title: Knockdown of AGR2 induces cellular senescence in prostate cancer cells.
abstract: Anterior-gradient 2 (AGR2), overexpressed in many tumors including prostate cancer (PCa), is implicated in stimulation of cell proliferation, adhesion, anti-apoptosis and cell cycle regulation. Here, a potential role of AGR2 in cellular senescence was investigated. We first observed that AGR2 was overexpressed in Chinese Han PCa tissues and had a positive correlation with cyclin D1 and p-Rb but not with p16(INK4a). AGR2 expression profiles varied among cell lines, with PC3 cells being the highest level, LNCaP and DU145 relatively less. The expression of cyclin D1 showed similar pattern to the AGR2 in cell lines. Knockdown of AGR2 caused a decrease in cell viability in PC3 cells, whereas forced expression of AGR2 led to an increased cell proliferation of LNCaP and DU145 cells. Importantly, AGR2 depletion resulted in accumulation of cells at the G(0)/G(1) phase and induction of cellular senescence in all three PCa cell lines as indicated by an increase of flat, enlarged and senescence-associated β-galactosidase (SA-β-Gal) positive cells. Senescent response to AGR2 silencing was also evidenced by elevated γH2AX and fluorescent punctuate formation of tri-methyl-histone H3 in AGR2-depleted cells. Further studies indicated that LNCaP underwent a p21(CIP1)-dependent cellular senescence in response to AGR2 depletion that requires inactivation of ERK signaling, whereas PC-3 was also p21(CIP1) dependent but involved in suppression of PI3K/Akt. Unlike LNCaP and PC-3, senescent response of DU145 was found to be mainly p27(KIP1) dependent that may require upregulation of PTEN and inhibition of PI3K/Akt signaling. Thus, these findings suggest a novel role of AGR2 in regulation of cellular senescence.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China.
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Hu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Gu
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.forename: Jinsan
authors.initials: J
authors.lastname: Zhang
authors.forename: Zunling
authors.initials: Z
authors.lastname: Li
authors.forename: Keli
authors.initials: K
authors.lastname: Tian
authors.forename: Charles Y F
authors.initials: CY
authors.lastname: Young
authors.forename: Huiqing
authors.initials: H
authors.lastname: Yuan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D019938:Cyclin D1 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D006657:Histones / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009088:Mucoproteins; D015513:Oncogene Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000378:metabolism; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: C502296:AGR2 protein, human; C436291:CDKN1B protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D009088:Mucoproteins; D015513:Oncogene Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; D001616:beta-Galactosidase