title: Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis.
abstract: Methoxyacetic acid (MAA) is a primary metabolite of ester phthalates that are used in production of consumer products and pharmaceutical products. MAA causes embryo malformation and spermatocyte death through inhibition of histone deacetylases (HDACs). Little is known about MAA's effects on cancer cells. In this study, two immortalized human normal prostatic epithelial cell lines (RWPE-1 and pRNS-1-1) and four human prostate cancer cell lines (LNCaP, C4-2B, PC-3, and DU-145) were treated with MAA at different doses and for different time periods. Cell viability, apoptosis, and cell cycle analysis were performed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR, Western blot, and chromatin immunoprecipitation analyses. We found that MAA dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. MAA-induced apoptosis was due to down-regulation of the anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, also named cIAP1), leading to activation of caspases 7 and 3 and turning on the downstream apoptotic events. MAA-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and CDK2 expression at the late time. MAA up-regulated p21 expression through inhibition of HDAC activities, independently of p53/p63/p73. These findings demonstrate that MAA suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which suggests that MAA could be used as a potential therapeutic drug for prostate cancer.
authors.affiliation: Department of Structural & Cellular Biology, Tulane University New Orleans, LA, USA.
authors.forename: Keshab R
authors.initials: KR
authors.lastname: Parajuli
authors.affiliation: Department of Structural & Cellular Biology, Tulane University New Orleans, LA, USA.
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Structural & Cellular Biology, Tulane University New Orleans, LA, USA.
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Structural & Cellular Biology, Tulane University New Orleans, LA, USA.
authors.forename: Neil K
authors.initials: NK
authors.lastname: Patel
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University New Orleans, LA, USA ; Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University New Orleans, LA, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University New Orleans, LA, USA ; Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University New Orleans, LA, USA.
authors.forename: Shelya X
authors.initials: SX
authors.lastname: Zeng
authors.affiliation: Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana New Orleans, LA, USA.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana New Orleans, LA, USA.
authors.forename: Changde
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Structural & Cellular Biology, Tulane University New Orleans, LA, USA ; Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University New Orleans, LA, USA ; Department of Orthopaedic Surgery, Tulane University New Orleans, LA, USA ; Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University New Orleans, LA, USA ; Tulane Center for Aging, Tulane University New Orleans, LA, USA.
authors.forename: Zongbing
authors.initials: Z
authors.lastname: You
keywords: Prostate cancer; apoptosis; cell cycle; cell death; p21