Aerobic Cells Research Articles

Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10

BackgroundRadiotherapy resistance is a major obstacle in the treatment of oesophageal squamous cell carcinoma (OSCC). Hypoxia is a critical cause of radioresistance. However, the communication between hypoxic cells and aerobic cells via exosomes during the transfer of radiation resistance remains unclear.MethodsExo-miR-340-5p levels were analysed by RNA-seq and qRT-PCR. We co-cultured OSCC cells with isolated normoxic and hypoxic exosomes to study their impact on radiosensitivity. We used a specific exo-miR-340-5p mimic and knock-down retrovirus to explore the role of this miRNA in the transfer of radioresistance from hypoxic to normoxic cells. Dual-luciferase reporter and RIP assays were used to verify KLF10 as a putative target of miR-340-5p. Several in vitro assays were conducted and xenograft models were established to investigate the effect of exo-miR-340-5p on OSCC radiosensitivity. The plasma exo-miR-340-5p levels in OSCC patients were analysed to study the clinical value of this parameter.ResultsHypoxic exosomes alleviated radiation-induced apoptosis and accelerated DNA damage repair. miR-340-5p was highly expressed in hypoxic exosomes and was transferred into normoxic cells, where it induced radioresistance. Overexpression of miR-340-5p in normoxic OSCC cells mimicked the radioresistance of cells co-cultured with hypoxic exosomes. Knockdown of miR-340-5p in hypoxic exosomes reversed the radioresistance effect, indicating that exo-miR-340-5p is critical for hypoxic EV-transferred radioresistance. KLF10 was identified as the direct target of miR-340-5p. Moreover, metformin was found to increase the expression of KLF10 and enhance the radiosensitivity of OSCC. Higher levels of miR-340-5p in the plasma exosomes from OSCC patients are related to a poorer radiotherapy response and prognosis.ConclusionsHypoxic tumour cell-derived exosomal miR-340-5p confers radioresistance in OSCC by targeting KLF10/UVRAG, suggesting that miR-340-5p could be a potential biomarker and therapeutic target for the enhancement of radiosensitivity in OSCC. Metformin can increase KLF10 expression, which ameliorates the radioresistance induced by exo-miR-340-5p transfer. Therefore, metformin could be further investigated as a therapeutic option for the treatment of OSCC.

Dichloroacetate Radiosensitizes Hypoxic Breast Cancer Cells.

Mitochondrial metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways can potentially sensitize tumors with limited treatment options, such as triple-negative breast cancer (TNBC), to chemo- and/or radiotherapy. Dichloroacetate (DCA) is a specific inhibitor of the pyruvate dehydrogenase kinase (PDK), which leads to enhanced reactive oxygen species (ROS) production. ROS are the primary effector molecules of radiation and an increase hereof will enhance the radioresponse. In this study, we evaluated the effects of DCA and radiotherapy on two TNBC cell lines, namely EMT6 and 4T1, under aerobic and hypoxic conditions. As expected, DCA treatment decreased phosphorylated pyruvate dehydrogenase (PDH) and lowered both extracellular acidification rate (ECAR) and lactate production. Remarkably, DCA treatment led to a significant increase in ROS production (up to 15-fold) in hypoxic cancer cells but not in aerobic cells. Consistently, DCA radiosensitized hypoxic tumor cells and 3D spheroids while leaving the intrinsic radiosensitivity of the tumor cells unchanged. Our results suggest that although described as an oxidative phosphorylation (OXPHOS)-promoting drug, DCA can also increase hypoxic radioresponses. This study therefore paves the way for the targeting of mitochondrial metabolism of hypoxic cancer cells, in particular to combat radioresistance.

Effect of reoxygenation on hypofractionated radiotherapy of prostate cancer.

To assess the role of reoxygenation of hypoxic tumor cells in hypofractionated radiotherapy of prostate cancer. The considered radiobiological model is based on the assumption of two populations (compartments) of cells: oxygenated (aerobic) cells and hypoxic cells. After each fraction of radiation, some of the hypoxic cells reoxygenate while a fraction of initially aerobic cells becomes hypoxic. The kinetics of this process between successive treatments is described by coupled, first-order differential equations. To determine the effect of reoxygenation on cell kill in the treatment target, we utilize the linear-quadratic (LQ) model assuming different radiosensitivities for the aerobic and hypoxic cells. Analytical solutions for the number of surviving malignant cells are obtained for special cases of slow and fast reoxygenation. The radiobiological effect of reoxygenation for different fractionation regimens is also evaluated numerically. In this study, a radiobiological model for kinetics of reoxygenation in tumors is used to evaluate different fractionation schedules in radiotherapy of prostate cancer. The obtained results indicate that in the case of low alpha/beta ratio for malignant cells (e.g., =1.5Gy), treatment schedule with 4-10 fractions and dose per fraction >4-5Gy can result in increased cell kill in the treatment target at the same level of rectal toxicity as compared to conventional fractionation. The findings of this study also suggest that radiotherapy of the prostate with 1-3 fractions can be radiobiologically inferior to treatments with greater number of fractions.

Coupling Pyrite-Fenton Process with Aerobic Biodegradation for the Treatment of 2-Chlorophenol

This study investigates the performance of a sequential pyrite-Fenton and biological process for the treatment of 2-chlorophenol (2-CP) containing wastewater using pyrite-Fenton process as a pretreatment stage. Pyrite was tested as a catalyst material in Fenton reaction due to its low cost and high abundance in the environment. All experiments were run in batch mode. The biodegradation experiments were performed under aerobic conditions using glucose as the co-substrate with untreated or Fenton-pretreated 2-CP. Despite the 100% removal of 2-CP in batch pyrite-Fenton reactors, the total organic carbon (TOC) removal only approached 70%, implying the transformation of 2-CP into some chemically stable intermediate reaction by products during pyrite-Fenton oxidation. In systems with no pyrite-Fenton pretreatment, a combined effect of biotic and abiotic processes including biological degradation, sorption, and volatilization played a significant role on 2-CP removal. The pyrite-Fenton pretreatment of 2-CP significantly improved the performance of aerobic biological reactor relative to system with no pyrite-Fenton pretreatment by (1) reducing the toxicity of 2-CP on aerobic microbial cells and (2) enhancing cell growth. Overall, this study shows that pyrite-Fenton pretreatment coupled with aerobic biological degradation could provide a cost-effective solution for the treatment of wastewater containing low-biodegradable toxic compounds such as chlorophenols.

Antioxidant Potential of Ziziphora Clinopodioides Lam: A Narrative Review

Reactive oxygen species (ROS) are generated by many redox processes that normally occur in the metabolism of aerobic cells. They are highly reactive and harmful to normal cells. If not eliminated, they can damage important molecules, such as DNA and proteins. These harmful effects of free radicals can be blocked by antioxidants, which scavenge the free radicals and detoxify the organism. Plants and plant-derived products contain a wide range of phytochemicals, such as antioxidants, which are thought to have a protective role against the risk of oxidative stress-related diseases. Oxidative stress is an important contributor to the pathophysiology of a variety of pathological conditions such as arteriosclerosis, cancer, gastrointestinal tract disorders, rheumatism, diabetes mellitus, cardiovascular diseases, nephritis, neurodegenerative disease, and inflammatory injury. Recently, interest has considerably increased in finding naturally occurring antioxidants to replace synthetic antioxidants, which were restricted due to their adverse reactions such as carcinogenesis. Natural products have been the basis to treat some human diseases. There is emerging interest in the use of naturally occurring antioxidants for the management of a number of these pathophysiological conditions. Among the various natural sources, endemic medicinal plant species are of particular interest because they may be used for producing raw materials or preparations containing phytochemicals with significant antioxidant capacities and possible health benefits. Ziziphora Clinopodioides, known as Kakuti-e kuhi, Ankh, Lip vanilla, and mountain mint, is a wild flowering plant of Lamiaceae family. It is native to the parts of Iran and Iraq. In traditional medicine of Iran, this plant has been used to treat stomach and gastrointestinal pain, inflammatory, and cardiovascular disease, asthma, cough, bronchitis, insomnia, colds, flu, and other infectious diseases. In this paper, published antioxidant activities of Z. Clinopodioides were reviewed.

Cyclic Organoselenide BODIPY-Based Probe: Targeting Superoxide in MCF-7 Cancer Cells.

All aerobic cells contain reactive oxygen species (ROSs) in balance with biochemical antioxidants. Oxidative stress is developed when this balance gets disturbed because of excessive production of ROSs or depletion of antioxidants. Here, in this work, we have developed the first cyclic diselenide BODIPY-based (organoselenium-containing) probe for the selective detection of superoxide. The probe demonstrates excellent selective response for superoxide over other ROSs with nine-fold increase in fluorescence intensity. The detection limit was found to be 0.924 μM. The plausible “turn-on” mechanism has been proposed based on the spectroscopic and quantum chemical data. Usefulness of the probe for selective detection of superoxide was confirmed in mammalian breast cancer cell lines.

Autooscillatory Dynamics in a Mathematical Model of the Metabolic Process in Aerobic Bacteria. Influence of the Krebs Cycle on the Self-Organization of a Biosystem

We have modeled the metabolic process running in aerobic cells as open nonlinear dissipative systems. The map of metabolic paths and the general scheme of a dissipative system participating in the transformation of steroids are constructed. We have studied the influence of the Krebs cycle on the dynamics of the whole metabolic process and constructed projections of the phase portrait in the strange attractor mode. The total spectra of Lyapunov exponents, divergences, Lyapunov’s dimensions of the fractality, Kolmogorov–Sinai entropies, and predictability horizons for the given modes are calculated. We have determined the bifurcation diagram presenting the dependence of the dynamics on a small parameter, which defines system’s physical state.

Comparison of different industrial scale palm oil mill effluent anaerobic systems in degradation of organic contaminants and kinetic performance

Palm oil mill effluent has been extensively researched via three different technologies, namely chemical, physicochemical and biological treatment methods. Biological treatment by anaerobic and aerobic means is currently the most commonly used method for palm oil mill effluent. However, the greatest challenge posed by them is the inconsistent biological oxygen demand of 20 mg/L for the final treated effluent. Large amount of investment for additional polishing plant prior to the final discharge has been utilised intentionally to further reduce the biochemical oxygen demand values, but the problem remains unresolved. The performance of current palm oil mill effluent treatment system deployed by the industry was evaluated by comparing two different types of anaerobic treatments: open ponding and covered lagoon systems (with hydraulic and gas mixing). The covered lagoon with hydraulic mixing achieved the highest chemical oxygen demand, total suspended solids, total volatile solids and lignin removal efficiencies of >80% compared to other systems which showed <50% removal. Sufficient hydraulic retention time, extended aeration system coupled with presence of pure aerobic microbial cells in the stabilisation pond were able to produce effluent that abided the final discharge limit of biochemical oxygen demand 20 mg/L. Stover-Kincannon, Monod Contois and Grau second-order kinetic models were applied to the chemical oxygen demand data obtained to gauge the performance of anaerobic treatment of covered lagoon system with hydraulic mixing. The modified Stover-Kincannon model was found to define the system most appropriately with R2 of 0.9767. This work provided an up-to-date and representative palm oil mill effluent characteristics and contaminants degradation performance of the three commonly used palm oil mill effluent treatment methods in Malaysia. It helps in method selection and equipment sizing for palm oil mill effluent as well as other industrial-scale wastewater treatment and management.

Succination of Protein Thiols in Human Brain Aging.

Human brain evolution toward complexity has been achieved with increasing energy supply as the main adaptation in brain metabolism. Energy metabolism, like other biochemical reactions in aerobic cells, is under enzymatic control and strictly regulated. Nevertheless, physiologically uncontrolled and deleterious reactions take place. It has been proposed that these reactions constitute the basic molecular mechanisms that underlie the maintenance or loss-of-function of neurons and, by extension, cerebral functions during brain aging. In this review article, we focus attention on the role of the nonenzymatic and irreversible adduction of fumarate to the protein thiols, which leads to the formation of S-(2-succino)cysteine (2SC; protein succination) in the human brain. In particular, we first offer a brief approach to the succination reaction, features related to the specificity of protein succination, methods for their detection and quantification, the bases for considering 2SC as a biomarker of mitochondrial stress, the succinated proteome, the cross-regional differences in 2SC content, and changes during brain aging, as well as the potential regulatory significance of fumarate and 2SC. We propose that 2SC defines cross-regional differences of metabolic mitochondrial stress in the human brain and that mitochondrial stress is sustained throughout the healthy adult lifespan in order to preserve neuronal function and survival.

Effect of temperature treatment on postharvest quality of the cherry tomato (Lycopersicon esculentum var. cerasiforme)

Heat accumulation in the field accelerates softening and shortens the shelf life of cherry tomatoes. The purpose of this study was to investigate the effect of temperature treatment after harvest on the postharvest quality and microbial communities of cherry tomatoes. Regarding fruit quality properties, a 10℃ treatment after harvest caused a delay in increasing weight loss, firmness, electrolyte leakage and decay rate. After the temperature treatment, an approximately 1-2 log reduction on total viable cells, fungi, Enterobacteriaceae and coliforms was observed in the 10℃ treatment group compared with those at 20 and 30℃. However, total viable cells and decay rate remarkably increased at 10℃ treatment after 26 days. The microbial communities of cherry tomatoes in intitial day after temperature treatment were composed mainly of Staphylococcus xylosus or Bacillus pumilus. During storage, the relative abundance of Staphylococcus xylosus and Bacillus pumilus decreased while Pseudomonas fluorescens, Rahnella aquatilis and Leuconostoc mesenteroid increased during late storage. The rapid increase of total aerobic cells and decay rate in the 10℃ treatment group may be associated with a marked increase in Pseudomonas fluorescens. The results from this study demonstrate the effectiveness of pre-cooling to suppress the softening and indicate an impact on microbial community composition and dynamics during storage.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis.

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. SIGNIFICANCE: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.

Lysobacter psychrotolerans sp. nov., isolated from soil in the Tianshan Mountains, Xinjiang, China.

A novel aerobic bacterial strain, designated ZS60T, with long, rod-shaped, Gram-staining-negative, aerobic cells was isolated from the soil in the Tianshan Mountains, Xinjiang, China. Phylogenetic analysis based on its 16S rRNA gene sequence indicated that strain ZS60T was affiliated with the genus Lysobacter, and was most closely related to Lysobacter daejeonensis GH1-9T (96.9 %), Lysobacter caeni BUT-8T (96.8 %) and Lysobacter ruishenii CTN-1T (96.7 %). The average nucleotide identity values between strain ZS60T, L. daejeonensis GH1-9T and L. ruishenii CTN-1T were 78.14 and 78.39 %, respectively. The DNA-DNA relatedness between strain ZS60T, L. daejeonensis GH1-9T and L. caeni BUT-8T were 44.8 and 39.1 %, respectively. The genomic DNA G+C content of the strain ZS60T was 67.7 mol% (draft genome sequence), and Q-8 was the predominant ubiquinone. The major cellular fatty acids of strain ZS60T were iso-C15 : 0 (23.4 %), iso-C17 : 0 (17.2 %) and iso-C17 : 1 ω9c (12.6 %). On the basis of genotypic, phenotypic and biochemical data, strain ZS60T is considered to represent a novel species of the genus Lysobacter, for which the name Lysobacterpsychrotolerans sp. nov. is proposed. The type strain is ZS60T (=CGMCC 1.15509T=NBRC 112614T).

Genome-wide analysis of genomic alterations induced by oxidative DNA damage in yeast.

Oxidative DNA damage is a threat to genome stability. Using a genetic system in yeast that allows detection of mitotic recombination, we found that the frequency of crossovers is greatly elevated when cells are treated with hydrogen peroxide (H2O2). Using a combination of microarray analysis and genomic sequencing, we mapped the breakpoints of mitotic recombination events and other chromosome rearrangements at a resolution of about 1 kb. Gene conversions and crossovers were the two most common types of events, but we also observed deletions, duplications, and chromosome aneuploidy. In addition, H2O2-treated cells had elevated rates of point mutations (particularly A to T/T to A and C to G/G to C transversions) and small insertions/deletions (in/dels). In cells that underwent multiple rounds of H2O2 treatments, we identified a genetic alteration that resulted in improved H2O2 tolerance by amplification of the CTT1 gene that encodes cytosolic catalase T. Lastly, we showed that cells grown in the absence of oxygen have reduced levels of recombination. This study provided multiple novel insights into how oxidative stress affects genomic instability and phenotypic evolution in aerobic cells.

Insights into Hypoxia: Non-invasive Assessment through Imaging Modalities and Its Application in Breast Cancer.

Oxygen is crucial to maintain the homeostasis in aerobic cells. Hypoxia is a condition in which cells are deprived of the oxygen supply necessary for their optimum performance. Whereas oxygen deprivation may occur in normal physiological processes, hypoxia is frequently associated with pathological conditions. It has been identified as a stressor in the tumor microenvironment, acting as a key mediator of cancer development. Numerous pathways are activated in hypoxic cells that affect cell signaling and gene regulation to promote the survival of these cells by stimulating angiogenesis, switching cellular metabolism, slowing their growth rate, and preventing apoptosis. The induction of dysregulated metabolism in cancer cells by hypoxia results in aggressive tumor phenotypes that are characterized by rapid progression, treatment resistance, and poor prognosis. A non-invasive assessment of hypoxia-induced metabolic and architectural changes in tumors is advisable to fully improve breast cancer (BC) patient management, by potentially reducing the need for invasive biopsy procedures and evaluating tumor response to treatment. This review provides a comprehensive overview of the molecular changes in breast tumors secondary to hypoxia and the non-invasive imaging alternatives to evaluate oxygen deprivation, with an emphasis on their application in BC and the advantages and limitations of the currently available techniques.

Comparing Electron Leak in Vertebrate Muscle Mitochondria.

Mitochondrial electron transfer for oxidative ATP regeneration is linked to reactive oxygen species (ROS) production in aerobic eukaryotic cells. Because they can contribute to signaling as well as oxidative damage in cells, these ROS have profound impact for the physiology and survival of the organism. Although mitochondria have been recognized as a potential source for ROS for about 50years, the mechanistic understanding on molecular sites and processes has advanced recently. Most experimental approaches neglect thermal variability among species although temperature impacts mitochondrial processes significantly. Here we delineate the importance of temperature by comparing muscle mitochondrial ROS formation across species. Measuring the thermal sensitivity of respiration, electron leak rate (ROS formation), and the antioxidant capacity (measured as H2O2 consumption) in intact mitochondria of representative ectothermic and endothermic vertebrate species, our results suggest that using a common assay temperature is inappropriate for comparisons of organisms with differing body temperatures. Moreover, we propose that measuring electron leak relative to the mitochondrial antioxidant capacity (the oxidant ratio) may be superior to normalizing relative to respiration rates or mitochondrial protein for comparisons of mitochondrial metabolism of ROS across species of varying mitochondrial respiratory capacities.

Coupling heavy metal resistance and oxygen flexibility for bioremoval of copper ions by newly isolated Citrobacter freundii JPG1

The potential for bioremoval of copper ions was investigated by a novel strain of bacterium Citrobacter freundii JPG1, which was newly isolated from gold mining tailing in China and grew either aerobically or anaerobically. The strain cross-tolerated heavy metals of Ag+, Cd2+, Co2+, Cr6+, Cu2+ and Ni2+ and removed copper under both aerobic and anaerobic conditions with the stress of copper. Under aerobic conditions, the cells grew rapidly and exhibited higher biomass at low copper concentrations (<1 mmol L−1), while the growth of cells was almost completely inhibited at high copper concentrations (2 mmol L−1). However, the cell growths were less affected by copper under anaerobic conditions. Similarly, the copper-removal efficiency was affected by oxygen and the capability of copper removal by anaerobic cells was significantly higher than that of aerobic cells (P < 0.05). The quantitative measurement of extracellular biosorption and intercellular bioaccumulation of copper indicated that biosorption efficiencies for aerobic cells (37%) and anaerobic cells (38%) were similar but the bioaccumulation by anaerobic cells was almost ten-fold higher than that by aerobic cells, indicating bioaccumulation contributed most in copper reduction under anaerobic conditions. Overall, the results suggested the facultative strain C. freundii JPG1 had great potential in the treatment of copper-laden industrial wastewater under both aerobic and anaerobic conditions.

Redox-Driven Proton Pumps of the Respiratory Chain

In aerobic cells, the proton gradient that drives ATP synthesis is created by three different proton pumps—membrane enzymes of the respiratory electron transport chain known as complex I, III, and IV. Despite the striking dissimilarity of structures and apparent differences in molecular mechanisms of proton pumping, all three enzymes have much in common and employ the same universal physical principles of converting redox energy to proton pumping. In this study, we describe a simple mathematical model that illustrates the general principles of redox-driven proton pumps and discuss their implementation in complex I, III, and IV of the respiratory chain.

Downstream Simultaneous Electrochemical Detection of Primary Reactive Oxygen and Nitrogen Species Released by Cell Populations in an Integrated Microfluidic Device.

An innovative microfluidic platform was designed to monitor electrochemically four primary reactive oxygen (ROS) and reactive nitrogen species (RNS) released by aerobic cells. Taking advantage of the space confinement and electrode performances under flow conditions, only a few experiments were sufficient to directly provide significant statistical data relative to the average behavior of cells during oxidative-stress bursts. The microfluidic platform comprised an upstream microchamber for cell culture and four parallel microchannels located downstream for separately detecting H2O2, ONOO-, NO·, and NO2-. Amperometric measurements were performed at highly sensitive Pt-black electrodes implemented in the microchannels. RAW 264.7 macrophage secretions triggered by a calcium ionophore were used as a way to assess the performance, sensitivity, and specificity of the integrated microfluidic device. In comparison with some previous evaluations achieved from single-cell measurements, reproducible and relevant determinations validated the proof of concept of this microfluidic platform for analyzing statistically significant oxidative-stress responses of various cell types.

Abstract 5519: BAP1 modulates gene-environment interaction in carcinogenesis

Abstract We discovered that heterozygous germline BAP1 mutations (BAP1+/-) cause a novel cancer syndrome that we named “The BAP1 cancer syndrome” characterized by development of malignant mesothelioma (MM), uveal and cutaneous melanoma, and other cancers. We demonstrated how germline BAP1 mutations are transmitted over the centuries across generations and found that 100% of individuals who inherited germline BAP1 mutations have developed one or more malignancies in their lifetime. Very recently we demonstrated that the potent BAP1 tumor-suppressor activity is linked to its dual function in the nucleus, where it regulates DNA repair, and in the cytoplasm, where it regulates apoptosis by deubiquitylating and stabilizing the IP3R3 endoplasmic reticulum (ER) Ca2+ channel. In parallel we discovered that cells carrying heterozygous BAP1 mutations derive energy largely via aerobic glycolysis, Warburg effect. Now we have found the mechanisms regulated by BAP1 that are responsible for the changes in metabolism. We discovered that reduced BAP1 levels lead to reduced release of Ca2+ from the ER into the cytoplasm and reduced intra-mitochondrial Ca2+ levels. Reduced mitochondrial Ca2+ levels directly impair aerobic respiration and cells switch to glycolysis even in the presence of oxygen. We demonstrate that aerobic glycolysis can be induced in apparently any human cell type by reducing BAP1 levels using siRNAs or other strategies, and that in these cells glycolysis can be reverted to aerobic respiration upon re-establishing normal Ca2+ levels. In conclusion, our findings indicate how BAP1 deficiency regulates DNA repair and apoptosis and how low BAP1 levels induce the Warburg effect, an effect seen in all “normal” cell types from individuals born with inherited germline heterozygous BAP1 mutations. In these individuals aerobic glycolysis predates by many years malignant transformation. Citation Format: Michele Carbone, Angela Bononi, Carlotta Giorgi, Simone Patergnani, Harvey I. Pass, Wei Jia, Paolo Pinton, Haining Yang. BAP1 modulates gene-environment interaction in carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5519.