LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and γ-irradiation

Zulato, Elisabetta; Ciccarese, Francesco; Agnusdei, Valentina; Pinazza, Marica; Nardo, Giorgia; Iorio, Egidio; Curtarello, Matteo; Silic-Benussi, Micol; Rossi, Elisabetta; Venturoli, Carolina; Panieri, Emiliano; Santoro, Massimo; Paolo, Veronica Di; Quintieri, Luigi; Ciminale, Vincenzo; Indraccolo, Stefano

doi:10.1016/j.bcp.2018.09.019

Cited by 33 publications

(30 citation statements)

References 41 publications

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“…LKB1 loss in NSCLC cells was recently associated with glutathione deficiency under oxidative stress and with sensitivity of cancer cells to cisplatin and γ-irradiation [50], supporting the hypothesis that LKB1-deficient tumors could be targeted by therapies inducing oxidative stress.…”

Section: Lkb1 and Response To Non-immunotherapy Treatmentsmentioning

confidence: 87%

LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer

Bonanno

Zulato

Pavan

et al. 2019

IJMS

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Liver kinase B1 (LKB1) is a tumor suppressor gene whose inactivation is frequent in different tumor types, especially in lung adenocarcinoma (about 30% of cases). LKB1 has an essential role in the control of cellular redox homeostasis by regulating ROS production and detoxification. Loss of LKB1 makes the tumor cell more sensitive to oxidative stress and consequently to stress-inducing treatments, such as chemotherapy and radiotherapy. LKB1 loss triggers complex changes in tumor microenvironment, supporting a role in the regulation of angiogenesis and suggesting a potential role in the response to anti-angiogenic treatment. On the other hand, LKB1 deficiency can promote an immunosuppressive microenvironment and may be involved in primary resistance to anti-PD-1/anti-PD-L1, as it has been reported in lung cancer. The aim of this review is to discuss interactions of LKB1 with the tumor microenvironment and the potential applications of this knowledge in predicting response to treatment in lung cancer.

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Section: Lkb1 and Response To Non-immunotherapy Treatmentsmentioning

confidence: 87%

LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer

Bonanno

Zulato

Pavan

et al. 2019

IJMS

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“…The analysis of the total neuron population was performed by counting HuC/D + cells in 10 randomly chosen images per mouse. The total number of HuC/D + neurons was recorded in each image and normalized per myenteric ganglion area, as previously described [11,33,37]. To evaluate the distribution of nitrergic neurons in ileal myenteric plexus, the number of nNOS + enteric neurons was blindly counted in 10 randomly chosen images per mouse and normalized per myenteric ganglion area.…”

Section: Confocal Image Acquisition and Analysismentioning

confidence: 99%

Involvement of Enteric Glia in Small Intestine Neuromuscular Dysfunction of Toll-Like Receptor 4-Deficient Mice

Cerantola

Caputi

Marsilio

et al. 2020

Cells

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Enteric glial cells (EGCs) influence nitric oxide (NO)− and adenosine diphosphate (ADP)− mediated signaling in the enteric nervous system (ENS). Since Toll-like receptor 4 (TLR4) participates to EGC homoeostasis, this study aimed to evaluate the possible involvement of EGCs in the alterations of the inhibitory neurotransmission in TLR4−/− mice. Ileal segments from male TLR4−/− and wild-type (WT) C57BL/6J mice were incubated with the gliotoxin fluoroacetate (FA). Alterations in ENS morphology and neurochemical coding were investigated by immunohistochemistry whereas neuromuscular responses were determined by recording non-adrenergic non-cholinergic (NANC) relaxations in isometrically suspended isolated ileal preparations. TLR4−/− ileal segments showed increased iNOS immunoreactivity associated with enhanced NANC relaxation, mediated by iNOS-derived NO and sensitive to P2Y1 inhibition. Treatment with FA diminished iNOS immunoreactivity and partially abolished NO− and ADP− mediated relaxation in the TLR4−/− mouse ileum, with no changes of P2Y1 and connexin-43 immunofluorescence distribution in the ENS. After FA treatment, S100β and GFAP immunoreactivity in TLR4−/− myenteric plexus was reduced to levels comparable to those observed in WT. Our findings show the involvement of EGCs in the alterations of ENS architecture and in the increased purinergic and nitrergic-mediated relaxation, determining gut dysmotility in TLR4−/− mice.

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“…Although miRNAs have also been implicated in ROS level regulation through the regulation of enzymes involved in ROS metabolism [37], the relationship between exogenous ROS and intercellular communication via exosomes has not been elucidated. ROS production has been implicated in mediating radiotherapy responses due to DNA damage on downstream cell survival or death signaling cascades [38][39]. Cancer cell-derived exosomes have been demonstrated to play a role in promoting cancer cell invasiveness and metastasis, and activation of relevant oncogenic pathways [40][41].…”

Section: Discussionmentioning

confidence: 99%

Exosome-mediated radiosensitizing effect on neighboring cancer cells via reactive oxygen species production

Nakaoka¹,

Nakahana²,

Inubushi³

et al. 2020

Preprint

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Purpose/Objectives: The mechanism of intercellular communication after radiation exposure in cancer cells remains fully undetermined. Exosomes are lipid bilayer-constituted, membrane-enclosed small vesicles that are recognized as mediators transporting a variety of intracellular components including miRNA. Here we identified the novel role of exosomes released from irradiated cells to neighboring cancer cells. Materials/Methods: Human pancreatic cancer cell line MIAPaCa-2 was used in this study. Purified exosome product (PEP) was obtained from cultured media by ultra-centrifugation. PEP was morphologically confirmed by transmission electron microscopy (TEM), and analyzed by NanoSight. Exosome-specific surface markers CD9 and CD63 were evaluated by western blotting. Endocytosis of irradiated exosomes was confirmed by fluorescent microscopy by using the PKH26 dye. Cell survival after irradiation was evaluated by a colony-forming assay. Intracellular reactive oxygen species (ROS) levels were determined using the oxidation-sensitive fluorescent probe dye C-H 2 DCF, and DNA damage was evaluated by detecting phosphorylated histone 2AX (γ-H2AX) foci by immunocytochemistry. MiRNAs were isolated from the exosomes after 5 Gy or 8 Gy of irradiation and comprehensive miRNA expression analysis was performed by miRNA microarray analyses. Expressions of Cu/Zn superoxide dismutase enzyme (SOD1) or Mn superoxide dismutase enzyme (SOD2), catalase, and glutathione peroxidase were studied to determine whether the exosomes received by the neighboring cells may have influence to them and lead to production of ROS or not. Results: Exosome characteristics were confirmed by multiple methods. The uptake of irradiated exosomes was significantly higher than that of nonirradiated exosomes. Notably, nonirradiated neighboring cells with irradiated exosomes induced higher intracellular levels of ROS, and a higher frequency of DNA damage. These neighboring cells also showed greater sensitivity to radiation. Seven upregulated and 5 downregulated miRNAs were identified that correlated with the miRNA microarray analyses results obtained after 5 Gy and 8 Gy radiation. Among them, miR-6823-5p was identified as a possible candidate for SOD1 inhibition, leading to intracellular ROS production and DNA damage. Conclusions : This is the first study to determine that irradiated exosomes can enhance the radiation effect via ROS production in cancer cells. This novel finding may lead to the understanding of the bystander effect of neighboring cancer cells.

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LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and γ-irradiation

Cited by 33 publications

References 41 publications

LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer

LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer

Involvement of Enteric Glia in Small Intestine Neuromuscular Dysfunction of Toll-Like Receptor 4-Deficient Mice

Exosome-mediated radiosensitizing effect on neighboring cancer cells via reactive oxygen species production

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