Nek2 as an Effective Target for Inhibition of Tumorigenic Growth and Peritoneal Dissemination of Cholangiocarcinoma

Kokuryo, Toshio; Senga, Takeshi; Yokoyama, Yukihiro; Nagino, Masato; Nimura, Yuji; Hamaguchi, Michinari

doi:10.1158/0008-5472.can-07-1489

Cited by 83 publications

(95 citation statements)

References 18 publications

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“…Nek2 is degraded by anaphasepromoting complex or cyclosome (APC/C) during cell cycle progression (24). Depletion of Nek2 prevents centrosome separation, delays mitosis, and results in increased apoptosis, possibly as a result of mitotic errors, suggesting possible therapeutic potential for cancer (25). Very little is known about the remaining members of the Nek family.…”

Section: Introductionmentioning

confidence: 99%

Nek6 Mediates Human Cancer Cell Transformation and Is a Potential Cancer Therapeutic Target

Nassirpour

Shao

Flanagan

et al. 2010

Molecular Cancer Research

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We investigated the role of Nek6, a member of the NIMA-related serine/threonine kinase family, in tumorigenesis. Transcript, protein, and kinase activity levels of Nek6 were highly elevated in the malignant tumors and human cancer cell lines compared with normal tissue and fibroblast cells. Expression of exogenous wild-type Nek6 increased anchorage-independent growth of a variety of human cancer cell lines, whereas overexpression of the kinase-dead Nek6 and RNAi knockdown of endogenous Nek6 suppressed cancer cell transformation and induced apoptosis. Additionally, in in vivo xenograft nude mouse model, knockdown of Nek6 in HeLa cells resulted in reduction of tumor size relative to control siRNA tumors. Most importantly, knocking down endogenous Nek6 levels or exogenous expression of the kinase-dead form did not inhibit cell proliferation, nor did it induce apoptosis in normal fibroblast cells. Taken together, our data indicate a pivotal role for Nek6 in tumorigenesis and establish Nek6 as a potential target for treatment of a variety of human cancers.

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Section: Introductionmentioning

confidence: 99%

Nek6 Mediates Human Cancer Cell Transformation and Is a Potential Cancer Therapeutic Target

Nassirpour

Shao

Flanagan

et al. 2010

Molecular Cancer Research

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“…Mice were inoculated with KLM1 and KP4 cells (1 · 10 7 ), injected subcutaneously into the femoral area. (16) After 1 week, a-bisabolol (1000 mg ⁄ kg), diluted in olive oil (total volume 200 lL), was administered intragastrically using an orogastric tube once a week for 3 weeks. Intragastric administration of an equal volume of olive oil alone was used as a control.…”

Section: Methodsmentioning

confidence: 99%

Antitumor effects of α‐bisabolol against pancreatic cancer

et al. 2011

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In the present study, we investigated whether a-bisabolol, a sesquiterpene alcohol present in essential oils derived from a variety of plants, has antitumor effects against pancreatic cancer. a-Bisabolol induced a decrease in cell proliferation and viability in pancreatic cancer cell lines (KLM1, KP4, Panc1, MIA Paca2), but not in pancreatic epithelial cells (ACBRI515). a-Bisabolol treatment induced apoptosis and suppressed Akt activation in pancreatic cancer cell lines. Furthermore, a-bisabolol treatment induced the overexpression of early growth response-1 (EGR1), whereas EGR1 siRNA decreased the a-bisabolol-induced cell death of KLM1 cells. Tumor growth in both subcutaneous and peritoneal xenograft nude mouse models was significantly inhibited by intragastric administration of 1000 mg ⁄ kg of a-bisabolol, once a week for three weeks. The results indicate that a-bisabolol could be a novel therapeutic option for the treatment of pancreatic cancer. (Cancer Sci 2011; 102: 2199-2205

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“…NEK2 is a potential drug target in breast cancer (Hayward et al, 2004;Tsunoda et al, 2009;Wu et al, 2008), as well as cholangiocarcinoma and colorectal cancer (Kokuryo et al, 2007;Suzuki et al, 2010). The availability of NEK2-selective inhibitors should enable further target validation studies in these and other cancers.…”

Section: Box 2 Mitotic Kinases As Anti-cancer Targetsmentioning

confidence: 99%

Cell cycle regulation by the NEK family of protein kinases

Fry

O’Regan

Sabir

et al. 2012

Journal of Cell Science

306

322

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SummaryGenetic screens for cell division cycle mutants in the filamentous fungus Aspergillus nidulans led to the discovery of never-in-mitosis A (NIMA), a serine/threonine kinase that is required for mitotic entry. Since that discovery, NIMA-related kinases, or NEKs, have been identified in most eukaryotes, including humans where eleven genetically distinct proteins named NEK1 to NEK11 are expressed. Although there is no evidence that human NEKs are essential for mitotic entry, it is clear that several NEK family members have important roles in cell cycle control. In particular, NEK2, NEK6, NEK7 and NEK9 contribute to the establishment of the microtubulebased mitotic spindle, whereas NEK1, NEK10 and NEK11 have been implicated in the DNA damage response. Roles for NEKs in other aspects of mitotic progression, such as chromatin condensation, nuclear envelope breakdown, spindle assembly checkpoint signalling and cytokinesis have also been proposed. Interestingly, NEK1 and NEK8 also function within cilia, the microtubule-based structures that are nucleated from basal bodies. This has led to the current hypothesis that NEKs have evolved to coordinate microtubule-dependent processes in both dividing and non-dividing cells. Here, we review the functions of the human NEKs, with particular emphasis on those family members that are involved in cell cycle control, and consider their potential as therapeutic targets in cancer.

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Nek2 as an Effective Target for Inhibition of Tumorigenic Growth and Peritoneal Dissemination of Cholangiocarcinoma

Cited by 83 publications

References 18 publications

Nek6 Mediates Human Cancer Cell Transformation and Is a Potential Cancer Therapeutic Target

Nek6 Mediates Human Cancer Cell Transformation and Is a Potential Cancer Therapeutic Target

Antitumor effects of α‐bisabolol against pancreatic cancer

Cell cycle regulation by the NEK family of protein kinases

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