title: Docosahexaenoic acid in combination with celecoxib modulates HSP70 and p53 proteins in prostate cancer cells.
abstract: The role of cyclooxygenase-2 (COX-2) and the mechanism by which it influences the development and behavior of prostate cancer is unclear. Selective COX-2 inhibitors may be effective against prostate cancer via COX-2-independent mechanisms. But administration of high doses of COX-2 inhibitors over longer period of time may not be devoid of side effects. There is increasing interest in using COX-2 inhibitors in combination with other chemopreventive agents to overcome the issue of toxicity. However, the molecular mechanisms underlying their combined actions are not well understood. Therefore, the present study was designed to determine the effects of low doses of docosahexaenoic acid (DHA) in combination with celecoxib on the molecular targets at the proteins level in rat prostate cancer cells. Two-dimensional gel electrophoresis, in combination with mass spectrometry analysis, was used for protein identification. Western blot analysis confirmed the proteins identified. Paraffin-embedded tissue sections from the rat prostate tumor were used to detect base level expression of heat shock protein 70 (HSP70) and p53. The rate of cancer cell growth was inhibited more effectively (p < 0.01) by DHA in combination with celecoxib at lower doses (2.5 microM each). A total number of twelve proteins were differentially expressed by the combined action of DHA and celecoxib at low doses. It was interesting to note that these agents activated both HSP70 and p53 proteins. Activation of HSP70 by the combined actions of DHA and celecoxib in the presence of wild-type p53 reveals a unique COX-2 independent mode of action against prostate cancer.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA. nnarayan@env.med.nyu.edu
authors.forename: Narayanan K
authors.initials: NK
authors.lastname: Narayanan
authors.forename: Bhagavathi A
authors.initials: BA
authors.lastname: Narayanan
authors.forename: Maarten
authors.initials: M
authors.lastname: Bosland
authors.forename: Mark S
authors.initials: MS
authors.lastname: Condon
authors.forename: Dominick
authors.initials: D
authors.lastname: Nargi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D015180:Electrophoresis, Gel, Two-Dimensional; D004789:Enzyme Activation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D018832:Molecular Chaperones / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000068579:Celecoxib; D004281:Docosahexaenoic Acids; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007527:Isoenzymes; D018832:Molecular Chaperones; D052247:Nitric Oxide Synthase Type II; D019704:Protein Disulfide-Isomerases; D011720:Pyrazoles; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP