Cancer-educated neutrophils promote lung cancer progression via PARP-1-ALOX5-mediated MMP-9 expression.

OBJECTIVE: Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression. How neutrophils promote lung cancer progression, however, has not been established. METHODS: Kaplan-Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients. The effect of neutrophils on lung cancer was determined using the Transwell migration assay, a proliferation assay, and a murine tumor model. Gene knockdown was used to determine poly ADP-ribose polymerase (PARP)-1 function in lung cancer-educated neutrophils. Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9 (MMP-9). Immunoprecipitation coupled to mass spectrometry (IP/MS) was used to identify the proteins interacting with PARP-1. Co-immunoprecipitation (Co-IP) was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase (ALOX5). Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression. RESULTS: An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients (P < 0.001). Neutrophil activation promoted lung cancer cell invasion, migration, and proliferation in vitro, and murine lung cancer growth in vivo. Mechanistically, PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification (PARylation). Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production, and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth. CONCLUSIONS: We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression, which exacerbates lung cancer progression.

5-lipoxygenase as a target to sensitize glioblastoma to temozolomide treatment via ß-catenin-dependent pathway.

Sensitizing strategy is required to improve the clinical management of glioblastoma (GBM). 5-Lipoxygenase (Alox5) has been recently garnered attention due to its pro-carcinogenic roles in various cancers. This study demonstrates that Alox5 is overexpressed in GBM but not normal neuronal tissues. Alox5 depletion inhibits the growth of GBM cells, both in bulky and stem-like populations, and enhances the anti-cancer effects of temozolomide. The mechanism behind this involves a decrease in ß-catenin level and activity upon Alox5 depletion. The inhibitory effects of Alox5 can be reversed by the addition of a Wnt agonist. Additionally, the study reveals that zileuton, an Alox5 inhibitor approved for asthma treatment, significantly improves the efficacy of temozolomide in mice without causing toxicity. Combination index analysis clearly demonstrates that zileuton and temozolomide act synergistically. These findings highlight the importance of Alox5 as a critical regulator of glioblastoma sensitivity and suggest the potential repurposing of zileuton for GBM treatment.

[Controlling arachidonic acid metabolic network: from single- to multi-target inhibitors of key enzymes].

Inflammatory diseases are common medical conditions seen in disorders of human immune system. There is a great demand for anti-inflammatory drugs. There are major inflammatory mediators in arachidonic acid metabolic network. Several enzymes in this network have been used as key targets for the development of anti-inflammatory drugs. However, specific single-target inhibitors can not sufficiently control the network balance and may cause side effects at the same time. Most inflammation induced diseases come from the complicated coupling of inflammatory cascades involving multiple targets. In order to treat these complicated diseases, drugs that can intervene multi-targets at the same time attracted much attention. The goal of this review is mainly focused on the key enzymes in arachidonic acid metabolic network, such as phospholipase A2, cyclooxygenase, 5-lipoxygenase and eukotriene A4 hydrolase. Advance in single target and multi-targe inhibitors is summarized.

A double-blind vehicle-controlled study of R 68 151 in psoriasis: a topical 5-lipoxygenase inhibitor.

Recently the pharmacologic role of leukotrienes (LTs), especially that of LTB4, has been intensively investigated in psoriasis. In vitro, R 68 151 is a potent 5-lipoxygenase inhibitor and consequently reduces LTB4 formation. Therefore the role of an in vitro 5-lipoxygenase inhibitor and its clinical use in psoriasis were evaluated with topical R 68 151 in a double-blind vehicle-controlled study. Eighty-eight patients with localized psoriatic lesions were treated twice daily with R 68 151 2% ointment (n = 44) or vehicle ointment (n = 44) during 4 weeks. Most patients (n = 73) had psoriasis vulgaris (n = 37, R 68 151; n = 36, vehicle). In 27% of the R 68 151-treated patients with psoriasis vulgaris, the lesions disappeared or showed marked improvement, compared with 8% in the vehicle group (X2, p = 0.06). The scores in global evaluation, however, were significantly different between both treatment groups (p less than 0.05, Mann-Whitney U test). The improvement of the mean symptom score with R 68 151 was 46% for scaling and 34% for erythema at the end of the study compared with an improvement of 6% and a deterioration of 3%, respectively, in the control group (p less than 0.05, p less than 0.01; Mann-Whitney U test). The global evaluation in the total group of patients with psoriasis (all different subtypes) was consistent with the response rate in the group of patients with psoriasis vulgaris: 30% in the test group versus 11% in the control group (X2, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)