A novel role for Plk4 in regulating cell spreading and motility

Rosario, Carla O.; Kazazian, Karineh; Zih, Francis Si Wai; Brashavitskaya, Olga; Haffani, Yosr Z.; Xu, Roland; George, A; Dennis, James W.; Swallow, Carol J.

doi:10.1038/onc.2014.275

Cited by 52 publications

(49 citation statements)

References 52 publications

(85 reference statements)

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“…Recently, Rosario et al. demonstrated that PLK4 is also involved in regulating cell spreading and motility promoting cell migration and may, therefore, be associated with cancer progression and death from metastasis in solid tumor patients . Remarkably, we also demonstrated that CFI‐400945 significantly impaired rhabdoid tumor cell migration and invasion while sparing non‐neoplastic human fibroblasts.…”

Section: Discussionsupporting

confidence: 66%

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A functional screening of the kinome identifies the Polo‐like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain

Sredni

Suzuki

Yang

et al. 2017

Pediatric Blood & Cancer

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Purpose: Malignant rhabdoid tumors (MRTs) are deadly embryonal tumors of the infancy. With poor survival and modest response to available therapies, more effective and less toxic treatments are needed. We hypothesized that a systematic screening of the kinome will reveal kinases that drive rhabdoid tumors and can be targeted by specific inhibitors. Methods:We individually mutated 160 kinases in a well-characterized rhabdoid tumor cell line (MON) using lentiviral clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The kinase that most significantly impaired cell growth was further validated. Its expression was evaluated by microarray gene expression (GE) within 111 pediatric tumors, and functional assays were performed. A small molecule inhibitor was tested in multiple rhabdoid tumor cell lines and its toxicity evaluated in zebrafish larvae. Results:The Polo-like kinase 4 (PLK4) was identified as the kinase that resulted in higher impairment of cell proliferation when mutated by CRISPR/Cas9. PLK4 CRISPR-mutated rhabdoid cells demonstrated significant decrease in proliferation, viability, and survival. GE showed upregulation of PLK4 in rhabdoid tumors and other embryonal tumors of the brain. The PLK4 inhibitor CFI-400945 showed cytotoxic effects on rhabdoid tumor cell lines while sparing non-neoplastic human fibroblasts and developing zebrafish larvae. Conclusions:Our findings indicate that rhabdoid tumor cell proliferation is highly dependent on PLK4 and suggest that targeting PLK4 with small-molecule inhibitors may hold a novel strategy for the treatment of MRT and possibly other embryonal tumors of the brain. This is the first time that PLK4 has been described as a potential target for both brain and pediatric tumors.

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Section: Discussionsupporting

confidence: 66%

“…PLK4 plays a key role in cell cycle control. It localizes to the centrosomes and is a critical regulator of centriole duplication . In normal conditions, PLK4 is expressed in proliferating tissues such as testis.…”

Section: Discussionmentioning

confidence: 99%

A functional screening of the kinome identifies the Polo‐like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain

Sredni

Suzuki

Yang

et al. 2017

Pediatric Blood & Cancer

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“…While roles of Plk4 outside of centrosome biogenesis have been proposed (Rosario, et al, 2015; Rosario, et al, 2010; Martindill, et al, 2007), multiple lines of evidence argue that centrosome amplification is responsible for triggering spontaneous tumorigenesis in mice that overexpress Plk4. First, modest increases in Plk4 protein are sufficient to promote persistent centrosome amplification and spontaneous tumor development.…”

Section: Discussionmentioning

confidence: 99%

Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals

et al. 2017

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SUMMARY Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of cancer remains unclear. Here, we test the consequence of centrosome amplification by creating mice in which centrosome number can be chronically increased in the absence of additional genetic defects. We show that increasing centrosome number elevated tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive aneuploidy and the development of spontaneous tumors in multiple tissues. Tumors arising from centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship between centrosome amplification, genomic instability and tumor development.

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“…Moreover, recently an unexpected role for Plk4 in regulating cell motility has been identified. While Plk4 insufficiency promotes mitotic instability and tumorigenesis, increased Plk4 activity may promote invasion and disease progression in established malignancies …”

Section: The Plk Familymentioning

confidence: 99%

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Bossche

Lardon

Deschoolmeester

et al. 2016

Medicinal Research Reviews

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Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.

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A novel role for Plk4 in regulating cell spreading and motility

Cited by 52 publications

References 52 publications

A functional screening of the kinome identifies the Polo‐like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain

A functional screening of the kinome identifies the Polo‐like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain

Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

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