5-Lipoxygenase is a direct p53 target gene in humans

Gilbert, Bianca; Ahmad, Khalil; Roos, Jessica; Lehmann, Christian; Chiba, Tomohiro; Ulrich-Rückert, Sandra; Smeenk, Leonie; Heeringen, Simon J. van; Maier, Thorsten J.; Groner, Bernd; Steinhilber, Dieter

doi:10.1016/j.bbagrm.2015.06.004

Cited by 27 publications

(20 citation statements)

References 55 publications

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“…This is consistent with previous studies on other cancer types demonstrating an association between 5-LO expression and poor survival in patients with high-grade astrocytoma, and breast cancer (4,20). Furthermore, a larger panel of data supported that the 5-LO signaling pathway exerts profound effects on human tumorigenesis and progression, and that targeting 5-LO may lead to cancer treatment or prevention (20)(21)(22)(23)(24)(25). However, the mechanism underlying how 5-LO promotes malignant transformation and malignant tumor behavior in vivo remains unclear.…”

Section: -Lo Expression Regulates Escc Cell Viability and Migration supporting

confidence: 79%

“…In other cancer types, 5-LO was revealed to enhance cell proliferation and inhibit apoptosis (22). 5-LO was also reported to selectively inhibit tumor suppressor gene p53 transcription (23). Furthermore, 5-LO expression promoted tumor angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF) (24), which is currently one of the strongest targets in promoting or generating tumor blood vessel formation (20).…”

Section: -Lo Expression Regulates Escc Cell Viability and Migration mentioning

confidence: 99%

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Association between 5‑lipoxygenase expression, and malignant behaviors and poor prognosis in esophageal squamous cell carcinoma

et al. 2018

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Abstract. 5-lipoxygenase (5-LO) catalyzes the first step of arachidonic acid metabolism to inflammatory mediator leukotrienes. The present study assessed 5-LO expression in esophageal squamous cell carcinoma (ESCC) tissue specimens for associations with clinicopathological and survival data from patients, then explored 5-LO activity in ESCC cells in vitro. 5-LO expression was detected in tissue microarrays containing 297 ESCC samples using immunohistochemistry. Kaplan-Meier curves were used to analyze the survival significance of 5-LO expression and relative risk was evaluated using the multivariate Cox proportional hazards model. Cultured tumor cells were subjected to gene transfection, western blotting, and cell migration and proliferation assays. 5-LO protein was primarily expressed in normal cell cytoplasm and/or membrane, and never in the whole cytoplasm, whereas 5-LO was expressed diffusely in ESCC tissues with nearly homogeneous whole-cytoplasm staining. 5-LO expression was significantly associated with tumor regional lymph node metastasis (P=0.013) and pTNM stage (P=0.004). 5-LO expression was associated with poor overall survival (P=0.029). Multivariate analysis demonstrated that 5-LO overexpression was an independent prognostic factor for ESCC patients (P=0.041). Furthermore, the inhibition of 5-LO expression reduced ESCC cell viability and migration in vitro. These data provide further evidence that the upregulation of 5-LO expression is associated with advanced stages of disease and poor ESCC prognosis, and that 5-LO expression may independently predict overall survival in patients with ESCC. The inhibition of 5-LO expression reduced ESCC malignant behavior in vitro.

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Section: -Lo Expression Regulates Escc Cell Viability and Migration supporting

confidence: 79%

Section: -Lo Expression Regulates Escc Cell Viability and Migration mentioning

confidence: 99%

Association between 5‑lipoxygenase expression, and malignant behaviors and poor prognosis in esophageal squamous cell carcinoma

et al. 2018

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“…6a and Supplementary Table 2 ). Remarkably, we found that the transcripts of two unique genes, arachidonate 5-lipoxygenase ( ALOX5 ) 42 and arachidonate 12-lipoxygenase,12R type ( ALOX12B ), were most significantly enriched in doxorubicin-treated HCT116 and A549 cells in a p53-dependent manner, similar to p21 , a canonical p53 target gene (Fig. 6a–c and Supplementary Figure 6a ).…”

Section: Resultsmentioning

confidence: 86%

Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers

et al. 2018

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There are considerable challenges in directly targeting the mutant p53 protein, given the large heterogeneity of p53 mutations in the clinic. An alternative approach is to exploit the altered fitness of cells imposed by loss-of-wild-type p53. Here we identify niclosamide through a HTS screen for compounds selectively killing p53-deficient cells. Niclosamide impairs the growth of p53-deficient cells and of p53 mutant patient-derived ovarian xenografts. Metabolome profiling reveals that niclosamide induces mitochondrial uncoupling, which renders mutant p53 cells susceptible to mitochondrial-dependent apoptosis through preferential accumulation of arachidonic acid (AA), and represents a first-in-class inhibitor of p53 mutant tumors. Wild-type p53 evades the cytotoxicity by promoting the transcriptional induction of two key lipid oxygenation genes, ALOX5 and ALOX12B, which catalyzes the dioxygenation and breakdown of AA. Therefore, we propose a new paradigm for targeting cancers defective in the p53 pathway, by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling.

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“…Nonetheless, we found that 17‐HDHA exposure led to increased 5‐LOX levels in ECs above baseline expression levels. Transcriptional regulation of 5‐LOX has been linked to the transcription factors Sp1, Egr‐1, and p53 (41, 42). The mechanisms through which 17‐HDHA causes these changes in 5‐LOX expression in vascular cells require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Biosynthesis of proresolving lipid mediators by vascular cells and tissues

et al. 2017

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Recent evidence suggests that specialized proresolving lipid mediators (SPMs) generated from docosahexaenoic acid (DHA) can modulate the vascular injury response. However, cellular sources for these autacoids within the vessel wall remain unclear. Here, we investigated whether isolated vascular cells and tissues can produce SPMs and assessed expression and subcellular localization of the key SPM biosynthetic enzyme 5-lipoxygenase (LOX) in vascular cells. Intact human arteries incubated with DHA produced 17-hydroxy DHA (17-HDHA) and D-series resolvins, as assessed by liquid chromatography-tandem mass spectrometry. Addition of 17-HDHA to human arteries similarly increased resolvin production. Primary cultures of human saphenous vein endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) converted 17-HDHA to SPMs, including resolvin D1 (RvD1) and other D-series resolvins and protectins. This was accompanied by a rapid translocation of 5-LOX from nucleus to cytoplasm in both ECs and VSMCs, potentially facilitating SPM biosynthesis. Conditioned medium from cells exposed to 17-HDHA inhibited monocyte adhesion to TNF-α-stimulated EC monolayers. These downstream effects were partially reversed by antibodies against the RvD1 receptors ALX/FPR2 and GPR32. These results suggest that autocrine and/or paracrine signaling locally generated SPMs in the vasculature may represent a novel homeostatic mechanism of relevance to vascular health and disease.-Chatterjee, A., Komshian, S., Sansbury, B. E., Wu, B., Mottola, G., Chen, M., Spite, M., Conte, M. S. Biosynthesis of proresolving lipid mediators by vascular cells and tissues.

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5-Lipoxygenase is a direct p53 target gene in humans

Cited by 27 publications

References 55 publications

Association between 5‑lipoxygenase expression, and malignant behaviors and poor prognosis in esophageal squamous cell carcinoma

Association between 5‑lipoxygenase expression, and malignant behaviors and poor prognosis in esophageal squamous cell carcinoma

Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers

Biosynthesis of proresolving lipid mediators by vascular cells and tissues

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