Natura-Alpha Targets Forkhead Box M1 and Inhibits Androgen-Dependent and -Independent Prostate Cancer Growth and Invasion

Li, Yirong; Ligr, Martin; McCarron, James P.; Daniels, Garrett; Zhang, David; Zhao, Xin; Ye, Fei; Wang, Jinhua; Liu, Xiaomei; Osman, Iman; Mencher, Simon K.; Lepor, Hebert; Wang, Long G.; Lee, Peng

doi:10.1158/1078-0432.ccr-11-0431

Cited by 34 publications

(24 citation statements)

References 40 publications

(36 reference statements)

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“…RC165 and RC170 were maintained in DMEM with 10% heat-inactivated FBS, 1% PS. BD matrigel Chamber Assay and migration assay were performed as previously described (35). …”

Section: Methodsmentioning

confidence: 99%

LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a

Liang

Daniels

et al. 2015

Molecular Cancer Research

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The microRNA-34a (miR-34a), a tumor suppressive microRNA (miRNA), is implicated in epithelial-mesenchymal transition (EMT) and cancer stem cells. Lymphoid enhancer-binding factor-1 (LEF1) is a key transcription factor in the Wnt signaling pathway, and has been suggested to be involved in regulation of cell proliferation and invasion. Here, the molecular mechanism of miR-34a and LEF1 in cooperatively regulating prostate cancer (PCa) cell invasion is described. Molecular profiling analysis of miRNA levels in PCa cells revealed a negative correlation between miR-34a and LEF1 expression, and the downregulation of LEF1 by miR-34a was confirmed by luciferase assays. Further, miR-34a specifically repressed LEF1 expression through direct binding to its 3′-untranslated (3′-UTR) regions. miR-34a modulated the levels of LEF1 to regulate EMT in PCa cells. Functionally, miR-34a negatively correlated with the migration and invasion of PCa cells through LEF1. An analysis of miR-34a expression levels in matched human tumor and benign tissues demonstrated consistent and statistically significant downregulation of miR-34a in primary PCa specimens. These data strongly suggest that miR-34a/LEF1 regulation of EMT plays an important role in PCa migration and invasion. Implications The miR-34a/LEF1 axis represents a potential molecular target for novel therapeutic strategies in PCa.

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“…RC165 and RC170 were maintained in DMEM with 10% heat-inactivated FBS, 1% PS. BD matrigel Chamber Assay and migration assay were performed as previously described (35). …”

Section: Methodsmentioning

confidence: 99%

LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a

Liang

Daniels

et al. 2015

Molecular Cancer Research

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“…The androgen-independent LNCaP-AI cells, a derivative of LNCaP, were maintained in RPMI 1640 medium containing 10% charcoal-stripped, heat-inactivated FBS (CSFBS) (Hyclone Laboratories, Inc., Logan, UT) and 5 µg/ml of insulin, as described previously [15]. Cell proliferation was determined by WST-1 as described previously [16].…”

Section: Methodsmentioning

confidence: 99%

Functional Domains of Androgen Receptor Coactivator p44/Mep50/WDR77and Its Interaction with Smad1

Tian

Ligr

et al. 2013

PLoS ONE

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p44/MEP50/WDR77 has been identified as a coactivator of androgen receptor (AR), with distinct growth suppression and promotion function in gender specific endocrine organs and their malignancies. We dissected the functional domains of p44 for protein interaction with transcription factors, transcriptional activation, as well as the functional domains in p44 related to its growth inhibition in prostate cancer. Using a yeast two-hybrid screen, we identified a novel transcription complex AR-p44-Smad1, confirmed for physical interaction by co-immunoprecipitaion and functional interaction with luciferase assays in human prostate cancer cells. Yeast two-hybrid assay revealed that the N-terminal region of p44, instead of the traditional WD40 domain at the C-terminus, mediates the interaction among p44, N-terminus of AR and full length Smad1. Although both N and C terminal domains of p44 are necessary for maximum AR transcriptional activation, the N terminal fragment of p44 alone maintains the basic effect on AR transcriptional activation. Cell proliferation assays with N- and C- terminal deletion mutations indicated that the central portion of p44 is required for nuclear p44 mediated prostate cancer growth inhibition.

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“…In line with these observations, its expression appears to be suppressed in differentiated cells. FOXM1 expression is often upregulated in human malignancies including tumors arising from the lung (12, 13), prostate (14), breast (15), liver (10) and brain (GBMs) (16, 17). Such alterations may be associated with cancer genesis and progression as well as therapeutic resistance.…”

Section: Introductionmentioning

confidence: 99%

Transcription Factor Interactions Mediate EGF-Dependent COX-2 Expression

Shu

2013

Molecular Cancer Research

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Cyclooxygenase-2 (COX-2) is linked to worse prognosis in patients with malignant gliomas and other tumor types. Amplification/overexpression of epidermal growth factor receptor (EGFR) is commonly seen in these tumors. We have previously shown that EGFR signaling, through activation of p38-mitogen activated protein kinase (MAPK), protein kinase C-δ (PKC-δ), and Sp1, plays an important role in the regulation of COX-2 expression in glioma cells. Here, we report that the Src kinase also has a role in this signaling cascade upstream of p38-MAPK/PKC-δ. In addition, more detailed analysis revealed the involvement of FOXM1, a member of the forkhead box family of transcriptional activators, in EGF-dependent COX-2 induction. FOXM1 protein levels increase after stimulation with EGF although its role in modulating COX-2 expression does not depend on this increase. While a conventional FOXM1 responsive element resides in a distal region (−2872/−2539 relative to the transcriptional start site) of the COX-2 promoter, this is not required for EGF-dependent induction of COX-2. Instead, FOXM1 is capable of interacting with Sp1 at the Sp1 binding site (−245/−240 relative to the start site) of the COX-2 promoter and appears to act in cooperation with Sp1 to mediate EGF-induced COX-2 expression. Definition of this novel interaction provides us with a clearer understanding of the mechanistic basis for the induction of COX-2 with EGF and guides our evaluation of potential newer therapeutic targets that have relevance in this disease.

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Natura-Alpha Targets Forkhead Box M1 and Inhibits Androgen-Dependent and -Independent Prostate Cancer Growth and Invasion

Cited by 34 publications

References 40 publications

LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a

LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a

Functional Domains of Androgen Receptor Coactivator p44/Mep50/WDR77and Its Interaction with Smad1

Transcription Factor Interactions Mediate EGF-Dependent COX-2 Expression

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