title: ARF1 promotes prostate tumorigenesis via targeting oncogenic MAPK signaling.
abstract: ADP-ribosylation factor 1 (ARF1) is a crucial regulator in vesicle-mediated membrane trafficking and involved in the activation of signaling molecules. However, virtually nothing is known about its function in prostate cancer. Here we have demonstrated that ARF1 expression is significantly elevated in prostate cancer cells and human tissues and that the expression levels of ARF1 correlate with the activation of mitogen-activated protein kinases (MAPK) ERK1/2. Furthermore, we have shown that overexpression and knockdown of ARF1 produce opposing effects on prostate cancer cell proliferation, anchorage-independent growth and tumor growth in mouse xenograft models and that ARF1-mediated cell proliferation can be abolished by the Raf1 inhibitor GW5074 and the MEK inhibitors U0126 and PD98059. Moreover, inhibition of ARF1 activation achieved by mutating Thr48 abolishes ARF1's abilities to activate the ERK1/2 and to promote cell proliferation. These data demonstrate that the aberrant MAPK signaling in prostate cancer is, at least in part, under the control of ARF1 and that, similar to Ras, ARF1 is a critical regulator in prostate cancer progression. These data also suggest that ARF1 may represent a key molecular target for prostate cancer therapeutics and diagnosis.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Davis
authors.affiliation: Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Xiayang
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Chu
authors.affiliation: Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Cancer Center, Augusta University, Augusta, GA, USA.|Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Wu
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism*; D000818:Animals; D002070:Butadienes / Q000737:chemistry; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005419:Flavonoids / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009570:Nitriles / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002070:Butadienes; D005419:Flavonoids; D009570:Nitriles; C113580:U 0126; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020823:ADP-Ribosylation Factor 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: ARF1; Raf1/MEK/ERK1/2; cell growth; prostate cancer; tumorigenesis