“…It is known that Ac deficiency may increase substrate lysosomal CER and even upstream sphingomyelin, but reduces lysosomal Sph or its metabolite, S1P. Some of them were recently shown to alter lysosomal TRPML1 channel activity 71 and Ca 2+ release regulating lysosome trafficking 33,72,73 . The present study tested the hypothesis that the role of Ac may be associated with lysosomal TRPML1-mediated Ca 2+ release.…”

<p>Comprehensive Transcriptomic Analysis and Experimental Validation Identify lncRNA HOXA-AS2/miR-184/COL6A2 as the Critical ceRNA Regulation Involved in Low-Grade Glioma Recurrence</p>

“…28 For example, the markedly enriched GO terms (MF) in recurrent GBMs were protein heterodimerization activity and structural constituent of ribosome in CGGA database and channel activity and passive transmembrane transporter activity in the TCGA database, although these GO terms have been reported to contribute to GBM progression. [28][29][30][31] Glioma stem cells play critical roles in glioblastoma multiforme chemotherapy resistance and recurrence, such as CD133 cells. 32 Glioma stem cells can self-renew and differentiate into other specific GBM subpopulations, which is involved in activation of Wnt/β-catenin pathway.…”

Ion channels as potential redox sensors in lysosomes

“…Besides LSDs, emerging evidence suggests that TRPML1 is also important for cancer cell survival [59][60][61]. Interestingly, the effect of TRPML1 activity modulation on cancer cell survival differs, possibly dependent on the type of cancers and stimuli.…”

“…Specifically, TRPML1 inhibition suppresses the growth of triple-negative breast cancers (TNBCs) [59] and reduces the proliferation of oncogenic HRAS-expressing cancer cells [61]. On the other hand, a very recent research reported that glioblastoma (GBM) patients survival are negatively correlated with TRPML1 expression level, while glioma cells are vulnerable to ROS when TRPML1 is activated [60].…”