title: Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells.
abstract: Chromosomal instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms influencing CIN and its consequences on tumour growth are largely unknown. We identified an increase in microtubule plus-end assembly rates as a mechanism influencing CIN in colorectal cancer cells. This phenotype is induced by overexpression of the oncogene AURKA or by loss of the tumour suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and influencing CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumour growth in vitro and in vivo. Thus, we identify a fundamental mechanism influencing CIN in cancer cells and reveal its adverse consequence on tumour growth.
authors: 1] Institute of Molecular Oncology, Section for Cellular Oncology, Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Georg-August University, D-37077 Goettingen, Germany [2].
authors: Norman
authors: N
authors: Ertych
authors: 1] Institute of Molecular Oncology, Section for Cellular Oncology, Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Georg-August University, D-37077 Goettingen, Germany [2].
authors: Ailine
authors: A
authors: Stolz
authors: Institute for Pathology, University Medical Center, Ruprecht-Karls-University, D-69120 Heidelberg, Germany.
authors: Albrecht
authors: A
authors: Stenzinger
authors: 1] Institute for Pathology, University Medical Center, Ruprecht-Karls-University, D-69120 Heidelberg, Germany [2] German Consortium for Translational Cancer Research, D-69120 Heidelberg, Germany.
authors: Wilko
authors: W
authors: Weichert
authors: Institute for Human Genetics, University Medical Center, Georg-August University, D-37073 Goettingen, Germany.
authors: Silke
authors: S
authors: Kaulfuß
authors: Institute for Human Genetics, University Medical Center, Georg-August University, D-37073 Goettingen, Germany.
authors: Peter
authors: P
authors: Burfeind
authors: Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, D-04107 Leipzig, Germany.
authors: Achim
authors: A
authors: Aigner
authors: Department of Physiology and Biophysics, University of Washington, School of Medicine, Seattle, Washington 98195, USA.
authors: Linda
authors: L
authors: Wordeman
authors: Institute of Molecular Oncology, Section for Cellular Oncology, Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Georg-August University, D-37077 Goettingen, Germany.
authors: Holger
authors: H
authors: Bastians
mesh_terms: D064096:Aurora Kinase A / Q000235:genetics*; D019313:BRCA1 Protein / Q000235:genetics; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D043171:Chromosomal Instability; D020090:Chromosome Segregation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008870:Microtubules / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008954:Models, Biological; D009857:Oncogenes; D008941:Spindle Apparatus / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D064447:Checkpoint Kinase 2; C576917:AURKA protein, human; D064096:Aurora Kinase A; C578634:CHEK2 protein, human