Hypoxic Voltage-Dependent Anion Channel 1, VDAC1-ΔC, increases cancer cells metabolism and resistance to cell death in hypoxia by modulating the tubulin L. Fabbri, M. Dufies, D. Ambrosetti, M. Meyenberg, J. Contenti, F. Bost and N.M. Mazure INSERM U1065, Nice, France The Voltage-dependent anion channel 1 (VDAC1) is a mitochondrial porin of the outer membrane that mediates the flux of small ions, metabolites and ATP in and out from mitochondria and plays a major role in the regulation of cellular metabolism and apoptosis. Our previous findings pointed out a new post-translational modification of VDAC1, which was linked to an higher metabolic capacity and a greater resistance to cell death of cancer cells exposed to a long-term hypoxia (1% O2), a feature of locally advanced solid tumors (Brahimi-Horn et al., 2012). We identified the molecular mechanism behind the cleavage of VDAC1 that occurs not only in vitro but also in vivo in patients with lung cancer. In hypoxic cancer cells, this cleavage involves direct contact between mitochondria and endolysosomes and is mediated by a lysosomal peptidase named Legumain (Brahimi-Horn et al., 2015). Importantly, mitochondria of hypoxic cells, involved in this novel mechanism of microfusion with endolysosomes, were characterized by changes in the phenotype, from a tubular network to an enlarged morphology, as a result of mitochondrial hyperfusion. These findings reveal that this new form of VDAC1-C and this new mechanism of mitochondrial-endolysosomal microfusion confer cytoprotection to apoptotic death of cancer cells and represent an additional defense mechanism that cancer cells have developed to resist to chemotherapy. We generated a mutated form of the protein carrying mutations at the positions corresponding to the sites of cleavage in a RAS transformed mouse embryonic fibroblasts (MEFs) model knocked out for Vdac1 (MEF-RAS- Vdac1-/-). The impact of the overexpression of VDAC1 on resistance to chemotherapy has been assessed on different clones obtained from MEF-RAS- Vdac1-/-, overexpressing the WT form of VDAC1 or the mutated form of the protein. In hypoxia, cells harboring VDAC1-C present (i) enlarged mitochondria, (ii) are resistant to staurosporine (STS)- induced cell death and (iii) show an increase in cellular metabolism + OXPHOS in respect to the clones with the mutated form of VDAC1. Moreover, we showed that formation of VDAC1-C leads to the loss of one of the phosphorylated site that attracts tubulin into the pore, thus releasing the tubulin blockage and consequently increasing the mitochondria metabolism responsible for the resistance to cell death. By modulating the tubulin into the cell, hypoxic VDAC may modulate also other tubulin-dependent processes. These are currently studied. We are strongly convinced that VDAC1, at the center stage of both metabolism and cell death resistance, might represent such a novel and innovative therapeutic option.
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