Small Molecule Targeting the Hec1/Nek2 Mitotic Pathway Suppresses Tumor Cell Growth in Culture and in Animal

Wu, Guikai; Qiu, Xiao‐Long; Zhou, Lihua; Zhu, Jiewen; Chamberlin, Richard; Lau, Johnson Y. N.; Chen, Phang-Lang; Lee, Wen‐Hwa

doi:10.1158/0008-5472.can-08-1915

Cited by 97 publications

(132 citation statements)

References 43 publications

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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

308

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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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

308

322

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“…NDC80/Hec1 is a key component of the mitotic kinetochore complex and an attractive molecular target for cancer (9). As a conserved mitotic regulator, Hec1 is critical for spindle checkpoint control, kinetochore functionality, and cell survival (9).…”

Section: Introductionmentioning

confidence: 99%

“…As a conserved mitotic regulator, Hec1 is critical for spindle checkpoint control, kinetochore functionality, and cell survival (9). Hec1 is expressed in rapidly dividing cells, and its levels are increased in cell lines upon transformation (10).…”

Section: Introductionmentioning

confidence: 99%

“…Hec1 is expressed in rapidly dividing cells, and its levels are increased in cell lines upon transformation (10). Hec1 is overexpressed in human cancers, including breast, lung, cervical, brain, liver, colorectal, and gastric cancers (9,11,12). Hec1 expression is low in slow dividing and differentiated organs such as the heart, lung, liver, kidney, and brain (10).…”

Section: Introductionmentioning

confidence: 99%

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Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines In Vitro and In Vivo

Huang¹,

Chang²,

Lee³

et al. 2014

Molecular Cancer Therapeutics

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Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI 50 ¼ 14.29-73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI 50 > 10 mmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of in vivo tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers.

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“…Loss of NEK2 activity inhibits centrosome separation, whereas overexpression leads to premature centrosome separation. NEK2 overexpression has also been described in a number of human tumor types (10 -13), making it an attractive drug target especially for breast cancer treatment (14,15).…”

mentioning

confidence: 99%

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

Nabilsi

Ryder

Peraza-Penton

et al. 2013

Journal of Biological Chemistry

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Background: NEK2 is a mammalian kinase that promotes centrosome separation during the cell cycle. Results: Agents that demethylate the NEK2 promoter or induce DNA damage repress NEK2 expression in a p53-dependent manner. Conclusion: p53 represses NEK2 expression and protects its binding region from accumulating DNA methylation. Significance: Knowledge regarding novel mechanisms of NEK2 regulation may help inform clinical application of NEK2-based anticancer therapeutics.

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Small Molecule Targeting the Hec1/Nek2 Mitotic Pathway Suppresses Tumor Cell Growth in Culture and in Animal

Cited by 97 publications

References 43 publications

Cell cycle regulation by the NEK family of protein kinases

Cell cycle regulation by the NEK family of protein kinases

Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines In Vitro and In Vivo

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

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