GILZ overexpression attenuates endoplasmic reticulum stress-mediated cell death via the activation of mitochondrial oxidative phosphorylation.

The Glucocorticoïd-induced leucine zipper (GILZ) protein has profound anti-inflammatory activities in haematopoietic cells. GILZ regulates numerous signal transduction pathways involved in proliferation and survival of normal and neoplastic cells. Here, we have demonstrated the potential of GILZ in alleviating apoptosis induced by ER stress inducers. Whereas the glucocorticoid, dexamethasone, protects from tunicamycin-induced cell death, silencing endogeneous GILZ in dexamethasone-treated cancer cells alter the capacity of glucocorticoids to protect from tunicamycin-mediated apoptosis. Under ER stress conditions, overexpression of GILZ significantly reduced activation of mitochondrial pathway of apoptosis by maintaining Bcl-xl level. GILZ protein affects the UPR signaling shifting the balance towards pro-survival signals as judged by down-regulation of CHOP, ATF4, XBP1s mRNA and increase in GRP78 protein level. Interestingly, GILZ sustains high mitochondrial OXPHOS during ER stress and cytoprotection mediated by GILZ is abolished in cells depleted of mitochondrial DNA, which are OXPHOS-deficient. These findings reveal a new role of GILZ, which acts as a cytoprotector against ER stress through a pathway involving mitochondrial OXPHOS.

Oxidative potential of aerosolized metalworking fluids in occupational settings.

The oxidative potential (OP) measures the ability of pollutants to oxidize a chemical/biological probe. Such assays are starting to gain acceptance as integrative exposure metrics associated with inflammatory-based pathologies. Diseases such as asthma, rhinitis or cancers are reported for workers exposed to oil mist, which are aerosols of metal working fluids (MWF) emitted during the machining of metals. Measuring oil mist in the air is challenging, and exposures are often quantified as the mass fraction, which does not account for exposures to the gaseous fraction. Consequently, exposures are underestimated and furthermore, the hazardous property of oil mist is not assessed. We postulate that it is more relevant to assess occupational exposures to the hazardous fractions of oil mist by measuring OP than by simply measuring mass. We characterized exposures to straight and water-based MWF among workers in the French and Swiss mechanical industry using standard methods for oil mist and the ferrous orange xylenol assay for OP assessment (OPFOX). Considering the particulate fraction, the water-based MWF presented the greatest OPFOX. The OP was associated with organic carbon and iron content. The gaseous fraction of the oil mist presented also an important redox activity, particularly in workshops where straight oils were used. The hexanal concentration was associated with this OPFOX. The OPFOX measurement is thus integrative of multiple parameters, and bring complementary information when assessing MWF exposures. Our results highlight that OPFOX account for MWF type and could be an interesting parameter to characterize such exposure.

[The revolution of immuno-oncology therapy: specificities for the physicians]. / L'immunothérapie, une révolution en oncologie - Spécificités de l'immunothérapie pour le clinicien.

The use of immune checkpoint inhibitors has revolutionized the treatment and prognosis of many cancer patients. Associated with the raise of these new treatments, new side effects have been observed, requiring specific management. In addition, the tumor evolution and its monitoring under immunotherapy differ from conventional treatments, and require an adaptation of the radiological criteria for tumor lesions monitoring. Many other therapeutic targets exist and could potentially be associated with immune checkpoint inhibitors. Many challenges still need to be overcome in order to better understand and optimize the use of these new molecules.

TITLE: L'immunothérapie, une révolution en oncologie - Spécificités de l'immunothérapie pour le clinicien. ABSTRACT: L'utilisation des inhibiteurs de points de contrôle immunitaire a révolutionné la prise en charge et le pronostic de nombreux patients atteints de cancer. L'arrivée de ces nouveaux traitements s'est accompagnée de la découverte de nouveaux effets indésirables nécessitant des prises en charge spécifiques. De plus, l'évolution tumorale et sa surveillance sous immunothérapie est différente de celle sous traitements classiques, et ont nécessité une adaptation des critères radiologiques et du suivi des lésions tumorales. De nombreuses autres cibles thérapeutiques existent, et pourraient potentiellement être associées aux inhibiteurs des points de contrôle immunitaires. Il existe donc encore de nombreux défis à relever afin de mieux comprendre et d'optimiser l'utilisation de ces nouvelles molécules.

[The revolution of immuno-oncology therapy: review of immune checkpoint inhibitors efficacy]. / L'immunothérapie, une révolution en oncologie - Revue de l'efficacité des inhibiteurs de points de contrôle immunitaire.

Immunotherapy represents a major paradigm shift, as the treatment no longer directly targets tumor cells, but the patient him/herself, in order to restore an effective anti-tumor immunity. This article illustrates the growing place of immune checkpoint inhibitors in the available therapeutic options, by focusing on two cancers with poor outcome: metastatic melanoma and metastatic non-small cell lung cancer (NSCLC), against which Immune checkpoints inhibitors now occupy a central place. Many questions remain unresolved, such as the search for markers predicting a good response to treatment, which would allow the selection of responder patients. Numerous trials are in progress, evaluating the relevance of these new molecules at earlier stages of the disease (adjuvant and neoadjuvant strategies) and their place in combined strategies (associated with chemotherapy, targeted therapies, and other types of immunotherapy).

TITLE: L'immunothérapie, une révolution en oncologie - Revue de l'efficacité des inhibiteurs de points de contrôle immunitaire. ABSTRACT: L'immunothérapie anti-tumorale représente un changement de paradigme majeur où le traitement ne cible plus directement les cellules tumorales mais le patient lui-même, afin de restaurer une immunité anti-tumorale efficace. Parmi les différentes immunothérapies, les inhibiteurs de points de contrôle immunitaire occupent une place centrale dans les options thérapeutiques disponibles de deux cancers au pronostic particulièrement péjoratif: le mélanome malin et le cancer pulmonaire non à petites cellules métastatique. De nombreux essais sont en cours, évaluant la pertinence de ces molécules à des stades plus précoces de la maladie (stratégies adjuvantes ou d'induction) et leur place dans des stratégies combinatoires (associés à de la chimiothérapie, des thérapies ciblées, d'autres types d'immunothérapies, etc.).

Metabolic rewiring in cancer cells overexpressing the glucocorticoid-induced leucine zipper protein (GILZ): Activation of mitochondrial oxidative phosphorylation and sensitization to oxidative cell death induced by mitochondrial targeted drugs.

Cancer cell metabolism is largely controlled by oncogenic signals and nutrient availability. Here, we highlighted that the glucocorticoid-induced leucine zipper (GILZ), an intracellular protein influencing many signaling pathways, reprograms cancer cell metabolism to promote proliferation. We provided evidence that GILZ overexpression induced a significant increase of mitochondrial oxidative phosphorylation as evidenced by the augmentation in basal respiration, ATP-linked respiration as well as respiratory capacity. Pharmacological inhibition of glucose, glutamine and fatty acid oxidation reduced the activation of GILZ-induced mitochondrial oxidative phosphorylation. At glycolysis level, GILZ-overexpressing cells enhanced the expression of glucose transporters in their plasmatic membrane and showed higher glycolytic reserve. 1H NMR metabolites quantification showed an up-regulation of amino acid biosynthesis. The GILZ-induced metabolic reprograming is present in various cancer cell lines regardless of their driver mutations status and is associated with higher proliferation rates persisting under metabolic stress conditions. Interestingly, high levels of OXPHOS made GILZ-overexpressing cells vulnerable to cell death induced by mitochondrial pro-oxidants. Altogether, these data indicate that GILZ reprograms cancer metabolism towards mitochondrial OXPHOS and sensitizes cancer cells to mitochondria-targeted drugs with pro-oxidant activities.

Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors.

Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER-mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.

Mitochondrial oxidative stress is the Achille's heel of melanoma cells resistant to Braf-mutant inhibitor.

Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy. Unfortunately, acquired resistance, which unavoidably occurs, represents one major limitation to clinical responses. Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1α. However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown. We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients. Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1α. Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib. Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol. Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition.