KNOCKDOWN OF ASTROCYTE ELEVATED GENE-1 INHIBITS PROSTATE CANCER PROGRESSION THROUGH UPREGULATION OF FOXO3a ACTIVITY

Kikuno, Nobuyuki; Shiina, Hìroaki; Urakami, Shinji; Kawamoto, Ken; Hirata, Hiroshi; Tanaka, Yuichiro; Place, Robert F.; Pookot, Deepa; Majid, Shahana; Igawa, Mikio; Dahiya, Rajvir

doi:10.1016/s0022-5347(08)60132-9

Cited by 60 publications

(120 citation statements)

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“…Recently, a newly identified astrocyte elevated gene-1 (AEG-1), originally discovered as a protein induced in primary human fetal astrocytes infected with HIV-1 or treated with HIV gp120 or tumor necrosis factor-a, was implicated in promotion of oncogenesis, abrogation of cancer cell apoptosis and induction of metastasis (Kang et al, 2005;Emdad et al, 2006Emdad et al, , 2007Lee et al, 2006Lee et al, , 2008Kikuno et al, 2007;Ash et al, 2008;Li et al, 2008;Sarkar et al, 2008). It was found that ectopic expression of AEG-1 could augment anchorage-independent growth of nontumorigenic melanocytes and astrocytes (Kang et al, 2005;Emdad et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1

et al. 2009

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We have previously reported that astrocyte elevated gene-1 (AEG-1) was upregulated in human breast cancer. However, the biological function of AEG-1 in the development and progression of breast cancer remains to be clarified. In this study, we examined the effect of AEG-1 on cell proliferation and found that AEG-1 upregulation was significantly linked to increased Ki67 (Po0.001). Ectopic expression of AEG-1 in MCF-7 and MDA-MB-435 breast cancer cells dramatically enhanced cell proliferation and their ability of anchorage-independent growth, whereas silencing endogenous AEG-1 with shRNAs inhibited cell proliferation and colony-forming ability of the cells on soft agar. Furthermore, these proliferative effects were significantly associated with decreases of p27 Kip1 and p21 Cip1 two key cell-cycle inhibitors. Moreover, we further demonstrated that AEG-1 could downregulate the transcriptional activity of FOXO1 by inducing its phosphorylation through the PI3K/Akt signaling pathway. These observations were further confirmed in clinical human primary breast cancer specimens, in which high-level expression of AEG-1 was inversely correlated with the expression of FOXO1. Taken together, our results provide the first demonstration of a novel mechanism by which AEG-1 induces proliferation of breast cancer cell, and our findings suggest that AEG-1 might play an important role in tumorigenesis of breast cancer.

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Section: Introductionmentioning

confidence: 99%

Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1

et al. 2009

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“…Elevated expression has been reported in breast and prostate tumors, melanoma and glioblastoma [1][2][3][4], and evidence suggests that LYRIC/AEG-1 actively contributes to malignant progression. LYRIC/AEG-1 overexpression activates both NF-kappaB and Akt signaling pathways [5,6], and the protein acts synergistically with Ha-Ras to promote anchorage-independent growth [1,7].…”

Section: Introductionmentioning

confidence: 99%

“…LYRIC/AEG-1 overexpression activates both NF-kappaB and Akt signaling pathways [5,6], and the protein acts synergistically with Ha-Ras to promote anchorage-independent growth [1,7]. In prostate tumor cell lines, LYRIC/AEG-1 knockdown resulted in reduced viability and invasiveness [3]. Overexpression of LYRIC/AEG-1 in nontumorigenic cells is not sufficient to induce transformation [1,7], but studies to date suggest that LYRIC/AEG-1 is an important factor promoting progression or metastasis of a variety of tumors.…”

Section: Introductionmentioning

confidence: 99%

LYRIC/AEG-1 overexpression modulates BCCIPα protein levels in prostate tumor cells

Ash

Britt

2008

Biochemical and Biophysical Research Communications

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LYRIC/AEG-1 is a unique protein that has been shown to promote tumor cell migration and invasion through activation of the transcription factor NF-κB. We performed yeast two-hybrid screening to detect LYRIC/AEG-1 associated proteins, and identified BCCIP, a CDKN1A and BRCA2-associated protein involved in cell cycle regulation and DNA repair. Here we demonstrate association between LYRIC/AEG-1 and BCCIP in mammalian cells, and define the region of interaction. Coexpression of the two proteins resulted in decreased levels of BCCIPα, an effect partially abrogated by proteasome inhibition. A truncated LYRIC/AEG-1 construct lacking the interaction region did not alter BCCIPα protein levels. Coincidentally, it was observed that overexpression of BCCIPα in DU145 prostate tumor cells induced an apparent neuroendocrine differentiation. In summary, our data suggest LYRIC/AEG-1 is a negative regulator of BCCIPα, promoting proteasomal degradation either through direct interaction, or potentially through an indirect mechanism involving downstream effects of the NF-κB signaling pathway.

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“…Increasing evidence exists that LYRIC/AEG-1 may act as an oncogene and promote tumourigenesis, chemoresistance and metastases (Brown and Ruoslahti, 2004;Emdad et al, 2006;Kikuno et al, 2007;Ash et al, 2008;Li et al, 2008;Sarkar et al, 2008;Hu et al, 2009;Kwong and Chin, 2009;Thirkettle et al, 2009). LYRIC/ AEG-1 is reported to be regulated by HA-RAS and c-myc (Lee et al, 2006), to suppress activators of apoptosis such as FOXO3a (Kikuno et al, 2007), and to activate nuclear factor-kB which regulates the expression of cell adhesion molecules implicated in cancer progression and metastasis .…”

mentioning

confidence: 99%

“…LYRIC/ AEG-1 is reported to be regulated by HA-RAS and c-myc (Lee et al, 2006), to suppress activators of apoptosis such as FOXO3a (Kikuno et al, 2007), and to activate nuclear factor-kB which regulates the expression of cell adhesion molecules implicated in cancer progression and metastasis . Recently, it has been shown that LYRIC/AEG-1 is overexpressed in breast and prostate tumourigenesis (Li et al, 2008;Hu et al, 2009;Thirkettle et al, 2009).…”

mentioning

confidence: 99%

Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression

et al. 2009

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KNOCKDOWN OF ASTROCYTE ELEVATED GENE-1 INHIBITS PROSTATE CANCER PROGRESSION THROUGH UPREGULATION OF FOXO3a ACTIVITY

Cited by 60 publications

References 0 publications

Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1

Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1

LYRIC/AEG-1 overexpression modulates BCCIPα protein levels in prostate tumor cells

Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression

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