Inhibition of 5-lipoxygenase selectively triggers disruption of c-Myc signaling in prostate cancer cells

Myc is up-regulated in almost all cancer types and is the subject of intense investigation because of its pleiotropic effects controlling a broad spectrum of cell functions. However, despite its recognition as a stand-alone molecular target, development of suitable strategies to block its function i...

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Published in:The Journal of biological chemistry Vol. 290; no. 8; p. 4994
Main Authors: Sarveswaran, Sivalokanathan, Chakraborty, Debrup, Chitale, Dhananjay, Sears, Rosalie, Ghosh, Jagadananda
Format: Journal Article
Language:English
Published: United States 20.02.2015
Subjects:
5-Lipoxygenase-Activating Protein Inhibitors - pharmacology
Apoptosis - drug effects
Arachidonate 5-Lipoxygenase - genetics
Arachidonate 5-Lipoxygenase - metabolism
Cell Line, Tumor
Down-Regulation - drug effects
Down-Regulation - genetics
Gene Expression Regulation, Enzymologic - drug effects
Gene Expression Regulation, Enzymologic - genetics
Gene Expression Regulation, Neoplastic - drug effects
Gene Expression Regulation, Neoplastic - genetics
Humans
Indoles - pharmacology
Lipoxygenase Inhibitors - pharmacology
Male
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - enzymology
Prostatic Neoplasms - genetics
Prostatic Neoplasms - pathology
Proto-Oncogene Proteins c-myc - biosynthesis
Proto-Oncogene Proteins c-myc - genetics
Quinolines - pharmacology
Signal Transduction - drug effects
Transcription, Genetic - drug effects
Transcription, Genetic - genetics
MK591
Eicosanoid
5-Lipoxygenase
Prostate Cancer
Lipoxygenase Pathway
Apoptosis
Myc (c-Myc)
ISSN:1083-351X, 1083-351X
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Summary:Myc is up-regulated in almost all cancer types and is the subject of intense investigation because of its pleiotropic effects controlling a broad spectrum of cell functions. However, despite its recognition as a stand-alone molecular target, development of suitable strategies to block its function is hindered because of its nonenzymatic nature. We reported earlier that arachidonate 5-lipoxygenase (5-Lox) plays an important role in the survival and growth of prostate cancer cells, although details of the underlying mechanisms have yet to be characterized. By whole genome gene expression array, we observed that inhibition of 5-Lox severely down-regulates the expression of c-Myc oncogene in prostate cancer cells. Moreover, inhibition of 5-Lox dramatically decreases the protein level, nuclear accumulation, DNA binding, and transcriptional activities of c-Myc. Both the 5-Lox inhibition-induced down-regulation of c-Myc and induction of apoptosis are mitigated when the cells are treated with 5-oxoeicosatetraenoic acid, a metabolite of 5-Lox, confirming a role of 5-Lox in these processes. c-Myc is a transforming oncogene widely expressed in prostate cancer cells and maintains their transformed phenotype. Interestingly, MK591, a specific 5-Lox inhibitor, strongly affects the viability of Myc-overactivated prostate cancer cells and completely blocks their invasive and soft agar colony-forming abilities, but it spares nontransformed cells where expression of 5-Lox is undetectable. These findings indicate that the oncogenic function of c-Myc in prostate cancer cells is regulated by 5-Lox activity, revealing a novel mechanism of 5-Lox action and suggesting that the oncogenic function of c-Myc can be suppressed by suitable inhibitors of 5-Lox.
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ISSN:1083-351X
1083-351X
DOI:10.1074/jbc.M114.599035