title: Inhibition of 5-lipoxygenase selectively triggers disruption of c-Myc signaling in prostate cancer cells.
abstract: 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.
authors.affiliation: From the Departments of Urology and.
authors.forename: Sivalokanathan
authors.initials: S
authors.lastname: Sarveswaran
authors.affiliation: From the Departments of Urology and.
authors.forename: Debrup
authors.initials: D
authors.lastname: Chakraborty
authors.affiliation: Pathology,; The Josephine Ford Cancer Center, Henry Ford Health System, Detroit, Michigan 48202 and.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Chitale
authors.affiliation: the Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon 97239.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Sears
authors.affiliation: From the Departments of Urology and; The Josephine Ford Cancer Center, Henry Ford Health System, Detroit, Michigan 48202 and. Electronic address: jghosh1@hfhs.org.
authors.forename: Jagadananda
authors.initials: J
authors.lastname: Ghosh
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D058946:5-Lipoxygenase-Activating Protein Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; C078266:MK 0591; D001094:Arachidonate 5-Lipoxygenase
keywords: 5-Lipoxygenase; Apoptosis; Eicosanoid; Lipoxygenase Pathway; MK591; Myc (c-Myc); Prostate Cancer