Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis

Liu, Junli; Wang, Xiaoyan; Huang, Bangxing; Zhu, Fang; Zhang, Ruiguang; Wu, Gang

doi:10.1007/s12032-010-9510-7

Cited by 53 publications

(55 citation statements)

References 22 publications

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“…However, the involvement of the biological functions of CDK5 have diversified into cancer (10,16). In our previous study (14), Cdk5 and/or p35 were commonly expressed in two-thirds of NSCLC cases and its high expression level was indicative of an unfavorable prognosis in patients with NSCLC, which suggested novel concepts for use as a biomarker or for the development of molecular-targeted treatments for NSCLC. Demelash et al (10) extended these observations to lung neuroendocrine carcinoma, including small cell lung carcinoma and carcinoid.…”

Section: Discussionmentioning

confidence: 93%

“…The inhibition of the activity of CDK5 decreases cancer cell migration and invasion (13), however, the mechanism underlying the involvement of CDK5 in tumorigenesis remains to be fully elucidated. Our previous study demonstrated that the overexpression of CDK5 is closely correlated with reduced survival rates in patients (14), however, its intracellular mechanisms, linking the activity of CDK5 with the progression of cancer remain to be determined. The present study investigated the impact of CDK5 on the proliferation, migration and invasiveness of the A549 human NSCLC cell line, by using its functional inhibitor, roscovitine, and CDK5 small interfering (si)RNA, to attempt to elucidate its underlying molecular mechanisms.…”

Section: Introductionmentioning

confidence: 98%

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Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling

Zhou

et al. 2015

Molecular Medicine Reports

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Abstract. Determining the molecular phenotype is a key to understanding and predicting the metastatic potential and the prognosis for patients with lung cancer. Our previous study demonstrated that increased expression of cyclin-dependent kinase 5 (CDK5) in patients with non-small cell lung cancer (NSCLC) is associated with a poorer prognosis. The present study aimed to further investigate the underlying mechanism of CDK5 in vitro and in vivo using the A549 human NSCLC cell line. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to quantify the proliferation of the A549 cells; migration assay and invasiveness assays were performed using Transwell chambers and wound healing assays were used to assess cell motility, which was assessed by measuring the movement of cells. Inhibition of CDK5 by roscovitine and small interfering (si)RNA was used to investigate the mechanism of CDK5 in the process of A549 lung cancer cell proliferation, migration and invasion. The results demonstrated that functional inhibition of CDK5 using roscovitine and siRNA markedly suppressed the proliferation of A549 cells and resulted in a reduced tumor mass in vivo. In addition, the hinhibition of CDK5 reduced the migration and invasiveness of the A549 cells in vitro and in vivo. Notably, CDK5 inhibition also impaired tumor cell cytoskeletal remodeling and led to loss of cell polarity, which may partially explain the reduction of A549 cell mobility and invasiveness.The results of the present study revealed that CDK5 may be important in the regulation of migration and invasiveness in NSCLC through its effects on cytoskeletal remodeling. IntroductionLung cancer has long been the leading cause of cancer-associated mortality worldwide (1). Although numerous therapeutic strategies have improved significantly, the presence of locally advanced or metastatic lung cancer reduces the curability of this life-threatening disease. Several efforts have been made to understand the mechanism and molecular pathogenesis of this disease, with promise in the development of more effective targeted treatment strategies for lung cancer, particularly non-small cell lung cancer (NSCLC). Certain small molecular inhibitors have been developed against certain tyrosine kinases, including epidermal growth factor receptor and vascular endothelial growth factor receptor (2); however, the overall progression free survival rate has not improved satisfactorily (3). The poor survival rate is predominantly attributed to aggressive growth, advanced stage at diagnosis and local recurrence (4). The identification of effectors, which modulate growth, cell migration and invasion will assist in understanding the process of disease progression and enable the development of novel therapeutic targets for patients with NSCLC.Cyclin-dependent kinase 5 (CDK5) has been recognized as a key factor in regulating the migration and plasticity of neuron cells (5,6). Compared with other CDKs, CDK5 is considered to be an essential regulator of neuronal differentiation, ra...

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 98%

Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling

Zhou

et al. 2015

Molecular Medicine Reports

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“…Aberrant expression of CDK4 has been implicated in ovarian (Kusume et al 1999), urinary bladder , endometrial (Semczuk et al 2004) and oral (Poomsawat et al 2010) cancers. CDK5 has been shown to be involved in lung cancer (Choi et al 2009;Liu et al 2010). The expression of CDK 6 is also altered in oral cancer (Poomsawat et al 2010).…”

Section: Introductionmentioning

confidence: 99%

The CDK inhibitors in cancer research and therapy

Cicenas

Valius²

2011

J Cancer Res Clin Oncol

216

176

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Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in diVerent human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer's, Parkinson's diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the speciWc purpose of their research. For this purpose, the targets, commercial availability and IC 50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitors.

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“…LGR561, the most potent antiangiogenic compound, displayed the strongest inhibition of Cdk5. Beside its well known function in the nervous system, Cdk5 recently was shown to be upregulated in some cancer types and to regulate EC migration and angiogenesis [14,[26][27][28]. Thus, it might be a highly interesting target for the development of drugs that inhibit both, cancer growth and EC angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Anti-angiogenic effects of purine inhibitors of cyclin dependent kinases

et al. 2011

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Small molecular inhibitors of Cyclin dependent kinases (Cdks) are currently being developed as anticancer therapeutics due to their antiproliferative properties. The purine Cdk specific inhibitor (R)-roscovitine (seliciclib, CYC202) represents one of the most promising of these compounds. It is currently evaluated in clinical trials concerning cancer therapy. Recently, we have shown that roscovitine exerts potent antiangiogenic effects and elucidated Cdk5 as a new player in angiogenesis. These findings introduce Cdk5 as novel target for antiangiogenic therapy, and Cdk5 inhibitors as an attractive therapeutic approach. Here, we present the antiangiogenic profile of 15 derivatives of roscovitine in vitro and in vivo and provide structure activity relationships of the roscovitine analogs. The (S)-isomer LGR561 and the respective (R)- and (S)-isomers LGR848 and LGR849 strongly inhibited proliferation and cell cycle progression, induced cell death, and reduced migration of endothelial cells in vitro. In comparison to roscovitine, these compounds showed an increased potency to inhibit Cdk2, Cdk5, Cdk7, and Cdk9. By analyzing the effects of LGR561, LGR848, and LGR849 on endothelial cell tube formation, mouse aortic ring sprouting, angiogenesis in the chick chorioallantoic membrane, and neovessel formation in the mouse cornea, we elucidate the two (S)-isomers LGR561 and LGR849 as highly potent inhibitors of angiogenesis. This study provides first information on how to modify roscovitine to develop Cdk inhibitors with increased antiangiogenic activity and suggests the application of existing and the development of new Cdk inhibitors to inhibit both, cancer cell proliferation and angiogenesis.

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Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis

Cited by 53 publications

References 22 publications

Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling

Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling

The CDK inhibitors in cancer research and therapy

Anti-angiogenic effects of purine inhibitors of cyclin dependent kinases

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