Cell Division and Cancer Group

Madrid, Spain

Cell Division and Cancer Group

Madrid, Spain

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News Article | July 11, 2017
Site: www.biosciencetechnology.com

Plk1 inhibitors have recently been acknowledged as an "Innovative Therapy for leukemia" by the US Food and Drug Administration (FDA). However, a study published in Nature Medicine by researchers from the Spanish National Cancer Research Centre (CNIO) suggests that prolonged use of these inhibitors can not only lead to hypertension issues but also to the rupturing of blood vessels and severe cardiovascular problems. The idea behind personalized medicine is knowing the function of each one of our genes and proteins and selecting the appropriate drugs against these proteins according to the alterations in each patient. In recent years, cell cycle regulator inhibitors, the process that controls the proliferation of tumor cells, have shown their usefulness in various tumors, such as breast cancer. Among the new drugs used in this strategy is volasertib, a Plk1 protein inhibitor, which has shown very promising results in acute myeloid leukemia and has recently been acknowledged as an "Innovative Therapy" by the FDA for its effectiveness against this type of tumor in clinical trials. "One of the problems we encounter when testing new drugs on patients is that we know very little about the real function of the protein they are targeting. And surprises are not good for the clinical development of these drugs," said Marcos Malumbres, coordinator of the study and head of the Cell Division and Cancer Group at the CNIO. His team wanted to study the actual function of this protein in mammals using laboratory mice as models. "Many of the proteins tested in clinical trials have been studied mainly in organisms such as yeast or flies or in human cells in cultures. However, these studies do not go far enough in identifying the relevance that a protein can have on a given organ," said Malumbres. To study the function of Plk1, the researchers generated a mouse strain with decreased levels of this protein. "It was amazing, half of the mice began to die from thoracic hemorrhages due to ruptured arteries," said Guillermo de Cárcer, a researcher at the CNIO and lead author of the paper. "One of the most striking findings was that the males died during the first night they spent with females in the same box. One of the situations that causes the highest rise in blood pressure in young males." Plk1 had been initially characterized as a protein that controls how cells multiply, which caught the attention of pharmaceutical companies who saw in it a new therapeutic target to slow down tumor growth. Several inhibitors of this protein are undergoing clinical trials to treat various types of tumors. One of these inhibitors, volasertib, has recently been acknowledged as one of the best therapies against acute myeloid leukemia. Like most chemotherapeutic drugs, volasertib causes some side effects that are still being studied. The team of researchers, including scientists from the Spanish Centre for Cardiovascular Research (CNIC), the Cancer Research Centre (CIC) at Salamanca, the University of Salamanca, and the London Research Institute (London), treated mice with low doses of volasertib for two months. Mice with low levels of Plk1 or that had been treated with volasertib did not have growth issues but they did display ruptured arteries and cardiovascular problems. These results indicated that arteries are even more sensitive to Plk1 inhibition than other tissues in adult organisms. In fact, the paper found that Plk1 is an essential protein needed to make the cells on the walls of arteries contract; a cellular movement that is responsible for maintaining blood pressure at acceptable levels. Cardiovascular problems and cancer are the major causes of morbidity-mortality in advanced societies. The involvement of Plk1 in controlling both processes will have a major impact on biomedical developments in the future. "Our data do not go against the use of Plk1 inhibitors in clinical treatments," said Malumbres. "Unfortunately, all drugs have some type of side effect. The problem is not being aware of them. We must study the biological functions of a protein very well and in appropriate models before using it as a target on people. This is the only way in which we will be able to use it correctly," concluded the CNIO researcher.


News Article | July 10, 2017
Site: www.eurekalert.org

Plk1 inhibitors have recently been acknowledged as an "Innovative Therapy for leukaemia" by the US Food and Drug Administration (FDA). However, a study published in Nature Medicine by researchers from the Spanish National Cancer Research Centre (CNIO) suggests that prolonged use of these inhibitors can not only lead to hypertension issues but also to the rupturing of blood vessels and severe cardiovascular problems. The idea behind personalised medicine is knowing the function of each one of our genes and proteins and selecting the appropriate drugs against these proteins according to the alterations in each patient. In recent years, cell cycle regulator inhibitors, the process that controls the proliferation of tumour cells, have shown their usefulness in various tumours, such as breast cancer. Among the new drugs used in this strategy is volasertib, a Plk1 protein inhibitor, which has shown very promising results in acute myeloid leukaemia and has recently been acknowledged as an "Innovative Therapy" by the FDA for its effectiveness against this type of tumour in clinical trials. "One of the problems we encounter when testing new drugs on patients is that we know very little about the real function of the protein they are targeting. And surprises are not good for the clinical development of these drugs," says Marcos Malumbres, coordinator of the study and head of the Cell Division and Cancer Group at the CNIO. His team wanted to study the actual function of this protein in mammals using laboratory mice as models. "Many of the proteins tested in clinical trials have been studied mainly in organisms such as yeast or flies or in human cells in cultures. However, these studies do not go far enough in identifying the relevance that a protein can have on a given organ," says Malumbres. To study the function of Plk1, the researchers generated a mouse strain with decreased levels of this protein. "It was amazing, half of the mice began to die from thoracic haemorrhages due to ruptured arteries," says Guillermo de Cárcer, a researcher at the CNIO and lead author of the paper. "One of the most striking findings was that the males died during the first night they spent with females in the same box. One of the situations that causes the highest rise in blood pressure in young males." Plk1 had been initially characterised as a protein that controls how cells multiply, which caught the attention of pharmaceutical companies who saw in it a new therapeutic target to slow down tumour growth. Several inhibitors of this protein are undergoing clinical trials to treat various types of tumours. One of these inhibitors, volasertib, has recently been acknowledged as one of the best therapies against acute myeloid leukaemia. Like most chemotherapeutic drugs, volasertib causes some side effects that are still being studied. The team of researchers, including scientists from the Spanish Centre for Cardiovascular Research (CNIC), the Cancer Research Centre (CIC) at Salamanca, the University of Salamanca, and the London Research Institute (London), treated mice with low doses of volasertib for two months. Mice with low levels of Plk1 or that had been treated with volasertib did not have growth issues but they did display ruptured arteries and cardiovascular problems. These results indicated that arteries are even more sensitive to Plk1 inhibition than other tissues in adult organisms. In fact, the paper found that Plk1 is an essential protein needed to make the cells on the walls of arteries contract; a cellular movement that is responsible for maintaining blood pressure at acceptable levels. Cardiovascular problems and cancer are the major causes of morbidity-mortality in advanced societies. The involvement of Plk1 in controlling both processes will have a major impact on biomedical developments in the future. "Our data do not go against the use of Plk1 inhibitors in clinical treatments," says Malumbres. "Unfortunately, all drugs have some type of side effect. The problem is not being aware of them. We must study the biological functions of a protein very well and in appropriate models before using it as a target on people. This is the only way in which we will be able to use it correctly," concludes the CNIO researcher. This work has been funded by the Spanish Ministry of Economy, Industry and Competitiveness, CENIT, the Red de Investigación Cardiovascular cofinanced with FEDER funds, the Fundació La Marató TV3, the Madrid Regional Government, the Worldwide Cancer Research and the European Commission.


De Carcer G.,Cell Division and Cancer Group | Manning G.,La Jolla Salk Institute | Malumbres M.,Cell Division and Cancer Group
Cell Cycle | Year: 2011

Mammalian Polo-like kinases (Plks) are characterized by the presence of an N-terminal protein kinase domain and a C-terminal Polo Box Domain (PBD) involved in substrate binding and regulation of kinase activity. Plk1-4 have traditionally been linked to cell cycle progression, genotoxic stress and, more recently, neuron biology. Recently, a fifth mammalian Plk family member, Plk5, has been characterized in murine and human cells. Plk5 is expressed mainly in differentiated tissues such as the cerebellum. Despite apparent loss of catalytic activity and a stop codon in the middle of the human gene, Plk5 proteins retain important functions in neuron biology. Notably, its expression is silenced by epigenetic alterations in brain tumors such as glioblastomas, and its re-expression prevents cell proliferation of these tumor cells. In this review, we will focus on the non-cell cycle roles of Plks, the biology of the new member of the family, and the possible kinase- and PBD-independent functions of Polo-like kinases. © 2011 Landes Bioscience.


de Castro I.P.,Cell Division and Cancer Group | Malumbres M.,Cell Division and Cancer Group
Genes and Cancer | Year: 2012

Cell cycle deregulation is a common motif in human cancer, and multiple therapeutic strategies are aimed to prevent tumor cell proliferation. Whereas most current therapies are designed to arrest cell cycle progression either in G1/S or in mitosis, new proposals include targeting the intrinsic chromosomal instability (CIN, an increased rate of gain or losses of chromosomes during cell division) or aneuploidy (a genomic composition that differs from diploid) that many tumor cells display. Why tumors cells are chromosomally unstable or aneuploid and what are the consequences of these alterations are not completely clear at present. Several mitotic regulators are overexpressed as a consequence of oncogenic alterations, and they are likely to alter the proper regulation of chromosome segregation in cancer cells. In this review, we propose the relevance of TPX2, a mitotic regulator involved in the formation of the mitotic spindle, in oncogene-induced mitotic stress. This protein, as well as its partner Aurora-A, is frequently overexpressed in human cancer, and its deregulation may participate not only in chromosome numeric aberrations but also in other forms of genomic instability in cancer cells. © The Author(s) 2013.


Manchado E.,Cell Division and Cancer Group | Guillamot M.,Cell Division and Cancer Group | Malumbres M.,Cell Division and Cancer Group
Cell Death and Differentiation | Year: 2012

Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis. As the efficacy of cell-cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic. © 2012 Macmillan Publishers Limited All rights reserved.


Malumbres M.,Cell Division and Cancer Group
Physiological Reviews | Year: 2011

The basic biology of the cell division cycle and its control by protein kinases was originally studied through genetic and biochemical studies in yeast and other model organisms. The major regulatory mechanisms identified in this pioneer work are conserved in mammals. However, recent studies in different cell types or genetic models are now providing a new perspective on the function of these major cell cycle regulators in different tissues. Here, we review the physiological relevance of mammalian cell cycle kinases such as cyclin-dependent kinases (Cdks), Aurora and Polo-like kinases, and mitotic checkpoint regulators (Bub1, BubR1, and Mps1) as well as other less-studied enzymes such as Cdc7, Nek proteins, or Mastl and their implications in development, tissue homeostasis, and human disease. Among these functions, the control of self-renewal or asymmetric cell division in stem/progenitor cells and the ability to regenerate injured tissues is a central issue in current research. In addition, many of these proteins play previously unexpected roles in metabolism, cardiovascular function, or neuron biology. The modulation of their enzymatic activity may therefore have multiple therapeutic benefits in human disease.


Malumbres M.,Cell Division and Cancer Group
Molecular Aspects of Medicine | Year: 2013

microRNAs (miRNAs) are small, non-coding RNAs with critical roles in fine-tuning a wide array of biological processes including development, metabolism, and homeostasis. miRNAs expression, similarly to that of protein-coding genes, is regulated by multiple transcriptional networks as well as the epigenetic machinery. miRNA genes can be epigenetically regulated by DNA methylation or specific histone modifications. In addition, miRNAs can themselves repress key enzymes that drive epigenetic remodeling, generating regulatory circuits that have a significant effect in the transcriptional landscape of the cell. Recent evidences also suggest that miRNAs can directly modulate gene transcription in the nucleus through the recognition of specific target sites in promoter regions. Given the widespread distribution of epigenetic marks and miRNA target sites in the genome, the regulatory circuits linking both mechanisms are likely to have a major impact in genome transcription and cell physiology. Not surprisingly, tumor-associated aberrations in the miRNA or epigenetic machineries are widely distributed in human cancer, and we are just starting to understand their relevance in diagnosis, prognosis or therapy. © 2012 Elsevier Ltd. All rights reserved.


Alvarez-Fernandez M.,Cell Division and Cancer Group | Malumbres M.,Cell Division and Cancer Group
BioEssays | Year: 2014

Chromosome segregation requires the ordered separation of the newly replicated chromosomes between the two daughter cells. In most cells, this requires nuclear envelope (NE) disassembly during mitotic entry and its reformation at mitotic exit. Nuclear envelope breakdown (NEB) results in the mixture of two cellular compartments. This process is controlled through phosphorylation of multiple targets by cyclin-dependent kinase 1 (Cdk1)-cyclin B complexes as well as other mitotic enzymes. Experimental evidence also suggests that nucleo-cytoplasmic transport of critical cell cycle regulators such as Cdk1-cyclin B complexes or Greatwall, a kinase responsible for the inactivation of PP2A phosphatases, plays a major role in maintaining the boost of mitotic phosphorylation thus preventing the potential mitotic collapse derived from NEB. These data suggest the relevance of nucleo-cytoplasmic transport not only to communicate cytoplasmic and nuclear compartments during interphase, but also to prepare cells for the mixture of these two compartments during mitosis. © 2014 WILEY Periodicals, Inc.


De Carcer G.,Cell Division and Cancer Group | Malumbres M.,Cell Division and Cancer Group
Nature Cell Biology | Year: 2014

Despite the widespread occurrence of aneuploidy in cancer cells, the molecular causes for chromosomal instability are not well established. Cyclin B2 is now shown to control a pathway-involving the centrosomal kinases aurora A and Plk1 and the tumour suppressor p53-the alteration of which causes defective centrosome separation, aneuploidy and tumour development. © 2014 Macmillan Publishers Limited. All rights reserved.


Song M.S.,Harvard University | Carracedo A.,Harvard University | Salmena L.,Harvard University | Song S.J.,Harvard University | And 3 more authors.
Cell | Year: 2011

PTEN is a frequently mutated tumor suppressor gene that opposes the PI3K/AKT pathway through dephosphorylation of phosphoinositide-3,4,5- triphosphate. Recently, nuclear compartmentalization of PTEN was found as a key component of its tumor-suppressive activity; however its nuclear function remains poorly defined. Here we show that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex. We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1. This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss and the tumor-suppressive activity of catalytically inactive PTEN. Importantly, we demonstrate that PTEN mutant and PTEN null states are not synonymous as they are differentially sensitive to pharmacological inhibition of APC-CDH1 targets such as PLK1 and Aurora kinases. This finding identifies a strategy for cancer patient stratification and, thus, optimization of targeted therapies. PaperClip: © 2011 Elsevier Inc.

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