bims-noxint 2019-04-07 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2019–04–07
seven papers selected by
Laia Caja Puigsubira, Uppsala University

The Role of Acrolein and NADPH Oxidase in the Granulocyte-Mediated Growth-Inhibition of Tumor Cells.
Reactive oxygen species: a volatile driver of field cancerization and metastasis.
CO-Releasing Molecule-2 Induces Nrf2/ARE-Dependent Heme Oxygenase-1 Expression Suppressing TNF-α-Induced Pulmonary Inflammation.
The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells.
VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure.
Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer.
Targeting glutamine metabolism and redox state for leukemia therapy.

Cells. 2019 Mar 29. pii: E292. [Epub ahead of print]8(4):

The Role of Acrolein and NADPH Oxidase in the Granulocyte-Mediated Growth-Inhibition of Tumor Cells.

Morana Jaganjac, Tanja Matijevic Glavan, Neven Zarkovic.

  : Although granulocytes are the most abundant leukocytes in human blood, their involvement in the immune response against cancer is not well understood. While granulocytes are known for their "oxidative burst" when challenged with tumor cells, it is less known that oxygen-dependent killing of tumor cells by granulocytes includes peroxidation of lipids in tumor cell membranes, yielding formation of reactive aldehydes like 4-hydroxynonenal (4-HNE) and acrolein. In the present work, we investigate the role of reactive aldehydes on cellular redox homeostasis and surface toll-like receptor 4 (TLR4) expression. We have further study the granulocyte-tumor cell intercellular redox signaling pathways. The data obtained show that granulocytes in the presence of 4-HNE and acrolein induce excessive ROS formation in tumor cells. Acrolein was also shown to induce granulocyte TLR4 expression. Furthermore, granulocyte-mediated antitumor effects were shown to be mediated via HOCl intracellular pathway by the action of NADPH oxidase. However, further studies are needed to understand interaction between TLR4 and granulocyte-tumor cell intercellular signaling pathways.

Keywords:  4-hydroxynonenal (4-HNE); acrolein; cancer cells; cancer regression; granulocytes; growth control; lipid peroxidation; oxidative burst; oxidative stress; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/cells8040292
Mol Cancer. 2019 03 30. 18(1): 65

Reactive oxygen species: a volatile driver of field cancerization and metastasis.

Zehuan Liao, Damien Chua, Nguan Soon Tan.

  Field cancerization and metastasis are the leading causes for cancer recurrence and mortality in cancer patients. The formation of primary, secondary tumors or metastasis is greatly influenced by multifaceted tumor-stroma interactions, in which stromal components of the tumor microenvironment (TME) can affect the behavior of the cancer cells. Many studies have identified cytokines and growth factors as cell signaling molecules that aid cell to cell communication. However, the functional contribution of reactive oxygen species (ROS), a family of volatile chemicals, as communication molecules are less understood. Cancer cells and various tumor-associated stromal cells produce and secrete a copious amount of ROS into the TME. Intracellular ROS modulate cell signaling cascades that aid in the acquisition of several hallmarks of cancers. Extracellular ROS help to propagate, amplify, and effectively create a mutagenic and oncogenic field which facilitate the formation of multifoci tumors and act as a springboard for metastatic tumor cells. In this review, we summarize our current knowledge of ROS as atypical paracrine signaling molecules for field cancerization and metastasis. Field cancerization and metastasis are often discussed separately; we offer a model that placed these events with ROS as the focal instigating agent in a broader "seed-soil" hypothesis.

Keywords:  Cancer-associated fibroblasts; Field cancerization; Metastasis; Reactive oxygen species; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12943-019-0961-y
J Clin Med. 2019 Mar 30. pii: E436. [Epub ahead of print]8(4):

CO-Releasing Molecule-2 Induces Nrf2/ARE-Dependent Heme Oxygenase-1 Expression Suppressing TNF-α-Induced Pulmonary Inflammation.

Chih-Chung Lin, Li-Der Hsiao, Rou-Ling Cho, Chuen-Mao Yang.

  The upregulation of heme oxygenase-1 (HO-1) by the carbon monoxide-releasing molecule (CORM)-2 may be mediated through the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases [Nox] and reactive oxygen species (ROS) generation, which could provide cytoprotection against various cellular injuries. However, the detailed mechanisms of CORM-2-induced HO-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain largely unknown. Therefore, we dissected the mechanisms underlying CORM-2-induced HO-1 expression in HPAEpiCs. We found that the administration of mice with CORM-2 attenuated the tumor necrosis factor-alpha (TNF-α)-induced intercellular adhesion molecule-1 (ICAM-1) expression and leukocyte count as revealed by immunohistochemical staining, western blot, real-time polymerase chain reaction (PCR), and cell count. Furthermore, TNF-α-induced ICAM-1 expression associated with monocyte adhesion to HPAEpiCs was attenuated by infection with adenovirus (adv)-HO-1 or incubation with CORM-2. These inhibitory effects of HO-1 were reversed by pretreatment with hemoglobin (Hb). Moreover, CORM-2-induced HO-1 expression was mediated via the phosphorylation of p47phox, c-Src, epidermal growth factor receptor (EGFR), Akt, and NF-E2-related factor 2 (Nrf2), which were inhibited by their pharmacological inhibitors, including diphenyleneiodonium (DPI) or apocynin (APO), ROS [N-acetyl-L-cysteine (NAC)], PP1, AG1478, PI3K (LY294002), or Akt (SH-5), and small interfering RNAs (siRNAs). CORM-2-enhanced Nrf2 expression, and anti-oxidant response element (ARE) promoter activity was also inhibited by these pharmacological inhibitors. The interaction between Nrf2 and AREs was confirmed with a chromatin immunoprecipitation (ChIP) assay. These findings suggest that CORM-2 increases the formation of the Nrf2 and AREs complex and binds with ARE-binding sites via Src, EGFR, and PI3K/Akt, which further induces HO-1 expression in HPAEpiCs. Thus, the HO-1/CO system might suppress TNF-α-mediated inflammatory responses and exert a potential therapeutic strategy in pulmonary diseases.

Keywords:  AREs; CORM-2; NADPH oxidase; Nrf2; ROS; heme oxygenase-1

DOI:  https://doi.org/10.3390/jcm8040436
Cell Rep. 2019 Apr 02. pii: S2211-1247(19)30316-X. [Epub ahead of print]27(1): 238-254.e6

The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells.

Biniam Adane, Haobin Ye, Nabilah Khan, Shanshan Pei, Mohammad Minhajuddin, Brett M Stevens, Courtney L Jones, Angelo D'Alessandro, Julie A Reisz, Vadym Zaberezhnyy, Maura Gasparetto, Tzu-Chieh Ho, Kathleen K Kelly, Jason R Myers, John M Ashton, Julie Siegenthaler, Tsutomu Kume, Eric L Campbell, Daniel A Pollyea, Michael W Becker, Craig T Jordan.

  The NADPH-dependent oxidase NOX2 is an important effector of immune cell function, and its activity has been linked to oncogenic signaling. Here, we describe a role for NOX2 in leukemia-initiating stem cell populations (LSCs). In a murine model of leukemia, suppression of NOX2 impaired core metabolism, attenuated disease development, and depleted functionally defined LSCs. Transcriptional analysis of purified LSCs revealed that deficiency of NOX2 collapses the self-renewal program and activates inflammatory and myeloid-differentiation-associated programs. Downstream of NOX2, we identified the forkhead transcription factor FOXC1 as a mediator of the phenotype. Notably, suppression of NOX2 or FOXC1 led to marked differentiation of leukemic blasts. In xenotransplantation models of primary human myeloid leukemia, suppression of either NOX2 or FOXC1 significantly attenuated disease development. Collectively, these findings position NOX2 as a critical regulator of malignant hematopoiesis and highlight the clinical potential of inhibiting NOX2 as a means to target LSCs.

Keywords:  CEBPε; FOXC1; NF-κB; NOX2; ROS; acute myeloid leukemia; differentiation; fatty acid oxidation; glycolysis; leukemia stem cells; p22Phox; self-renewal

DOI:  https://doi.org/10.1016/j.celrep.2019.03.009
Proc Natl Acad Sci U S A. 2019 Apr 04. pii: 201902119. [Epub ahead of print]

VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure.

Hu Xu, Shengnan Du, Bingying Fang, Chaojie Li, Xiao Jia, Senfeng Zheng, Sailun Wang, Qingwei Li, Wen Su, Nanping Wang, Feng Zheng, Lihong Chen, Xiaoyan Zhang, Jan-Åke Gustafsson, Youfei Guan.

  Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic angiotensin II (AngII) infusion of mice with vascular smooth muscle cell (VSMC)-specific EP4 gene knockout (VSMC-EP4-/-) frequently developed aortic dissection (AD) with severe elastic fiber degradation and VSMC dedifferentiation. AngII-infused VSMC-EP4-/- mice also displayed more profound vascular inflammation with increased monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, matrix metalloproteinase-2 and -9 (MMP2/9) levels, NADPH oxidase 1 (NOX1) activity, and reactive oxygen species production. In addition, VSMC-EP4-/- mice exhibited higher blood pressure under basal and AngII-infused conditions. Ex vivo and in vitro studies further revealed that VSMC-specific EP4 gene deficiency significantly increased AngII-elicited vasoconstriction of the mesenteric artery, likely by stimulating intracellular calcium release in VSMCs. Furthermore, EP4 gene ablation and EP4 blockade in cultured VSMCs were associated with a significant increase in MCP-1 and NOX1 expression and a marked reduction in α-SM actin (α-SMA), SM22α, and SM differentiation marker genes myosin heavy chain (SMMHC) levels and serum response factor (SRF) transcriptional activity. To summarize, the present study demonstrates that VSMC EP4 is critical for vascular homeostasis, and its dysfunction exacerbates AngII-induced pathological vascular remodeling. EP4 may therefore represent a potential therapeutic target for the treatment of AD.

Keywords:  EP4; PGE2; hypertension; inflammation; vascular remodeling

DOI:  https://doi.org/10.1073/pnas.1902119116
Oncogene. 2019 Apr 01.

Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer.

Luigi Ippolito, Andrea Morandi, Maria Letizia Taddei, Matteo Parri, Giuseppina Comito, Alessandra Iscaro, Maria Rosaria Raspollini, Francesca Magherini, Elena Rapizzi, Julien Masquelier, Giulio G Muccioli, Pierre Sonveaux, Paola Chiarugi, Elisa Giannoni.

Cancer-associated fibroblasts (CAFs) are the major cellular stromal component of many solid tumors. In prostate cancer (PCa), CAFs establish a metabolic symbiosis with PCa cells, contributing to cancer aggressiveness through lactate shuttle. In this study, we report that lactate uptake alters the NAD+/NADH ratio in the cancer cells, which culminates with SIRT1-dependent PGC-1α activation and subsequent enhancement of mitochondrial mass and activity. The high exploitation of mitochondria results in tricarboxylic acid cycle deregulation, accumulation of oncometabolites and in the altered expression of mitochondrial complexes, responsible for superoxide generation. Additionally, cancer cells hijack CAF-derived functional mitochondria through the formation of cellular bridges, a phenomenon that we observed in both in vitro and in vivo PCa models. Our work reveals a crucial function of tumor mitochondria as the energy sensors and transducers of CAF-dependent metabolic reprogramming and underscores the reliance of PCa cells on CAF catabolic activity and mitochondria trading.

DOI: https://doi.org/10.1038/s41388-019-0805-7
Clin Cancer Res. 2019 Apr 02. pii: clincanres.3223.2018. [Epub ahead of print]

Targeting glutamine metabolism and redox state for leukemia therapy.

Mark A Gregory, Travis Nemkov, Hae J Park, Vadym Zaberezhnvv, Sarah Gehrke, Biniam Adane, Craig T Jordan, Kirk C Hansen, Angelo D'Alessandro, James DeGregori.

PURPOSE: Acute myeloid leukemia (AML) is a hematological malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically.
EXPERIMENTAL DESIGN: AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized.
RESULTS: We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples and in vivo using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating ALL cells in vitro and in vivo Conclusions: Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.

DOI: https://doi.org/10.1158/1078-0432.CCR-18-3223