Intracellular Redox-Balance Involvement in Temozolomide Resistance-Related Molecular Mechanisms in Glioblastoma

Abstract

Glioblastoma (GBM) is the most common astrocytic-derived brain tumor in adults, characterized by a poor prognosis mainly due to the resistance to the available therapy. The study of mitochondria-derived oxidative stress, and of the biological events that orbit around it, might help in the comprehension of the molecular mechanisms at the base of GBM responsiveness to Temozolomide (TMZ). Sensitive and resistant GBM cells were used to test the role of mitochondrial ROS release in TMZ-resistance. Chaperone-Mediated Autophagy (CMA) activation in relation to reactive oxygen species (ROS) release has been measured by monitoring the expression of specific genes. Treatments with H2O2 were used to test their potential in reverting resistance. Fluctuations of cytoplasmic ROS levels were accountable for CMA induction and cytotoxic effects observed in TMZ sensitive cells after treatment. On the other hand, in resistant cells, TMZ failed in producing an increase in cytoplasmic ROS levels and CMA activation, preventing GBM cell toxicity. By increasing oxidative stress, CMA activation was recovered, as also cell cytotoxicity, especially in combination with TMZ treatment. Herein, for the first time, it is shown the relation between mitochondrial ROS release, CMA activation and TMZ-responsiveness in GBM.

SIRT3 deficiency delays diabetic skin wound healing via oxidative stress and necroptosis enhancement

“…In our experiment, high‐glucose stimulation attenuated proliferation and migration while enhanced oxidative stress in mice skin fibroblasts, which was most serious in that from SIRT3 knockout mice. On the other hand, mitochondria provided a place for ROS generation, and the structural destruction or functional dysfunction was prone to destroy the homeostasis to induce oxidative damage . Indeed, we confirmed that SIRT3 KO mice did have above abnormal manifestations on ultrastructure and mitochondrial membrane potential.…”

A Potential Mechanism of Temozolomide Resistance in Glioma–Ferroptosis

“…The iron-dependent accumulation of ROS is the characteristic of ferroptosis (54). Furthermore, ROS-induced lipid peroxidation is not only a critical role in ferroptosis, but also affects the apoptosis, autophagy, and TMZ resistance in glioma cells (53,55,56). Biochemically, the intracellular GSH depletion, which inhibits anti-peroxidant defense and iron, involved in the Fenton reaction would result to the accumulation of lipid peroxidation, promoting ferroptosis.…”

Discovery of LAMP-2A as Potential Biomarkers for Glioblastoma Development by Modulating Apoptosis through N-CoR Degradation

“…Recently published research data identi ed the contribution of GBM cells to the up-regulation of LAMP-2A and CMA activity in pericytes through cell-cell interaction, which ablated pericytes antitumor immune function essential for GBM survival [12]. However, in terms of temozolomide (TMZ) treatment, in vitro studies showed CMA mediated downregulation of HIF-1α improved the response of TMZ-resistant GBM cells, and blocking CMA induced resistance of TMZ-sensitive cells [13,14]. While in breast cancer inhibiting CMA by downregulating LAMP-2A could augment sensitivity to doxorubicin [11].…”

“…Recent published papers identi ed the role of LAMP-2A in modulating GBM-pericytes interaction and temozolomide resistance via CMA [12][13][14]. However, the intrinsic function of LAMP-2A and CMA in GBM development and progression has been poorly elucidated.…”