Mechanisms of malignancy in glioblastoma cells are linked to mitochondrial Ca2+ uniporter upregulation and higher intracellular Ca2+ levels

Abstract

Glioblastoma (GBM) is one of the most malignant brain tumours and, despite advances in treatment modalities, it remains largely incurable. Ca²⁺ regulation and dynamics play crucial roles in different aspects of cancer, but they have never been investigated in detail in GBM. Here, we report that spontaneous Ca²⁺ waves in GBM cells cause unusual intracellular Ca²⁺ ([Ca²⁺]_i) elevations (>1 μM), often propagating through tumour microtubes (TMs) connecting adjacent cells. This unusual [Ca²⁺]_i elevation is not associated with the induction of cell death and is concomitant with overexpression of mitochondrial Ca²⁺ uniporter (MCU). We show that MCU silencing decreases proliferation and alters [Ca²⁺]_i dynamics in U87 GBM cells, while MCU overexpression increases [Ca²⁺]_i elevation in human astrocytes (HAs). These results suggest that changes in the expression level of MCU, a protein involved in intracellular Ca²⁺ regulation, influences GBM cell proliferation, contributing to GBM malignancy.This article has an associated First Person interview with the first author of the paper.

Keywords: Ca2+ waves; Glioblastoma; MCU; Malignancy.