Mitotic entry: The interplay between Cdk1, Plk1 and Bora

Parrilla, A.; Cirillo, Luca; Thomas, Y.; Gotta, Monica; Pintard, Lionel; Santamaría, Anna

doi:10.1080/15384101.2016.1249544

Cited by 37 publications

(32 citation statements)

References 39 publications

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“…PLK1 is the major player of the PLK family, which regulates diverse cell-cycle activities, including centrosome maturation, mitotic entry, spindle assembly, chromosomal alignment, and segregation and cytokinesis (40). To execute the different mitotic events it interacts with and regulates the function of numerous cell-cycle proteins (41)(42)(43)(44). In our study, PLK1 and its downstream cell-cycle regulatory genes were differentially expressed after LSD1 inhibition with HCI-2509, as well as after siLSD1-mediated knockdown.…”

Section: Discussionmentioning

confidence: 99%

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

Dalvi

Macheleidt

Lim

et al. 2019

Molecular Cancer Research

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Lysine-specific demethylase 1 (LSD1) is a histone modifier that is highly overexpressed in lung adenocarcinoma, which results in aggressive tumor biology. Tumor cell proliferation and migration analysis after LSD1 inhibition in the lung adenocarcinoma cell line PC9, using the LSD1 inhibitor HCI-2509 and siRNA, demonstrated that LSD1 activity was essential for proliferation and migration capacities of tumor cells. Moreover, reduced proliferation rates after LSD1 inhibition were shown to be associated with a cell-cycle arrest of the tumor cells in the G 2-M-phase. Expression profiling followed by functional classification and pathway analysis indicated prominent repression of the polo-like kinase 1 (PLK1) pathway upon LSD1 inhibition. In contrast, transient overexpression of exogenous PLK1 plasmid rescued the LSD1 inhibition-mediated downregulation of PLK1 pathway genes. Mechanistically, LSD1 directly regulates expression of PLK1 by binding to its promoter region that subsequently affects expression of its downstream target genes. Notably, using lung adenocarcinoma TCGA datasets a significant correlation between LSD1 and PLK1 along with its downstream targets was observed. Furthermore, the LSD1/PLK1 linkage was confirmed by IHC analysis in a clinical lung adenocarcinoma cohort (n ¼ 43). Conclusively, this is the first study showing a direct transcriptional link between LSD1 and PLK1. Implications: These findings point to a role of LSD1 in regulating PLK1 and thus efficient G 2-M-transitionmediating proliferation of tumor cells and suggest targeting the LSD1/PLK1 axis as a novel therapeutic approach for lung adenocarcinoma treatment.

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Section: Discussionmentioning

confidence: 99%

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

Dalvi

Macheleidt

Lim

et al. 2019

Molecular Cancer Research

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“…Moreover, Plk1 is also involved in maturation of centrosomes, spindle assembly, spindle checkpoint and exit from mitosis. Expression levels of Plk1 fluctuate during the cell cycle and are the highest at G2/M transition [ 30 , 31 ]. Aurora kinases are also involved in the maturation of centrosomes, spindle assembly, chromosome segregation and mitotic exit.…”

Section: Regulation Of the Cell Cyclementioning

confidence: 99%

The therapeutic potential of cell cycle targeting in multiple myeloma

Maes

Veirman

et al. 2017

Oncotarget

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Proper cell cycle progression through the interphase and mitosis is regulated by coordinated activation of important cell cycle proteins (including cyclin-dependent kinases and mitotic kinases) and several checkpoint pathways. Aberrant activity of these cell cycle proteins and checkpoint pathways results in deregulation of cell cycle progression, which is one of the key hallmarks of cancer. Consequently, intensive research on targeting these cell cycle regulatory proteins identified several candidate small molecule inhibitors that are able to induce cell cycle arrest and even apoptosis in cancer cells. Importantly, several of these cell cycle regulatory proteins have also been proposed as therapeutic targets in the plasma cell malignancy multiple myeloma (MM). Despite the enormous progress in the treatment of MM the past 5 years, MM still remains most often incurable due to the development of drug resistance. Deregulated expression of the cyclins D is observed in virtually all myeloma patients, emphasizing the potential therapeutic interest of cyclin-dependent kinase inhibitors in MM. Furthermore, other targets have also been identified in MM, such as microtubules, kinesin motor proteins, aurora kinases, polo-like kinases and the anaphase promoting complex/cyclosome. This review will provide an overview of the cell cycle proteins and checkpoint pathways deregulated in MM and discuss the therapeutic potential of targeting proteins or protein complexes involved in cell cycle control in MM.

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“…Similarly, in conditions of DNA damage and activation of the G2/M checkpoint, ataxia telangiectasia and Rad3 related kinase (ATR) phosphorylates BORA to degrade it and to sustain the G2/M blockade [4]. Under recovery conditions, Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of BORA on its N-terminal domain is essential for PLK1 re-activation and thus mitotic commitment [5][6][7], underlying its crucial role…”

Section: Introductionmentioning

confidence: 99%

Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer

Parrilla

Barber

Majem

et al. 2020

Cancers

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Identifying novel actionable factors that critically contribute to tumorigenesis is essential in ovarian cancer, an aggressive and disseminative tumor, with limited therapeutic options available. Here we show that Aurora Borealis (BORA), a mitotic protein that plays a key role in activating the master mitotic kinase polo-like kinase 1 (PLK1), has an oncogenic role in ovarian cancer. Gain and loss of function assays on mouse models and ex vivo patient-derived ascites cultures revealed an oncogenic role of BORA in tumor development and a transcriptome-analysis in clinically representative models depicted BORA's role in survival, dissemination and inflammatory cancer related-pathways. Importantly, combinatory treatments of FDA-approved inhibitors against oncogenic downstream effectors of BORA displayed synergistic effect in ovarian cancer models, offering promising therapeutic value. Altogether, our findings uncovered for the first time a critical role of BORA in the viability of human cancer cells providing potential novel therapeutic opportunities for ovarian cancer management.Cancers 2020, 12, 886 2 of 25 in cell cycle division. Nevertheless, even though BORA depletion has been reported to reduce the activity of PLK1 kinase, our understanding of its relevance in cancer is still very limited and there is no comprehensive study that defines the downstream biological consequences of BORA modulation in cancer. Recent evidence has shown that BORA is overexpressed in various tumors such breast, lung, and gastric adenocarcinomas and might serve as a prognostic biomarker [8].Ovarian cancer (OC), the most lethal gynecologic malignancy, is frequently diagnosed at advanced stages with disseminated disease, which limits the therapeutic options [9]. Despite improved cytoreductive surgical approaches and chemotherapy-based regimens, the survival of OC patients has remained largely unchanged during the last two decades [10,11]. Recent advances in cancer genomics have revealed that OC is molecularly a very heterogeneous disease, with extensive genomic instability, copy-number variations and defects in the homologous recombination repair pathway [12]. These genomic aberrations contribute to the development of tumor resistance, hampering effective treatment and ultimately causing disease recurrence [13], but also offer novel potential actionable vulnerabilities that can enhance the effectiveness of existing therapies.Molecular targeted therapies have been implemented routinely into the clinics changing OC management with the inclusion of anti-angiogenic compounds (i.e., monoclonal antibodies such Bevacizumab) [14,15] and poly ADP-ribose polymerases (PARP) inhibitors (i.e., Olaparib or Rucaparib) for breast-cancer (BRCA)-mutated carriers and BRCAness phenotype patients [16,17]. Synthetic lethality produced by PARP inhibitors enhances the therapeutic window after chemotherapy in recurrent platinum-sensitive OC subjects [18]. Nonetheless, it is effective in only a subset of patients, highlighting the urgent clinical need of searching...

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Mitotic entry: The interplay between Cdk1, Plk1 and Bora

Cited by 37 publications

References 39 publications

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

The therapeutic potential of cell cycle targeting in multiple myeloma

Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer

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