Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals

Levine, Marshall; Bakker, Björn; Boeckx, Bram; Moyett, Julia; Lu, James T.; Vitre, Benjamin; Spierings, Diana C.J.; Lansdorp, Peter M; Cleveland, Don W.; Lambrechts, Diether; Foijer, Floris; Holland, Andrew J.

doi:10.1016/j.devcel.2016.12.022

Cited by 327 publications

(386 citation statements)

References 47 publications

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“…However, it remains unknown why type 2 diabetes favours cancer development. Centrosome amplification can initiate or promote in different animal models [7, 15, 20] and increase cancer cell invasion potential [16]. In the present study, we showed that patients with type 2 diabetes had increased level of cell centrosome amplification by 2.6 folds (Fig.…”

Section: Discussionmentioning

confidence: 49%

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Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

Wang¹,

Lü²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Type 2 diabetes is associated with oxidative stress and DNA damage which can cause centrosome amplification. Thus, the study investigated centrosome amplification in type 2 diabetes and the underlying mechanisms. Methods: Centrosome numbers in human peripheral blood mononuclear blood cells (PBMC) from healthy subjects and patients with type 2 diabetes were compared to access the association between type 2 diabetes and centrosome amplification. Colon cancer cells were used to investigate the molecular mechanisms underlying the centrosome amplification triggered by high glucose, insulin and palmitic acid. Western blot analysis was used to quantify the level of protein and protein phosphorylation. Immunofluorescent staining was performed to detect centrosomes. ROS was quantified using flow cytometry technique. Transcriptpmic profiling was performed using Illumina HiSeq^TM500 platform. Results: We found that centrosome amplification was increased PBMC from the type 2 diabetic patients, which correlated with the levels of fasting blood glucose and HbA1c. High glucose, insulin and palmitic acid, alone or in combinations, induced ROS production and centrosome amplification. Together, they increased AKT activation as well as the expression, binding and centrosome translation of ROCK1 and 14-3-3σ. Results from further analyses showed that AKT-ROS-dependent upregulations of expression, binding and centrosome translocation of ROCK1 and 14-3-3σ was the molecular pathway underlying the centrosome amplification in vitro triggered by high glucose, insulin and palmitic acid. Moreover, the key in vitro molecular signalling events activated by high glucose, insulin and palmitic acid were verified in PBMC from the patients with type 2 diabetes. Conclusion: Our results show that type 2 diabetes promotes cell centrosome amplification, and suggest that the diabetic pathophysiological factors-activated AKT-ROS-dependent signalling of ROCK1 and 14-3-3σ is the underlying molecular mechanism.

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Section: Discussionmentioning

confidence: 49%

“…Robust centrosome amplification results in multipolar division follow by mitosis catastrophe [17]. Moderate centrosome amplification can induce genome instability [18, 19], cell immortalization and carcinogenesis [20]. …”

Section: Introductionmentioning

confidence: 99%

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

Wang¹,

Lü²,

Wang³

et al. 2018

Cell Physiol Biochem

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“…[36,72,90] While certain forms of aneuploidy can be beneficial to tumor growth, the relationship between cancer and CIN remains paradoxical. On the one hand CIN itself can lead to tumorigenesis in some models, [91,92] but on the other hand, CIN has been found to act as a tumor suppressor in other models. [75,93,94] Furthermore, yet other CIN models are suggesting that CIN only enhances tumorigenesis in a tumorprone background.…”

Section: Cin Can Have Highly Differential Effects On Cellsmentioning

confidence: 99%

CIN and Aneuploidy: Different Concepts, Different Consequences

Schukken

Foijer

2017

BioEssays

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Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg

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“…As such, they play a crucial role in cellular motility, for example of sperm, cell signalling via the primary cilium, and in the interaction of cells with their surroundings, as seen in tracheal lining cells that sweep mucus and dirt out of the respiratory system. Thus, aberrations in centriole structure or numbers are linked to disease conditions such as ciliopathies, male sterility, ectopic pregnancies, primary microcephaly and possibly cancer [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Coupling Form and Function: How the Oligomerisation Symmetry of the SAS-6 Protein Contributes to the Architecture of Centriole Organelles

2017

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Centrioles make up the centrosome and basal bodies in animals and as such play important roles in cell division, signalling and motility. They possess characteristic 9-fold radial symmetry strongly influenced by the protein SAS-6. SAS-6 is essential for canonical centriole assembly as it forms the central core of the organelle, which is then surrounded by microtubules. SAS-6 self-assembles into an oligomer with elongated spokes that emanate towards the outer microtubule wall; in this manner, the symmetry of the SAS-6 oligomer influences centriole architecture and symmetry. Here, we summarise the form and symmetry of SAS-6 oligomers inferred from crystal structures and directly observed in vitro. We discuss how the strict 9-fold symmetry of centrioles may emerge, and how different forms of SAS-6 oligomers may be accommodated in the organelle architecture.

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Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals

Cited by 327 publications

References 47 publications

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

CIN and Aneuploidy: Different Concepts, Different Consequences

Coupling Form and Function: How the Oligomerisation Symmetry of the SAS-6 Protein Contributes to the Architecture of Centriole Organelles

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