Centrosome amplification in tumorigenesis

Anderhub, Simon; Krämer, Alwin; Maier, Bettina

doi:10.1016/j.canlet.2012.02.006

Cited by 68 publications

(55 citation statements)

References 110 publications

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“…21 However, the occurrence of abnormal centrosome amplification due to g-actin depletion remains to be fully investigated to determine whether g-actin depletion causes centriole overduplication, denovo formation of centrioles, centrosome fragmentation or cytokinesis failure. 32 The accumulation of g-actin depleted cells in G 0 /G 1 cell cycle phase may have affected centrosome duplication.…”

Section: Discussionmentioning

confidence: 99%

Gamma-actin is involved in regulating centrosome function and mitotic progression in cancer cells

Po'uha

Kavallaris

2015

Cell Cycle

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Reorganization of the actin cytoskeleton during mitosis is crucial for regulating cell division. A functional role for g-actin in mitotic arrest induced by the microtubule-targeted agent, paclitaxel, has recently been demonstrated. We hypothesized that g-actin plays a role in mitosis. Herein, we investigated the effect of g-actin in mitosis and demonstrated that g-actin is important in the distribution of b-actin and formation of actin-rich retraction fibers during mitosis. The reduced ability of paclitaxel to induce mitotic arrest as a result of g-actin depletion was replicated with a range of mitotic inhibitors, suggesting that g-actin loss reduces the ability of broad classes of anti-mitotic agents to induce mitotic arrest. In addition, partial depletion of g-actin enhanced centrosome amplification in cancer cells and caused a significant delay in prometaphase/metaphase. This prolonged prometaphase/metaphase arrest was due to mitotic defects such as uncongressed and missegregated chromosomes, and correlated with an increased presence of mitotic spindle abnormalities in the g-actin depleted cells. Collectively, these results demonstrate a previously unknown role for g-actin in regulating centrosome function, chromosome alignment and maintenance of mitotic spindle integrity.

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Section: Discussionmentioning

confidence: 99%

Gamma-actin is involved in regulating centrosome function and mitotic progression in cancer cells

Po'uha

Kavallaris

2015

Cell Cycle

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“…13 Deregulation of centriole duplication factors in interphase can result in rampant centriole overduplication, as described in an excellent review recently. 30 Another important cause of centrosome amplification involves derailing of the 'licensing' mechanism that entrains the centrosome cycle with the nuclear cycle. In healthy cells, this system ensures that centriole duplication is only initiated when appropriate, that is, when only one pair of centrioles is present, and the cell is ready to divide.…”

Section: Excess Baggage: How Cancer Cells Acquire Extra Centrosomesmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

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“…Ras [13] which is a protein outside the centrosomes has been shown to cause centrosome amplification. At the cellular and organismal levels, centrosome amplification regulates cell division, movement and intracellular transport [14]. It can initiate tumorigenesis in flies [7] and mice [15], and increases cancer invasion potential [16].…”

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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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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Centrosome amplification in tumorigenesis

Cited by 68 publications

References 110 publications

Gamma-actin is involved in regulating centrosome function and mitotic progression in cancer cells

Gamma-actin is involved in regulating centrosome function and mitotic progression in cancer cells

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

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

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