VDAC1 offers a target for GBM treatment, allowing for attacks on the interplay between metabolism and oncogenic signaling networks, leading to tumor cell differentiation into neuron- and astrocyte-like cells. Simultaneously attacking all of these processes, VDAC1 depletion overcame GBM heterogeneity and can replace several anticancer drugs that separately target angiogenesis, proliferation, or metabolism.

The voltage-dependent anion channel 1 (VDAC1), found in the mitochondrial outer membrane, forms the main interface between mitochondrial and cellular metabolisms, mediates the passage of a variety of molecules across the mitochondrial outer membrane, and is central to mitochondria-mediated apoptosis. VDAC1 is overexpressed in post-mortem brains of Alzheimer disease (AD) patients. The development and progress of AD are associated with mitochondrial dysfunction resulting from the cytotoxic effects of accumulated amyloid ␤ (A␤). In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in A␤ cell penetration and cell death induction. A␤ directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated A␤ interacted with bilayer-reconstituted VDAC1 and increased its conductance ϳ2-fold. Incubation of cells with A␤ resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented A␤ cellular entry and A␤-induced mitochondria-mediated apoptosis. Likewise, silencing VDAC1 expression by specific siRNA prevented A␤ entry into the cytosol as well as A␤-induced toxicity. Finally, the mode of A␤-mediated action involves detachment of mitochondria-bound hexokinase, induction of VDAC1 oligomerization, and cytochrome c release, a sequence of events leading to apoptosis. As such, we suggest that A␤-mediated toxicity involves mitochondrial and plasma membrane VDAC1, leading to mitochondrial dysfunction and apoptosis induction. The VDAC1-N-Ter peptide targeting A␤ cytotoxicity is thus a potential new therapeutic strategy for AD treatment. Alzheimer disease (AD)3 pathology is characterized by cognitive decline, brain synaptic dysfunction, inflammatory responses, and mitochondrial dysfunction (1). The aggregation of the amyloid ␤ peptide (A␤) is proposed to play a key role in AD pathogenesis (2). A␤ is the post-proteolytic product of sequential cleavages of amyloid precursor protein by ␤-secretase and ␥-secretase. The commonly used 42-amino acid-long A␤ (A␤42) self-aggregates into oligomers, with larger aggregates forming A␤ plaques. However, soluble A␤ oligomers were proposed to be the cytotoxic form of the protein, acting extraor/and intracellularly (3).The severity of dementia and brain hypometabolism has been previously shown to be tightly linked (4), with brain hypometabolism preceding clinical signs of AD. This is directly associated with mitochondrial dysfunction being an early event in AD pathogenesis, as reflected in reduced metabolism, disruption of Ca 2ϩ homeostasis, increased free radical production, and lipid peroxidation (5-9). A␤ also affects mitochondrial respiration (10) and activates cytochrome c release, resulting in apoptosis (11). Importantly, A␤ does not cause toxicity in cells depleted of mitochondria (12). Finally, the mitochondrial protein, the voltage-dependent anion channel (VDAC), was shown to participate...

Vulval development in Caenorhabditis elegans serves as an excellent model to examine the crosstalk between different conserved signaling pathways that are deregulated in human cancer. The concerted action of the RAS/MAPK, NOTCH, and WNT pathways determines an invariant pattern of cell fates in three vulval precursor cells. We have discovered a novel form of crosstalk between components of the Insulin and the RAS/MAPK pathways. The insulin receptor DAF-2 stimulates, while DAF-18 PTEN inhibits, RAS/MAPK signaling in the vulval precursor cells. Surprisingly, the inhibitory activity of DAF-18 PTEN on the RAS/MAPK pathway is partially independent of its PIP3 lipid phosphatase activity and does not involve further downstream components of the insulin pathway, such as AKT and DAF-16 FOXO. Genetic and biochemical analyses indicate that DAF-18 negatively regulates vulval induction by inhibiting MAPK activation. Thus, mutations in the PTEN tumor suppressor gene may result in the simultaneous hyper-activation of two oncogenic signaling pathways.

Oxidative stress leads to the degeneration of retinal pigment epithelial (RPE) and photoreceptor cells. We evaluated the potential of adipose-derived mesenchymal stem cells (ASCs) as a therapeutic tool by studying the migration capacity of ASCs in vitro and their protective effect against RPE cell death under oxidative stress in vitro and in vivo. ASCs exhibited enhanced migration when exposed to conditioned medium of oxidative stressed RPE cells obtained by hydrogen peroxide. Migration-related axis SDF-1/CXCR4 was studied, and upregulation of SDF-1 in stressed RPE and of CXCR4 in ASCs was detected. Moreover, ASCs' conditioned medium prevented H2O2-induced cell death of RPE cells. Early passage ASCs had high expression level of HGF, low VEGF levels, and unmodulated IL-1β levels, compared to late passage ASCs. Thus, early passage ASCs show the potential to migrate towards damaged RPE cells and protect them in a paracrine manner from cell death induced by oxidative stress. In vivo, mice received systemic injection of NaIO3, and 72 h later, ASCs were transplanted in the subretinal space. Seven days after ASC transplantation, the eyes were enucleated fixed and frozen for immunohistochemical analysis. Under such conditions, ASC-treated mice showed preservation of nuclear layers in the outer nuclear layer and stronger staining of RPE and photoreceptor layer, compared to PBS-treated mice. Taken together, our results indicate that ASCs are able to home in on damaged RPE cells and protect against damage to the RPE and PR layers caused by oxidative stress. These data imply the potential that ASCs have in regenerating RPE under oxidative stress, providing the basis for a therapeutic approach to retinal degeneration diseases related to oxidative stress that could help save the eyesight of millions of people worldwide.