• Alpha lipoic acid (ALA)
• Epithelial Mesenchymal Transition (EMT) and Functional and tumor capacities
• Leukotriene A4 Hydrolase (LTA4H)
• Leukotriene B4 (LTB4)
• Small cell lung carcinoma and non-small cell lung cancer (NSCLC)

• inflammation
• non-coding rnas
• drug development

• Animals
• Humans
• Arachidonate 5-Lipoxygenase/metabolism
• Arachidonate 5-Lipoxygenase/genetics
• Carcinogenesis/metabolism
• Carcinogenesis/genetics
• Gene Expression Regulation, Neoplastic
• Leukotrienes/metabolism
• Neoplasms/pathology
• Neoplasms/metabolism
• Neoplasms/genetics
• Signal Transduction

• GRK2336 TP4 Deutsche Forschungsgemeinschaft (German Research Foundation)
• 535161404 Deutsche Forschungsgemeinschaft (German Research Foundation)
• SFB 1039 TP A02 Deutsche Forschungsgemeinschaft (German Research Foundation)
• SFB 1039 TPA02 Deutsche Forschungsgemeinschaft (German Research Foundation)
• GRK 2336 TP4 Deutsche Forschungsgemeinschaft (German Research Foundation)

• ALOX
• Pseudomonas aeruginosa
• cancer
• carcinogenesis
• cystic fibrosis
• inflammation
• lipoxygenase

• Humans
• Animals
• Mice
• Lipoxygenases
• Carcinogenesis
• Ferroptosis
• Immunocompromised Host
• Inflammation

• 75-15-2020-913 Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers 'Digital Biodesign and Personalized Healthcare'

• Intrahepatic cholangiocarcinoma
• Lipid metabolism
• Single-cell analysis
• Tumor microenvironment
• Tumor-associated macrophages

• Animals
• Mice
• Humans
• Phosphatidylinositol 3-Kinases
• Tumor-Associated Macrophages
• Mice, Nude
• Leukotriene B4
• Cholangiocarcinoma/genetics
• Tumor Microenvironment
• Cell Line, Tumor
• Arachidonate 5-Lipoxygenase

• 81772521 National Natural Science Foundation of China

• 5-Lipoxygenase
• JAK/STAT pathway
• M2 macrophage polarization
• Pancreatic cancer

• Mice
• Animals
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/pathology
• Arachidonate 5-Lipoxygenase/metabolism
• Tumor-Associated Macrophages/metabolism
• Leukotriene B4/metabolism

• arachidonic acid
• cancer
• fibrosis
• inflammation
• pancreas
• stroma

• Arachidonic Acid/metabolism
• Membrane Lipids
• Leukotrienes
• Prostaglandins/metabolism
• Phospholipases A2

• GR21037 Government of Extremadura

• Humans
• Arachidonate 5-Lipoxygenase/genetics
• Lipid Metabolism
• Colonic Neoplasms
• Mechanistic Target of Rapamycin Complex 2
• Phosphatidylinositol 3-Kinases

• Deutsche Forschungsgemeinschaft (DFG)

• 5-lipoxygenase
• DNA damage
• RNA interference
• benzo[a]pyrene
• cytotoxicity

• cell biology
• oncogenes
• gene expression

Three-dimensional (3D) cell culture technologies, which more closely mimic the complex microenvironment of tissue, are being increasingly evaluated as a tool for the preclinical screening of clinically promising new molecules, and studying of tissue metabolism. Studies of metabolites released into the extracellular space (secretome) allow understanding the metabolic dynamics of tissues and changes caused by therapeutic interventions. Although quite advanced in the field of proteomics, studies on the secretome of low molecular weight metabolites (< 1500 Da) are still very scarce. We present an untargeted metabolomic protocol based on the hybrid technique of liquid chromatography coupled with high-resolution mass spectrometry for the analysis of low-molecular-weight metabolites released into the culture medium by 3D cultures and co-culture (secretome model). For that we analyzed HT-29 human colon carcinoma cells and 3T3-L1 preadipocytes in 3D-monoculture and 3D-co-culture. The putative identification of the metabolites indicated a sort of metabolites, among them arachidonic acid, glyceric acid, docosapentaenoic acid and beta-Alanine which are related to cancer and obesity. This protocol represents a possibility to list metabolites released in the extracellular environment in a comprehensive and untargeted manner, opening the way for the generation of metabolic hypotheses that will certainly contribute to the understanding of tissue metabolism, tissue-tissue interactions, and metabolic responses to the most varied interventions. Moreover, it brings the potential to determine novel pathways and accurately identify biomarkers in cancer and other diseases. The metabolites indicated in our study have a close relationship with the tumor microenvironment in accordance with the literature review.

• Arachidonic Acid
• Biomarkers/metabolism
• Chromatography, Liquid/methods
• Coculture Techniques
• Colonic Neoplasms
• Humans
• Mass Spectrometry/methods
• Metabolomics/methods
• Secretome
• Tumor Microenvironment
• beta-Alanine/metabolism

• Coordination for the Improvement of Higher Education Personnel (CAPES)
• São Paulo Research Foundation (FAPESP)

Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators—prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line—CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC₅₀ values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent apoptosis and autophagy. In the presence of chloroquine, an autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of autophagy. Our in vivo experiment reports tumor growth attenuation in animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in cancer development, these results have a significant impact and are worthy of further evaluation.

• Animals
• Apoptosis
• Autophagy
• Boranes/pharmacology
• Carcinoma
• Caspase 3/metabolism
• Cell Line, Tumor
• Colonic Neoplasms/drug therapy
• Lipoxygenases
• Mice
• Mice, Inbred BALB C

Cysteinyl leukotrienes receptor antagonists (LTRAs) are promising chemoprevention options to target cysteinyl leukotriene signaling in cancer. However, only a number of randomized clinical trials (RCTs) or observational studies have been conducted to date; thus, the effect of LTRAs on patients is yet to be elucidated. Using insurance claim data, we aimed to evaluate whether LTRAs have cancer preventive effects by observing patients who took LTRAs.

Patients diagnosed with asthma, allergic rhinitis, chronic cough, and have no history of cancer were followed-up from 2005 to 2017. Cox proportional hazard regression analysis was conducted to estimate the hazard ratios (HRs) for cancer risk of LTRA users.

We followed-up (median: 5.6 years) 188,906 matched patients (94,453 LTRA users and 94,453 non-users). LTRA use was associated with a decreased risk of cancer (adjusted HR [aHR] = 0.85, 95% confidence interval [CI] = 0.83–0.87). The cancer risk showed a tendency to decrease rapidly when LTRAs were used in high dose (aHR = 0.56, 95% CI = 0.40–0.79) or for longer durations of more than 3 years (aHR = 0.68, 95% CI = 0.60–0.76) and 5 years (aHR = 0.33, 95% CI = 0.26–0.42). The greater preventive effects of LTRAs were also observed in patients with specific risk factors related to sex, age, smoking, and the presence of comorbidities.

In this study, we found that LTRA use was associated with a decreased risk of cancer. The high dose and long duration of the use of LTRAs correlated with a lower cancer risk. Since LTRAs are not yet used for the prevention or treatment of cancer, our findings could be used for developing a new chemo-regimen or designing feasible RCTs.

• cancer
• cancer prevention
• cysteinyl leukotriene receptor antagonists
• drug repurposing
• observational study

• immunoresolvents
• lipoxin
• lipoxygenase
• pancreatic cancer
• resolvin

• metastasis
• neutrophil extracellular traps
• neutrophil plasticity
• tumor microenvironment

• P30DK120531 NIH/NIDDK

• Cancer
• Leukotrienes (LTs)
• Lipoxygenase inhibitors
• Polyunsaturated Fatty Acid (PUFA)
• Structure-Activity Relationships (SAR)
• Synthesis

• 5-lipoxygenase
• apoptosis
• cell cycle
• polycythemia vera
• ruxolitinib
• zileuton

• cancer
• cardiovascular diseases

• Arachidonic Acids/genetics
• Arachidonic Acids/metabolism
• Cell Membrane/genetics
• Cytochrome P-450 Enzyme System/genetics
• Humans
• Leukotrienes/genetics
• Lipid Metabolism/genetics
• Lipoxins/genetics
• Lipoxygenases/genetics
• Metabolic Networks and Pathways/genetics
• Phospholipases A2/genetics
• Prostaglandin-Endoperoxide Synthases/genetics
• Prostaglandins/metabolism

• This work was supported in part by National Nature Science Foundation of China (No. 81790624)
• This work was supported in part by National Nature Science Foundation of China (No. 81700333)
• This work was supported in part by National Nature Science Foundation of China (No. 81900363)
• This work was supported in part by National Nature Science Foundation of China (No.81900244)
• Deutsche Forschungsgemeinschaft (German Research Foundation)

• cancer
• cysteinyl LTs
• inflammation
• metastasis

• 13-HODE
• GBM
• OXLAM
• eicosanoids
• glioblastoma
• hydroxyeicosapentaenoic acid
• hydroxyoctadecadienoic acid
• linoleic acid
• lipoxygenase
• luteolin

While enhanced expression of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) and their derived metabolites is associated with breast cancer (BC) risk, the precise link between BC carcinogenesis and enhanced inflammatory activity remains to be clarified. Human Cytomegalovirus (HCMV) may induce expression of COX-2 and 5-LO and is frequently found in breast cancer biopsies. Thus, we investigated whether there is an association between HCMV proteins and expression of COX-2 and 5-LO in human BC tissue and BC cell lines.

Paraffin embedded biopsies obtained from 49 patients with breast cancer and 26 tissue samples from adjacent, benign breast tissues were retrospectively examined for HCMV-immediate early (IE), HCMV-Late (LA), COX-2, and 5-LO proteins by immunohistochemistry. In vitro, uninfected and HCMV-infected BC cell lines were examined for COX-2 and 5-LO transcripts and proteins by PCR and flow cytometry.

Extensive expression of COX-2, 5-LO and HCMV-IE proteins were preferentially detected in BC samples. We found a statistically significant concordant correlation between extensive HCMV-IE and COX-2 (P < 0.0001) as well as with HCMV-IE and 5-LO (P = 0.0003) in infiltrating BC. In vitro, HCMV infection induced COX-2 and 5-LO transcripts and COX-2 proteins in MCF-7 cells (P =0.008, P =0.018, respectively). In MDA-MB-231 cells that already had high base line levels of COX-2 expression, HCMV induced both COX-2 and 5-LO proteins but not transcripts.

Our findings demonstrate a significant correlation between extensive HCMV-IE protein expression and overexpression of COX-2 and 5-LO in human breast cancer.

The online version of this article (10.1007/s00432-019-02946-8) contains supplementary material, which is available to authorized users.

• 5-LO
• Breast cancer
• COX-2
• Human cytomegalovirus
• MCF-7
• MDA-MB-231

• cystitis
• dog
• lipoxygenase
• transitional cell carcinoma

• Clinical trials
• Pancreatic carcinoma
• Resistance
• Targeted therapies
• Tyrosine kinase inhibitors

• Animals
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor
• Clinical Trials as Topic
• Drug Resistance, Neoplasm/genetics
• Humans
• Molecular Targeted Therapy
• Neovascularization, Pathologic/drug therapy
• Neovascularization, Pathologic/metabolism
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/etiology
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/pathology
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Retreatment
• Signal Transduction/drug effects
• Standard of Care
• Treatment Outcome

• Arachidonic acid
• Cancer
• EGFR
• Eicosanoids

• Animals
• Eicosanoids/metabolism
• ErbB Receptors/metabolism
• Heparin-binding EGF-like Growth Factor/metabolism
• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Signal Transduction

Advanced malignant pleural mesothelioma (MPM) has an extremely poor prognosis with limited chemotherapy options, therefore the identification of new therapeutic targets would aid in disease management. Arachidonic acid is metabolised by cyclooxygenase and lipoxygenase enzymes. The lipoxygenase isoenzymes 5-LOX and 12-LOX have been implicated in carcinogenesis. We aimed to examine 5-LOX and 12-LOX protein expression in a large retrospective series of mesothelioma samples. Further to this, the in vitro cytotoxic effects of lipoxygenase pathway inhibitors were investigated in mesothelioma cells. Archival samples from 83 patients with MPM were examined by immunohistochemistry for expression of the 5-LOX and 12-LOX proteins. The MTS assay was used to assess cell viability following 72 h treatment with the lipoxygenase pathway inhibitors baicalein, licofelone, MK-886 and zileuton in the MPM cell lines NCI-H2052, NCI-H2452 and MSTO-211H. Positive 12-LOX protein expression was recorded in 69/83 (83%) and positive 5-LOX expression was observed in 56/77 (73%) of MPM tissue samples. Co-expression of 5-LOX with 12-LOX was seen in 46/78 (58%) of MPM samples. Positive expression of 5-LOX, 12-LOX and COX-2 proteins was identified in the NCI-H2052, NCI-H2452 and MSTO-211H MPM cell lines. Baicalein (12-LOX and 15-LOX inhibitor) was effective in 3/3 MPM cell lines at low concentrations with an IC50 range of 9.6 μM to 20.7 μM. We have demonstrated that the 5-LOX and 12-LOX proteins are expressed in a significant proportion of MPM samples (73% and 83% respectively) and may represent novel therapeutic targets in this disease. We have demonstrated that the inhibition of the LOX pathway using baicalein may be effective as a novel treatment for MPM, however further human pharmacokinetic studies are required in order to establish whether the concentration used in vitro is clinically achievable.

• Arachidonic acid
• Cyclooxygenase
• Immunohistochemistry
• Lipoxygenase
• Mesothelioma

Inflammatory lipid mediators play an important role in several cancer types. Leukotrienes (LTs), pro-inflammatory lipid mediators, are involved in chronic inflammation and cancer progression. They are derived from arachidonic acid by 5-lipoxygenase (5-LOX) activity. On the other hand, 15-lipoxygenase (15-LOX-1) converts LTs into lipoxins (LXs), pro-resolving lipid mediators. LXs are involved in the attenuation of inflammation and cancer development.

We aimed to investigate the lipid mediator pathways, especially the LTs and LXs pathways, by studying 5-LOX and 15-LOX-1 expression in human cholangiocarcinoma (CCA) tissue. We also investigated the efficiency of zileuton (5-LOX inhibitor) treatment and BML-111 (LXA4 analog) addition on CCA cell lines properties.

The expression of 5-LOX and 15-LOX-1 in fifty human cholangiocarcinoma (CCA) tissue was analyzed using immunohistochemical staining. In addition, the effect of zileuton and BML-111 on CCA cell growth and migration was demonstrated using a cell viability assay and wound-healing assay, respectively. Furthermore, the molecular mechanism by which zileuton inhibits CCA cell migration was revealed using immunofluorescent staining and western blot analysis, respectively.

We demonstrate that the upregulation of 5-LOX is significantly correlated with CCA recurrent status. A positive 15-LOX-1 signal was significantly associated with a longer survival time in CCA patients. We found that co-expression of 5-LOX and 15-LOX-1 resulted in a relatively good prognosis in CCA patients. In addition, zileuton could inhibit CCA cell migration as well as BML-111. Interestingly, zileuton treatment not only downregulated 5-LOX, but also upregulated 15-LOX-1, together with reversing the epithelial-mesenchymal transition to mesenchymal-epithelial transition phenotype as observed in EMT marker western blot.

These findings suggest that 5-LOX and 15-LOX-1 play a key role in CCA and may serve as targets for CCA therapy.

• 15-LOX-1
• 5-LOX
• Akt pathway
• EMT
• cholangiocarcinoma
• zileuton

• Arachidonic acid
• hydroxyeicosatetraenoic acids
• lipoxygenase
• pancreatic cancer

• metabolism
• eicosanoids
• prostaglandins
• lipoxygenases
• inflammation

• Animals
• Arachidonic Acid/metabolism
• Eicosanoids/pharmacology
• Eicosanoids/physiology
• Fatty Acids, Unsaturated/metabolism
• Humans
• Inflammation/enzymology
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neoplasms/pathology
• Neovascularization, Pathologic/etiology
• Prostaglandin-Endoperoxide Synthases/metabolism
• Prostaglandins

• Endometrial hyperplasia
• Estradiol valerate
• Female rats
• Montelukast

• 5-Lipoxygenase
• GI cancer
• Leukotrienes

• Animals
• Arachidonate 5-Lipoxygenase/physiology
• Disease Progression
• Gastrointestinal Neoplasms/etiology
• Gastrointestinal Neoplasms/metabolism
• Gastrointestinal Neoplasms/pathology
• Humans
• Isoenzymes/physiology
• Lipid Metabolism/physiology
• Lipoxygenase/physiology

• 5-lipoxygenase
• biomarker
• esophageal squamous cell carcinoma
• prognosis
• tumor cell malignant behavior

Cathepsin G is a serine protease secreted from activated neutrophils, it has important roles in inflammation and immune response. Moreover, cathepsin G promotes tumor cell-cell adhesion and migration in cancer cells. In this study, we investigated whether inhibition of cathepsin G could sensitize TRAIL-mediated apoptosis in cancer cells. An inhibitor of cathepsin G [Cathepsin G inhibitor I (Cat GI); CAS 429676-93-7] markedly induced TRAIL-mediated apoptosis in human renal carcinoma (Caki, ACHN, and A498), lung cancer (A549) and cervical cancer (Hela) cells. In contrast, combined treatment with Cat GI and TRAIL had no effect on apoptosis in normal cells [mesangial cell (MC) and human skin fibroblast (HSF)]. Cat GI induced down-regulation of survivin expression at the post-translational level, and overexpression of survivin markedly blocked apoptosis induced by combined treatment with Cat GI plus TRAIL. Interestingly, Cat GI induced down-regulation of survivin via 5-lipoxygenase (5-LOX)-mediated reactive oxygen species (ROS) production. Inhibition of 5-LOX by gene silencing (siRNA) or a pharmacological inhibitor of 5-LOX (zileuton) markedly attenuated combined treatment-induced apoptosis. Taken together, our results indicate that inhibition of cathepsin G sensitizes TRAIL-induced apoptosis through 5-LOX-mediated down-regulation of survivin expression.

• 5-LOX
• ROS
• TRAIL
• cathepsin G
• survivin

• asthma
• cancer
• carboranes
• inhibitors
• lipoxygenase

• 5-lipoxygenase
• adipose tissue
• angiogenesis
• immune cells
• leukotrienes
• tumour microenvironment

• Adipose Tissue/immunology
• Adipose Tissue/metabolism
• Animals
• Arachidonate 5-Lipoxygenase/metabolism
• Biosynthetic Pathways/drug effects
• Cell Communication
• Cyclooxygenase 2/metabolism
• Fibroblasts/immunology
• Fibroblasts/metabolism
• Fibroblasts/pathology
• Humans
• Immunomodulation
• Leukotrienes/biosynthesis
• Lipid Metabolism
• Lymphocytes/immunology
• Lymphocytes/metabolism
• Myeloid Cells/immunology
• Myeloid Cells/metabolism
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/pathology
• Neovascularization, Pathologic/immunology
• Neovascularization, Pathologic/metabolism
• Signal Transduction
• Tumor Microenvironment/immunology
• Vascular Endothelial Growth Factor A/metabolism

• Anti-inflammatory agents
• Cholangiocarcinoma
• Inflammation
• Pancreatic adenocarcinoma

• BLT2
• Comp A
• EMT
• ERK2
• LTB(4)
• Vimentin

• A549 Cells
• Cell Line, Tumor
• Cell Movement/drug effects
• Dose-Response Relationship, Drug
• Epithelial-Mesenchymal Transition/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Leukotriene B4/pharmacology
• Mitogen-Activated Protein Kinase 1/genetics
• Mitogen-Activated Protein Kinase 1/metabolism
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Receptors, Leukotriene B4/genetics
• Receptors, Leukotriene B4/metabolism
• Vimentin/genetics
• Vimentin/metabolism

Leukotrienes (LTs) are inflammatory mediators that play a pivotal role in many diseases like asthma bronchiale, atherosclerosis and in various types of cancer. The key enzyme for generation of LTs is the 5-lipoxygenase (5-LO). Here, we present a novel putative protein isoform of human 5-LO that lacks exon 4, termed 5-LOΔ4, identified in cells of lymphoid origin, namely the Burkitt lymphoma cell lines Raji and BL41 as well as primary B and T cells. Deletion of exon 4 does not shift the reading frame and therefore the mRNA is not subjected to non-mediated mRNA decay (NMD). By eliminating exon 4, the amino acids Trp144 until Ala184 are omitted in the corresponding protein. Transfection of HEK293T cells with a 5-LOΔ4 expression plasmid led to expression of the corresponding protein which suggests that the 5-LOΔ4 isoform is a stable protein in eukaryotic cells. We were also able to obtain soluble protein after expression in E. coli and purification. The isoform itself lacks canonical enzymatic activity as it misses the non-heme iron but it still retains ATP-binding affinity. Differential scanning fluorimetric analysis shows two transitions, corresponding to the two domains of 5-LO. Whilst the catalytic domain of 5-LO WT is destabilized by calcium, addition of calcium has no influence on the catalytic domain of 5-LOΔ4. Furthermore, we investigated the influence of 5-LOΔ4 on the activity of 5-LO WT and proved that it stimulates 5-LO product formation at low protein concentrations. Therefore regulation of 5-LO by its isoform 5-LOΔ4 might represent a novel mechanism of controlling the biosynthesis of lipid mediators.

• Arachidonate 5-Lipoxygenase/chemistry
• Arachidonate 5-Lipoxygenase/isolation & purification
• Arachidonate 5-Lipoxygenase/metabolism
• Cell Line, Tumor
• Chromatography, High Pressure Liquid
• Enzyme Stability
• Escherichia coli/metabolism
• HEK293 Cells
• Humans
• Iron/metabolism
• Isoenzymes/chemistry
• Isoenzymes/isolation & purification
• Isoenzymes/metabolism
• Models, Molecular
• Recombinant Proteins/metabolism
• Temperature

• DFG
• Else Kröner Fresenius-Stiftung

Leukotriene B4 (LTB₄) is a potent pro-inflammatory eicosanoid that is derived from arachidonic acid, and its signaling is known to have a tumor-promoting role in several cancer types. In this study, we investigated whether enhanced LTB₄ signaling confers resistance to the cytostatic transforming growth factor-β1 (TGF-β1) response. We found that LTB₄ pretreatment or ectopic expression of BLT1, a high affinity LTB₄ receptor, fully abrogated TGF-β1-induced cell cycle arrest and expression of p15^INK4B and p27^KIP1. Mechanism study revealed that LTB₄-mediated suppression of TGF-β1-induced Smad3 activation and growth inhibition was due to enhanced phosphorylation of Smad3 linker region (pSmad3L) through activation of BLT1-NAD(P)H oxidase (NOX)-reactive oxygen species (ROS)-epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3-K)-extracellular signal-activated kinase1/2 (ERK1/2)-linked signaling cascade. Furthermore, the LTB₄/BLT1 signaling pathway leading to pSmad3L was constitutively activated in breast cancer cells and was correlated with TGF-β1-resistant growth of the cells in vitro and in vivo. In human breast cancer tissues, the expression level of pSmad3L (Thr179) had a positive correlation with BLT1 expression. Collectively, our data demonstrate for the first time that the induction of pSmad3L through BLT1-NOX-ROS-EGFR-PI3K-ERK1/2 signaling pathway is a key mechanism by which LTB₄ blocks the anti-proliferative responses of TGF-β1, providing a novel mechanistic insight into the connection between enhanced inflammatory signal and cancer cell growth.

• BLT1
• LTB4
• Smad3 linker region phosphorylation
• TGF-β1 resistance
• cancer cell growth

• Carcinogenesis
• Eicosanoids
• Esophageal squamous cell cancer
• Leukotriene receptors

• Arachidonic acid
• Cyclooxygenase
• Kaposi’s sarcoma associated herpes virus
• Leukotriene
• Lipid mediators
• Lipoxins
• Prostaglandins
• Resolvins

• Lipid mediators
• Oxylipin
• Phytomedicines
• Polypharmacology
• Tumor microenvironment

• 5-LO
• 5-Lipoxygenase
• Brain tumor
• Choroid plexus tumor
• Immunohistochemistry

• Cancer
• Lipoxygenase
• Mass spectrometry
• Protolichesterinic acid

• 4-Butyrolactone/analogs & derivatives
• 4-Butyrolactone/pharmacology
• Apoptosis
• Arachidonate 12-Lipoxygenase/metabolism
• Arachidonate 5-Lipoxygenase/metabolism
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cytoplasm/enzymology
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Enzymologic/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Lichens/chemistry
• Multiple Myeloma/drug therapy
• Multiple Myeloma/enzymology
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/enzymology