Chemotherapeutic induction of mitochondrial oxidative stress activates GSK-3α/β and Bax, leading to permeability transition pore opening and tumor cell death

Abstract

Survival of tumor cells is favored by mitochondrial changes that make death induction more difficult in a variety of stress conditions, such as exposure to chemotherapeutics. These changes are not fully characterized in tumor mitochondria, and include unbalance of the redox equilibrium, inhibition of permeability transition pore (PTP) opening through kinase signaling pathways and modulation of members of the Bcl-2 protein family. Here we show that a novel chemotherapeutic, the Gold(III)-dithiocarbamato complex AUL12, induces oxidative stress and tumor cell death both favoring PTP opening and activating the pro-apoptotic protein Bax of the Bcl-2 family. AUL12 inhibits the respiratory complex I and causes a rapid burst of mitochondrial superoxide levels, leading to activation of the mitochondrial fraction of GSK-3α/β and to the ensuing phosphorylation of the mitochondrial chaperone cyclophilin D, which in turn facilitates PTP opening. In addition, following AUL12 treatment, Bax interacts with active GSK-3α/β and translocates onto mitochondria, where it contributes to PTP induction and tumor cell death. These findings provide evidence that targeting the redox equilibrium maintained by mitochondria in tumor cells allows to hit crucial mechanisms that shield neoplasms from the toxicity of many anti-tumor strategies, and identify AUL12 as a promising chemotherapeutic compound.

Translocation of Glycogen Synthase Kinase-3β (GSK-3β), a Trigger of Permeability Transition, Is Kinase Activity-dependent and Mediated by Interaction with Voltage-dependent Anion Channel 2 (VDAC2)

“…The findings are consistent with an earlier finding by King et al (32) that transfection of unregulated GSK-3␤ fused to an MTS of subunit VIII of cytochrome oxidase significantly increased ROS production in SH-SY5Y cells. An association between mitochondrial translocation of GSK-3␤ and mPTP-mediated cell death has been observed in various cell and tissue preparations (33)(34)(35) and was also confirmed in this study (Figs. 1, 2, and 6).…”

How the Location of Superoxide Generation Influences the β-Cell Response to Nitric Oxide

“…This finding suggests that superoxide and peroxynitrite activate GSK3 through pathways independent of the unfolded protein response. Consistent with this interpretation, superoxide (44,45) and peroxynitrite (46) have been shown to induce GSK3 phosphorylation through a PI3K/Akt-dependent pathway. MAPK are differentially activated by ROS and RNS.…”

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

“…Glycogen synthase kinase-3 (GSK-3) is activated following nitrosylation [254] and by the presence of increased ROS generation in the cytosol and mitochondria [255,256]. This kinase is abundantly expressed in the brain and overexpression of this enzyme is implicated in neuronal apoptosis and neurodegeneration [256].…”