Cyclin D1 promotes anchorage-independent cell survival by inhibiting FOXO-mediated anoikis

Gan, Lu; Liu, P; Lü, Huixiong; Chen, S; Yang, Jiangbo; McCarthy, James B.; Knudsen, Karen E.; Huang, Haojie

doi:10.1038/cdd.2009.86

Cited by 36 publications

(27 citation statements)

References 37 publications

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“…Figure 5d shows that Matrigel weakened Bim accumulation. As in previous studies, the failure of Bim to accumulate corresponds with a failure to proceed with anoikis [24,25]. This finding also explains how Matrigel reverses the selective effect of anoikis in the fluorescence microscopy assay in which cells encounter less apoptosis stress in the presence of Matrigel; therefore, the survival advantage brought about by exogenous Pokemon would not be achieved.…”

Section: Resultssupporting

confidence: 79%

Pokemon Silencing Leads to Bim-Mediated Anoikis of Human Hepatoma Cell QGY7703

Liu

Zhang

et al. 2012

IJMS

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Pokemon is an important proto-oncogene that plays a critical role in cellular oncogenic transformation and tumorigenesis. Anoikis, which is regulated by Bim-mediated apoptosis, is critical to cancer cell invasion and metastasis. We investigated the role of Pokemon in anoikis, and our results show that Pokemon renders liver cells resistant to anoikis via suppression of Bim transcription. We knocked-down Pokemon in human hepatoma cells QGY7703 with small interfering RNAs (siRNA). Knockdown of Pokemon alone did not significantly affect the growth and survival of QGY7703 cells but notably enhanced their sensitivity to apoptotic stress due to the presence of chemical agents or cell detachment, thereby inducing anoikis, as evidenced by flow cytometry and caspase-3 activity assays. In contrast, ectopic expression of Pokemon in HL7702 cells led to resistance to anoikis. Dual-luciferase reporter and ChIP assays illustrated that Pokemon suppressed Bim transcription via direct binding to its promoter. Our results suggest that Pokemon prevents anoikis through the suppression of Bim expression, which facilitates tumor cell invasion and metastasis. This Pokemon-Bim pathway may be an effective target for therapeutic intervention for cancer.

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Section: Resultssupporting

confidence: 79%

Pokemon Silencing Leads to Bim-Mediated Anoikis of Human Hepatoma Cell QGY7703

Liu

Zhang

et al. 2012

IJMS

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“…2D (middle), Runx2 proteins were specially pulled down by GST-FOXO1 fusion protein FO1-2, which contains amino acids from 149 to 267 in FOXO1. The same region of FOXO1 has been shown to interact with other proteins such as cyclin D1 (39), suggesting that FO1-2 may act as a functional motif that interacts with other proteins. Collectively, both co-immunoprecipitation and GST pull-down assay demonstrated that FOXO1 interacts with Runx2 in vitro and in PCa cells.…”

Section: Resultsmentioning

confidence: 99%

FOXO1 Inhibits Runx2 Transcriptional Activity and Prostate Cancer Cell Migration and Invasion

et al. 2011

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Prostate cancer (PCa) patients with regional lymph node involvement at radical prostatectomy often experience disease progression to other organs, with the bone as the predominant site. The transcription factor Runx2 plays an important role in bone formation and PCa cell migration, invasion and metastasis. Here we demonstrated that the forkhead protein FOXO1, a key downstream effector of the tumor suppressor PTEN, inhibits the transcriptional activity of Runx2 in PCa cells. This inhibition was enhanced by PTEN but diminished by active Akt. FOXO1 bound to Runx2 in vitro and in vivo and suppressed Runx2’s activity independent of its transcriptional function. FOXO1 inhibited Runx2-promoted migration of PCa cells while silencing of endogenous FOXO1 enhanced PCa cell migration in a Runx2-dependent manner. Forced expression of FOXO1 also inhibited Runx2-promoted PCa cell invasion. Finally, we found that expression of PTEN and the level of FOXO1 in the nucleus is inversely correlated with expression of Runx2 in a cohort of PCa specimens from patients with lymph node and bone metastasis. These data reveal FOXO1 as a critical negative regulator of Runx2 in PCa cells. Inactivation of FOXO1 due to frequent loss of PTEN in PCa cells may leave the oncogenic activities of Runx2 unchecked, thereby driving promiscuous expression of Runx2 target genes involved in cell migration and invasion and favoring PCa progression.

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“…The Trop-2 transcription control network, including factors activating Trop-2 expression or downstream growth-stimulatory pathways has been recently reported [46]. Interestingly, Trop-2-cyclin D1 chimeric mRNAs have also been identified in a variety of tumors and appear to lend enhanced stability to cyclin D1, resulting in cellular immortalization [47] and possibly prevention of anoikis [48]. Of note, Trop-2 expression appears to discriminate populations with stem-like activity [49], which may be important for initiation and perpetuation of cancers [50,51].…”

Section: Discussionmentioning

confidence: 99%

Trop-2 protein overexpression is an independent marker for predicting disease recurrence in endometrioid endometrial carcinoma

et al. 2012

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BackgroundEndometrial cancer is the most common gynecologic malignancy in developed countries. Trop-2 is a glycoprotein involved in cellular signal transduction and is differentially overexpressed relative to normal tissue in a variety of human adenocarcinomas, including endometrioid endometrial carcinomas (EEC). Trop-2 overexpression has been proposed as a marker for biologically aggressive tumor phenotypes.MethodsTrop-2 protein expression was quantified using tissue microarrays consisting of formalin-fixed paraffin-embedded specimens from 118 patients who underwent surgical staging from 2001–9 by laparotomy for EEC. Clinicopathologic characteristics including age, stage, grade, lymphovascular space invasion, and medical comorbidities were correlated with immunostaining score. Univariate and multivariate analyses were performed for overall survival, disease-free survival, and progression-free survival in relation to clinical parameters and Trop-2 protein expression.ResultsClinical outcome data were available for 103 patients. Strong Trop-2 immunostaining was significantly associated with higher tumor grade (p=0.02) and cervical involvement (p<0.01). Univariate analyses showed a significant association with reduced disease-free survival (DFS) (p=0.01), and a trend towards significance for overall and progression-free survival (p=0.06 and p=0.05, respectively). Multivariate analyses revealed Trop-2 overexpression and advanced FIGO stage to be independent prognostic factors for poor DFS (p=0.04 and p <0.001, respectively).ConclusionsTrop-2 protein overexpression is significantly associated with higher tumor grade and serves as an independent prognostic factor for DFS in endometrioid endometrial cancer.

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Cyclin D1 promotes anchorage-independent cell survival by inhibiting FOXO-mediated anoikis

Cited by 36 publications

References 37 publications

Pokemon Silencing Leads to Bim-Mediated Anoikis of Human Hepatoma Cell QGY7703

Pokemon Silencing Leads to Bim-Mediated Anoikis of Human Hepatoma Cell QGY7703

FOXO1 Inhibits Runx2 Transcriptional Activity and Prostate Cancer Cell Migration and Invasion

Trop-2 protein overexpression is an independent marker for predicting disease recurrence in endometrioid endometrial carcinoma

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