The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention

Alao, John P.

doi:10.1186/1476-4598-6-24

Cited by 711 publications

(519 citation statements)

References 148 publications

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“…We consider that further studies to support this speculation would be of value because the Wnt signaling pathway and cyclin D1 could potentially be a future target of anticancer drugs. 3,25 Expression of MMP-7, which is another target of b-catenin, was limited in this study to only one case of endometrial stromal nodule and three of lowgrade endometrial stromal sarcoma, and there was no significant correlation between b-catenin overexpression and MMP-7 expression. MMP-7 did not seem to have a crucial function in tissue invasion and metastasis in low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma in this study.…”

Section: Discussionmentioning

confidence: 74%

Coincident expression of β-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas

et al. 2010

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Aberrant activation of the Wnt signaling pathway has been implicated in tumorigenesis of a wide range of tumors, including colorectal cancer. Regarding endometrial stromal tumors and related high-grade sarcomas, there have been some reports regarding nuclear accumulation of b-catenin. To clarify the function of the aberrant Wnt signaling pathway in these tumors, we searched for mutations of the CTNNB1 (b-catenin) gene and APC gene by PCR direct sequencing and analyzed the methylation status of SFRP genes. We also examined overexpression of cyclin D1 and MMP-7, which are direct target genes of b-catenin. Eight endometrial stromal nodules, 16 low-grade endometrial stromal sarcomas, and 13 undifferentiated endometrial sarcomas were examined. PCR and direct sequencing revealed no mutation of the b-catenin gene or the APC gene. Concerning the promoter methylation status of SFRP genes, methylation-specific PCR revealed no significant difference between the group with nuclear b-catenin expression and that without nuclear b-catenin expression. Immunohistochemistry revealed overexpression of cyclin D1 in 2 out of 8 endometrial stromal nodules, 1 out of 17 low-grade endometrial stromal sarcomas, and 6 out of 13 undifferentiated endometrial sarcomas, and these 6 undifferentiated endometrial sarcomas simultaneously expressed nuclear b-catenin. Interestingly, all six undifferentiated endometrial sarcoma cases with cyclin D1 overexpression histologically featured rather uniform nuclei. In contrast, the six cases of undifferentiated endometrial sarcoma with highly pleomorphic nuclei were all negative for cyclin D1. In conclusion, among endometrial stromal tumors and related sarcomas, undifferentiated endometrial sarcomas featuring uniform nuclei were characterized by frequent coincident expression of b-catenin and cyclin D1. This finding raises the possibility that cyclin D1 is upregulated by b-catenin in these high-grade sarcomas previously called high-grade endometrial stromal sarcoma.

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Section: Discussionmentioning

confidence: 74%

Coincident expression of β-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas

et al. 2010

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“…Figure 7 is the schematic representation of the positive feedback loop depicting the roles of DNA-PK, AKT, GSK3b and cyclin D1 in cyclin D1 overexpression, and the resulting acquisition of radioresistance. The present study suggests the importance of positive feedback loop of the DNA-PK/AKT/GSK3b/cyclin D1 pathway, and any of the member of the pathway may serve as a new target to improve the outcome of radioteherapy, especially on recurrent radioresistant tumors (Alao, 2007;TakahashiYanaga and Sasaguri, 2008).…”

Section: Discussionmentioning

confidence: 79%

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

et al. 2010

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Recurrence is frequently associated with the acquisition of radioresistance by tumors and resulting failures in radiotherapy. We report, in this study, that long-term fractionated radiation (FR) exposures conferred radioresistance to the human tumor cells, HepG2 and HeLa with cyclin D1 overexpression. A positive feedback loop was responsible for the cyclin D1 overexpression in which constitutively active AKT was involved. AKT is known to inactivate glycogen synthase kinase-3b (GSK3b), which is essential for the proteasomal degradation of cyclin D1. The resulting cyclin D1 overexpression led to the forced progression of S-phase with the induction of DNA double strand breaks. Cyclin D1-dependent DNA damage activated DNA-dependent protein kinase (DNA-PK), which in turn activated AKT and inactivated GSK3b, thus completing a positive feedback loop of cyclin D1 overproduction. Cyclin D1 overexpression led to the activation of DNA damage response (DDR) consisted of ataxia telangiectasia mutated (ATM)-and Chk1-dependent DNA damage checkpoint and homologous recombination repair (HRR). Long-term FR cells repaired radiation-induced DNA damage faster than non-FR cells. Thus, acquired radioresistance of long-term FR cells was the result of alterations in DDR mediated by cyclin D1 overexpression. Inhibition of the AKT/GSK3b/cyclin D1/ Cdk4 pathway by the AKT inhibitor, Cdk4 inhibitor or cyclin D1 targeting small interfering RNA (siRNA) suppressed the radioresistance. Present observations give a mechanistic insight for acquired radioresistance of tumor cells by cyclin D1 overexpression, and provide novel therapeutic targets for recurrent radioresistant tumors.

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“…The cyclin D1 gene (CCND1) is amplified and/or overexpressed in several types of human cancer (Alao, 2007). Cyclin D1 mRNA levels are increased in both primary prostate cancer samples (Han et al, 1998) and androgenindependent bone metastasis (Drobnjak et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G 0 /G 1 . This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27 kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

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The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention

Cited by 711 publications

References 148 publications

Coincident expression of β-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas

Coincident expression of β-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

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