Inhibition of 5-Lipoxygenase Selectively Triggers Disruption of c-Myc Signaling in Prostate Cancer Cells

Sarveswaran, Sivalokanathan; Chakraborty, Debrup; Chitale, Dhananjay; Sears, Rosalie C.; Ghosh, J. J.

doi:10.1074/jbc.m114.599035

Cited by 49 publications

(34 citation statements)

References 61 publications

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“…Alternatively, their response to MYC may be a result of complex interdependencies, occurring downstream of primary MYC targets. Inhibiting these two pathways in vivo resulted in marked reduction in tumor load and significantly decreased proliferation, highlighting their potential as targets for lung adenocarcinoma treatment, particularly with the involvement of MYC (43,44). Upregulation of lipid synthesis is a hallmark of cancers as a strategy to generate new cell membranes and signaling molecules, thus enabling the extensive proliferation of tumor cells (45).…”

Section: Discussionmentioning

confidence: 99%

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

et al. 2016

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MYC-mediated pathogenesis in lung cancer continues to attract interest for new therapeutic strategies. In this study, we describe a transgenic mouse model of KRAS-driven lung adenocarcinoma that affords reversible activation of MYC, used here as a tool for lipidomic profiling of MYC-dependent lung tumors formed in this model. Advanced mass spectrometric imaging and surface analysis techniques were used to characterize the spatial and temporal changes in lipid composition in lung tissue. We found that normal lung tissue was characterized predominantly by saturated phosphatidylcholines and phosphatidylglycerols, which are major lipid components of pulmonary surfactant. In contrast, tumor tissues displayed an increase in phosphatidylinositols and arachidonate-containing phospholipids that can serve as signaling precursors. Deactivating MYC resulted in a rapid and dramatic decrease in arachidonic acid and its eicosanoid metabolites. In tumors with high levels of MYC, we found an increase in cytosolic phospholipase A2 (cPLA2) activity with a preferential release of membrane-bound arachidonic acid, stimulating the lipoxygenase (LOX) and COX pathways also amplified by MYC at the level of gene expression. Deactivating MYC lowered cPLA2 activity along with COX2 and 5-LOX mRNA levels. Notably, inhibiting the COX/5-LOX pathways in vivo reduced tumor burden in a manner associated with reduced cell proliferation. Taken together, our results show how MYC drives the production of specific eicosanoids critical for lung cancer cell survival and proliferation, with possible implications for the use of COX and LOX pathway inhibitors for lung cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

et al. 2016

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“…Microscopic counting of the colony number and size is generally used and is a gold standard of quantification in the colony formation assay (Hernanda et al, 2013;Sarveswaran et al, 2015;Zhang et al, 2015). Due to different perceptions from personnel, the results from microscopic counting are subjective.…”

Section: Validation Of the Impedimetric Methodsmentioning

confidence: 99%

Impedimetric quantification of the formation process and the chemosensitivity of cancer cell colonies suspended in 3D environment

Lei

Huang

2015

Biosensors and Bioelectronics

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“…Cell viability was measured by MTS/PES One Solution Cell Titer Assay (Promega Corp, Madison, WI) as described before (11,25). …”

Section: Methodsmentioning

confidence: 99%

“…Various formulations of the source plant of WDL, Eclipta alba , have been used as remedies of a number of human ailments (17–22). Interestingly, the pure compound, WDL, has been reported to effectively inhibit the activity of 5-lipoxygenase (5-Lox) in some cells (23,24), and 5-Lox has been recently characterized to be a regulator of c-Myc oncogenic signaling in prostate cancer cells (25). However, details of the molecular mechanisms underlying the anti-cancer effects of WDL in prostate cancer cells are unknown, and possible involvement of the c-Myc oncogene as a down-stream target of WDL’s action has never been addressed before.…”

Section: Introductionmentioning

confidence: 99%

“…We reported earlier that WDL inhibits PKC-epsilon while inducing apoptosis in prostate cancer cells (11), and that PKC-epsilon has emerged as a newly characterized signaling intermediate in the 5-oxoETE/OXER1-driven prostate cancer cell-survival pathway (31,32). PKC-epsilon has been found to phosphorylate and activate Stat3 (33,34), and inhibition of Stat3 down-regulates expression of c-Myc gene in prostate cancer cells (25), suggesting that the inhibitory effect of WDL on c-Myc function in prostate cancer cells may be mediated via inhibition of PKC-epsilon and Stat3-mediated transcription of the c-Myc gene. Altogether, these findings revealed a new mechanism of action of WDL in prostate cancer cells, and since c-Myc is intimately associated with aggressive features in prostate cancer cells, our recent findings suggest that WDL may turn-out to be a novel agent to down-regulate c-Myc oncogenic signaling for development of an effective strategy for prostate cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

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Wedelolactone, an Anti-inflammatory Botanical, Interrupts c-Myc Oncogenic Signaling and Synergizes with Enzalutamide to Induce Apoptosis in Prostate Cancer Cells

Sarveswaran

Ghosh

Parikh

et al. 2016

Molecular Cancer Therapeutics

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The c-Myc gene encodes an oncoprotein transcription factor which is frequently up-regulated in almost all cancer types, and is the subject of intense investigation for management of cancer because of its pleiotropic effects controlling a spectrum of cellular functions. However, due of its non-enzymatic nature, development of suitable strategies to block its protein-protein or protein-DNA interaction is challenging. Thus, c-Myc has been recognized as an elusive molecular target for cancer control and various approaches are in development to inhibit c-Myc-transcriptional activity. We observed that wedelolactone (WDL), an anti-inflammatory botanical compound, severely down-regulates the expression of c-Myc mRNA in prostate cancer cells. Moreover, WDL dramatically decreases the protein level, nuclear localization, DNA-binding, and transcriptional activities of c-Myc. c-Myc is a transforming oncogene widely expressed in prostate cancer cells and is critical for maintaining their transformed phenotype. Interestingly, WDL was found to strongly affect the viability of Myc-activated prostate cancer cells, and completely blocks their invasion as well as soft-agar colony-formation in vitro. WDL was also found to down-regulate c-Myc in vivo in nude mice xenografts. Moreover, WDL synergizes with enzalutamide to decrease the viability of androgen-sensitive prostate cancer cells via induction of apoptosis. These findings reveal a novel anticancer mechanism of the natural compound, WDL, and suggest that the oncogenic function of c-Myc in prostate cancer cells can be effectively down-regulated by WDL for the development of a new therapeutic strategy against Myc-driven prostate cancer.

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Inhibition of 5-Lipoxygenase Selectively Triggers Disruption of c-Myc Signaling in Prostate Cancer Cells

Cited by 49 publications

References 61 publications

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

Impedimetric quantification of the formation process and the chemosensitivity of cancer cell colonies suspended in 3D environment

Wedelolactone, an Anti-inflammatory Botanical, Interrupts c-Myc Oncogenic Signaling and Synergizes with Enzalutamide to Induce Apoptosis in Prostate Cancer Cells

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