Assessing 12(S)-lipoxygenase inhibitory activity using colorectal cancer cells overexpressing the enzyme

Bednar, Wolfgang; Holzmann, Klaus; Marian, Brigitte

doi:10.1016/j.fct.2006.08.013

Cited by 23 publications

(13 citation statements)

References 25 publications

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“…CYP1A1 inhibition by siRNA and proadifen in breast cancer cells [10] or by proadifen in CRC cells [7] reduced the synthesis of 12(S)-HETE and the formation of CCIDs in EC monolayers as well and thus, further supports a role of 12(S)-HETE in the malignancy of CRC. Evidence for the pro-invasive contribution of 12(S)-HETE is provided by a CRC in vivo model in which the double amount of ALOX12-overexpressing SW480 cells [secreting four to fivefold more 12(S)-HETE as compared to control cells] [41] were detected in the vicinity of the lung blood vessels after transgrafting them into the rear flank of SCID mice [13]. ECs and CAFs are of mesenchymal origin and therefore quite mobile.…”

Section: Discussionmentioning

confidence: 99%

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling

Stadler

Nguyen

Schachner

et al. 2016

Cell. Mol. Life Sci.

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Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological- or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca2+-calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour–stroma interaction.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-016-2441-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling

Stadler

Nguyen

Schachner

et al. 2016

Cell. Mol. Life Sci.

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“…There are also numerous plant phenols including baicalein, kaempferol, quercetin, nordihydroguaretic acid and resveratrol which are known for their chemo preventive as well as LOX-inhibitory activity in different tumor models [152]. The 12-LOX inhibitor, baicalein, a flavonoid isolated from an important medicinal plant Scutellariae Radix (the root of Scutellaria baicalensis Georgi) has been shown to induce apoptosis in human colon, breast and prostate cancer cells [63,153,154].…”

Section: Regulation Of Adhesion Migration and Invasion By Loxmentioning

confidence: 99%

Lipoxygenase metabolism: roles in tumor progression and survival

Pidgeon

Lysaght

Krishnamoorthy

et al. 2007

Cancer Metastasis Rev

264

206

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The metabolism of arachidonic acid through lipoxygenase pathways leads to the generation of various biologically active eicosanoids. The expression of these enzymes vary throughout the progression of various cancers, and thereby they have been shown to regulate aspects of tumor development. Substantial evidence supports a functional role for lipoxygenase-catalyzed arachidonic and linoleic acid metabolism in cancer development. Pharmacologic and natural inhibitors of lipoxygenases have been shown to suppress carcinogenesis and tumor growth in a number of experimental models. Signaling of hydro[peroxy]fatty acids following arachidonic or linoleic acid metabolism potentially effect diverse biological phenomenon regulating processes such as cell growth, cell survival, angiogenesis, cell invasion, metastatic potential and immunomodulation. However, the effects of distinct LOX isoforms differ considerably with respect to their effects on both the individual mechanisms described and the tumor being examined. 5-LOX and platelet type 12-LOX are generally considered pro-carcinogenic, with the role of 15-LOX-1 remaining controversial, while 15-LOX-2 suppresses carcinogenesis. In this review, we focus on the molecular mechanisms regulated by LOX metabolism in some of the major cancers. We discuss the effects of LOXs on tumor cell proliferation, their roles in cell cycle control and cell death induction, effects on angiogenesis, migration and the immune response, as well as the signal transduction pathways involved in these processes. Understanding the molecular mechanisms underlying the anti-tumor effect of specific, or general, LOX inhibitors may lead to the design of biologically and pharmacologically targeted therapeutic strategies inhibiting LOX isoforms and/or their biologically active metabolites, that may ultimately prove useful in the treatment of cancer, either alone or in combination with conventional therapies.

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“…There are also numerous plant phenols including baicalein, kaempferol, quercetin, nordihydroguaretic acid and resveratrol which are known for their chemopreventative as well as LOX-inhibitory activity in different models [214]. The 12-LOX inhibitor, baicalein, a flavonoid isolated from an important medicinal plant Scutellariae Radix (the root of Scutellaria baicalensis Georgi) has been shown to induce apoptosis in human colon, breast and prostate cancer cells [215][216][217].…”

Section: Natural Agentsmentioning

confidence: 99%

Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention

Cathcart

Lysaght

Pidgeon

2011

Cancer Metastasis Rev

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Arachidonic acid metabolism through cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 epoxygenase (EPOX) pathways leads to the generation of biologically active eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acid and hydroperoxyeicosatetraenoic acids. Eicosanoid expression levels vary during tumor development and progression of a range of malignancies, including colorectal cancer. The actions of these autocoids are also directly influenced by diet, as demonstrated by recent evidence for omega-3 fatty acids in colorectal cancer (CRC) prevention and/or treatment. Eicosanoids regulate CRC development and progression, while inhibition of these pathways has generally been shown to inhibit tumor growth/progression. A progressive sequence of colorectal cancer development has been identified, ranging from normal colon, to colitis, dysplasia, and carcinoma. While both COX and LOX inhibition are both promising candidates for colorectal cancer prevention and/or treatment, there is an urgent need to understand the mechanisms through which these signalling pathways mediate their effects on tumorigenesis. This will allow identification of safer, more effective strategies for colorectal cancer prevention and/or treatment. In particular, binding to/signalling through prostanoid receptors have recently been the subject of considerable interest in this area. In this review, we discuss the role of the eicosanoid signalling pathways in the development and progression of colorectal cancer. We discuss the effects of the eicosanoids on tumor cell proliferation, their roles in cell death induction, effects on angiogenesis, migration, invasion and their regulation of the immune response. Signal transduction pathways involved in these processes are also discussed. Finally, novel approaches targeting these arachidonic acid-derived eicosanoids (using pharmacological or natural agents) for chemoprevention and/or treatment of colorectal cancer are outlined.

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Assessing 12(S)-lipoxygenase inhibitory activity using colorectal cancer cells overexpressing the enzyme

Cited by 23 publications

References 25 publications

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling

Lipoxygenase metabolism: roles in tumor progression and survival

Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention

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