Centrosomal Abnormalities in Pancreatic Cancer: Molecular Mechanisms and Clinical Implications

Ansari, Daniel; Bellido, Carolina Del Pino; Bauden, Monika; Andersson, Roland

doi:10.21873/anticanres.12345

Cited by 8 publications

(5 citation statements)

References 30 publications

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“…The primary microtubules organizing centers in human cells are named centrosomes and are important for the regulation of normal cell cycle progression and cell division. During mitosis, centrosome duplication and subsequent separation guarantee the formation of the mitotic spindle and the proper chromosomal segregation, in order to form stabilized daughter cells with the correct amount of DNA in each cell [116]. The centrosome is duplicated once during a normal cell cycle, starting at the G1 phase and completed by the end of the G2 phase [117].…”

Section: Trims and The Mitotic Spindle Machinerymentioning

confidence: 99%

“…Deregulation of this duplication machinery increases the number of centrosomes, raising the formation of multipolar spindles and thereby leading to aneuploidy and chromosomal instability. Centrosomal amplification has been associated with the initiation and progression of multiple malignancies and is related to a more aggressive tumor biology [116]. Together with centrosomes, other organelles that ensure reliable segregation of chromosomes during mitosis are the spindle poles [118].…”

Section: Trims and The Mitotic Spindle Machinerymentioning

confidence: 99%

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E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis

Venuto

Merla

2019

Cells

116

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The cell cycle is a series of events by which cellular components are accurately segregated into daughter cells, principally controlled by the oscillating activities of cyclin-dependent kinases (CDKs) and their co-activators. In eukaryotes, DNA replication is confined to a discrete synthesis phase while chromosome segregation occurs during mitosis. During mitosis, the chromosomes are pulled into each of the two daughter cells by the coordination of spindle microtubules, kinetochores, centromeres, and chromatin. These four functional units tie chromosomes to the microtubules, send signals to the cells when the attachment is completed and the division can proceed, and withstand the force generated by pulling the chromosomes to either daughter cell. Protein ubiquitination is a post-translational modification that plays a central role in cellular homeostasis. E3 ubiquitin ligases mediate the transfer of ubiquitin to substrate proteins determining their fate. One of the largest subfamilies of E3 ubiquitin ligases is the family of the tripartite motif (TRIM) proteins, whose dysregulation is associated with a variety of cellular processes and directly involved in human diseases and cancer. In this review we summarize the current knowledge and emerging concepts about TRIMs and their contribution to the correct regulation of cell cycle, describing how TRIMs control the cell cycle transition phases and their involvement in the different functional units of the mitotic process, along with implications in cancer progression.

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Section: Trims and The Mitotic Spindle Machinerymentioning

confidence: 99%

Section: Trims and The Mitotic Spindle Machinerymentioning

confidence: 99%

E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis

Venuto

Merla

2019

Cells

116

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“…These findings together indicate that SMYD2 is a positive glycolytic mediator and plays a promoting role in enhancing tumor growth in a glycolysis-dependent manner, likely through SMYD2-mediated methylation of p53 to promote aerobic glycolysis and tumorigenesis in cervical cancer[ 42 ]. Although the role of SMYD2-mediated p53 methylation in PDAC has not yet been explored, dysregulation of the p53 pathway is one of the primary molecular pathological events in PDAC, which promotes the development and progression of pancreatic tumors[ 83 ]. In a cohort of 272 PDAC patients, an aberrant alteration rate of the TP53 gene was about 38%[ 84 ], consistent with earlier reports demonstrating 40% and 47% of PDAC samples having p53 mutations[ 85 , 86 ].…”

Section: Functional Extrapolation Of Smyd2 From Other Cancers To Panc...mentioning

confidence: 99%

Mechanistic and functional extrapolation of SET and MYND domain-containing protein 2 to pancreatic cancer

Alshammari¹,

Zhang²,

Yang³

2022

WJG

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal neoplasms worldwide and represents the vast majority of pancreatic cancer cases. Understanding the molecular pathogenesis and the underlying mechanisms involved in the initiation, maintenance, and progression of PDAC is an urgent need, which may lead to the development of novel therapeutic strategies against this deadly cancer. Here, we review the role of SET and MYND domain-containing protein 2 (SMYD2) in initiating and maintaining PDAC development through methylating multiple tumor suppressors and oncogenic proteins. Given the broad substrate specificity of SMYD2 and its involvement in diverse oncogenic signaling pathways in many other cancers, the mechanistic extrapolation of SMYD2 from these cancers to PDAC may allow for developing new hypotheses about the mechanisms driving PDAC tumor growth and metastasis, supporting a proposition that targeting SMYD2 could be a powerful strategy for the prevention and treatment of PDAC.

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“…Furthermore, the suppression of ciliogenesis has been reported to promote the transformation of normal pancreatic ductal cells into cancer cells ( Deng et al, 2018 ). Centrosomal amplification and clustering also occur in PDAC ( Sato et al, 1999 ; Zhu et al, 2005 ; Mittal et al, 2015 ; Ansari et al, 2018 ); however, the molecular mechanisms underlying the centrosome clustering remain largely unclear.…”

Section: Introductionmentioning

confidence: 99%

KIF24 depletion induces clustering of supernumerary centrosomes in PDAC cells

et al. 2022

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Clustering of supernumerary centrosomes, which potentially leads to cell survival and chromosomal instability, is frequently observed in cancers. However, the molecular mechanisms that control centrosome clustering remain largely unknown. The centrosomal kinesin KIF24 was previously shown to restrain the assembly of primary cilia in mammalian cells. Here, we revealed that KIF24 depletion suppresses multipolar spindle formation by clustering centrosomes in pancreatic ductal adenocarcinoma (PDAC) cells harboring supernumerary centrosomes. KIF24 depletion also induced hyper-proliferation and improved mitotic progression in PDAC cells. In contrast, disruption of primary cilia failed to affect the proliferation and spindle formation in KIF24-depleted cells. These results suggest a novel role for KIF24 in suppressing centrosome clustering independent of primary ciliation in centrosome-amplified PDAC cells.

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Centrosomal Abnormalities in Pancreatic Cancer: Molecular Mechanisms and Clinical Implications

Abstract: Abstract. The

Cited by 8 publications

References 30 publications

E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis

E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis

Mechanistic and functional extrapolation of SET and MYND domain-containing protein 2 to pancreatic cancer

KIF24 depletion induces clustering of supernumerary centrosomes in PDAC cells

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