Coexpression of TRPML1 and TRPML2 Mucolipin Channels Affects the Survival of Glioblastoma Patients

Abstract

Among brain cancers, glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high cell heterogeneity, which can be linked to its high malignancy. We have previously demonstrated that TRPML1 channels affect the OS of GBM patients. Herein, by RT-PCR, FACS and Western blot, we demonstrated that TRPML1 and TRPML2 channels are differently expressed in GBM patients and cell lines. Moreover, these channels partially colocalized in ER and lysosomal compartments in GBM cell lines, as evaluated by confocal analysis. Interestingly, the silencing of TRPML1 or TRPML2 by RNA interference results in the decrease in the other receptor at protein level. Moreover, the double knockdown of TRPML1 and TRPML2 leads to increased GBM cell survival with respect to single-channel-silenced cells, and improves migration and invasion ability of U251 cells. Finally, the Kaplan–Meier survival analysis demonstrated that patients with high TRPML2 expression in absence of TRPML1 expression strongly correlates with short OS, whereas high TRPML1 associated with low TRPML2 mRNA expression correlates with longer OS in GBM patients. The worst OS in GBM patients is associated with the loss of both TRPML1 and TRPML2 channels.

TRPML2 Mucolipin Channels Drive the Response of Glioma Stem Cells to Temozolomide and Affect the Overall Survival in Glioblastoma Patients

“…In addition, an increased invasion capability, epithelial–mesenchymal transition markers expression, and sensitivity to doxorubicin in silenced TRPML2 and a shorter OS in TRPML2 overexpressing GBM patients was reported [ 19 ]. Finally, overexpression of TRPML2 as well as the complete loss of this channel have been associated with worse OS and prognosis, whereas lower TRPML2 expression shows a protective effect in GBM patients [ 18 , 20 ]. In agreement, the Chinese Glioma Genome Atlas (CGGA) database reveals high TRPML2 expression in high-grade GBM, which correlates with shorter OS and worse prognosis, whereas favorable DFS is associated with lower levels of TRPML2; moreover, high TRPML2 levels are associated with 1p/19q non-codeletion and IDH-wild type status [ 21 ].…”

Endolysosomal transient receptor potential mucolipins and two-pore channels: implications for cancer immunity

“…Also, it has been recognized that TRPML2 plays an important role in cancer development and therapy. The expression of TRPML2 in cancer tissue has been connected to higher proliferation rates and impaired apoptosis, whilst overall survival of patients negatively correlates with TRPML2 expression levels (78)(79)(80).…”