Paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres: Implication in multinucleation and chemosensitization

Park, Jeong Eun; Woo, Seon Rang; Kang, Chang Mo; Juhn, Kyoung Mi; Ju, Yeun Jin; Shin, Hyun Jin; Joo, Hyun Jin; Park, Eun Ran; Park, In chul; Hong, Sung Hee; Hwang, Sang‐Gu; Lee, Jung Kee; Kim, Hae Kwon; Cho, Myung‐Haing; Park, Gil Hong; Lee, Kee Ho

doi:10.1016/j.bbrc.2010.12.018

Cited by 15 publications

(13 citation statements)

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“…As mentioned before, colorectal carcinomas have high rates of genetic instability. Multinucleation and micronucleation represent common cellular aneuploidization processes derived from genetic instability events [21] , [22] . Due to this, we decided to evaluate whether the phenotypes related to genetic instability seen in breast cancer lines are reproducible in the DLD1 colorectal cancer line.…”

Section: Resultsmentioning

confidence: 99%

Deregulation of the Replisome Factor MCMBP Prompts Oncogenesis in Colorectal Carcinomas through Chromosomal Instability

et al. 2014

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Genetic instability has emerged as an important hallmark of human neoplasia. Although most types of cancers exhibit genetic instability to some extent, in colorectal cancers genetic instability is a distinctive characteristic. Recent studies have shown that deregulation of genes involved in sister chromatid cohesion can result in chromosomal instability in colorectal cancers. Here, we show that the replisome factor minichromosome maintenance complex–binding protein (MCMBP), which is directly involved in the dynamics of the minichromosome maintenance complex and contributes to maintaining sister chromatid cohesion, is transcriptionally misregulated in different types of carcinomas. Cellular studies revealed that both MCMBP knockdown and overexpression in different breast and colorectal cell lines is associated with the emergence of a subpopulation of cells with abnormal nuclear morphology that likely arise as a consequence of aberrant cohesion events. Association analysis integrating gene expression data with clinical information revealed that enhanced MCMBP transcript levels correlate with an increased probability of relapse risk in colorectal cancers and different types of carcinomas. Moreover, a detailed study of a cohort of colorectal tumors showed that the MCMBP protein accumulates to high levels in cancer cells, whereas in normal proliferating tissue its abundance is low, indicating that MCMBP could be exploited as a novel diagnostic marker for this type of carcinoma.

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Section: Resultsmentioning

confidence: 99%

Deregulation of the Replisome Factor MCMBP Prompts Oncogenesis in Colorectal Carcinomas through Chromosomal Instability

et al. 2014

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“…Anti-mitotics inhibit the function of microtubules by either binding to their subunits or by preventing their growth (Lee et al, 2004). In both cases normal mitotic spindle formation is disrupted, causing cell cycle arrest and eventually apoptosis (Blagosklonny and Fojo, 1999; Park et al, 2011). Previous studies have indicated that the hTERT gene might be involved in the spindle assembly checkpoint.…”

Section: Discussionmentioning

confidence: 99%

Association between hTERT rs2736100 polymorphism and sensitivity to anti-cancer agents

et al. 2013

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Background: The rs2736100 single nucleotide polymorphism (SNP) is located in the intron 2 of human telomerase reverse transcriptase (hTERT) gene. Recent genome-wide association studies (GWAS) have consistently supported the strong association between this SNP and risk for multiple cancers. Given the important role of the hTERT gene and this SNP in cancer biology, we hypothesize that rs2736100 may also confer susceptibility to anti-cancer drug sensitivity. In this study we aim to investigate the correlation between the rs2736100 genotype and the responsiveness to anti-cancer agents in the NCI-60 cancer cell panel.Methods and Materials: The hTERT rs2736100 was genotyped in the NCI-60 cancer cell lines. The relative telomere length (RTL) of each cell line was quantified using real-time PCR. The genotype was then correlated with publically available drug sensitivity data of two agents with telomerase-inhibition activity: Geldanamycin (HSP90 inhibitor) and RHPS4/BRACO19 (G-quadruplex stabilizer) as well as additional 110 commonly used agents with established mechanism of action. The association between rs2736100 and mutation status of TP53 gene was also tested.Results: The C allele of the SNP was significantly correlated with increased sensitivity to RHPS4/BRACO19 with an additive effect (r = −0.35, p = 0.009) but not with Geldanamycin. The same allele was also significantly associated with sensitivity to antimitotic agents compared to other agents (p = 0.003). The highest correlation was observed between the SNP and paclitaxel (r = −0.36, p = 0.005). The telomere length was neither associated with rs2736100 nor with sensitivity to anti-cancer agents. The C allele of rs2736100 was significantly associated with increased mutation rate in TP53 gene (p = 0.004).Conclusion: Our data suggested that the cancer risk allele of hTERT rs2736100 polymorphism may also affect the cancer cell response to both TERT inhibitor and anti-mitotic agents, which might be attributed to the elevated telomerase-independent activity of hTERT, as well as the increased risk for TP53 gene mutagenesis conferred by the polymorphism. Detailed mechanisms need to be further investigated.

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“…Telomere erosion induced by paclitaxel can be enhanced by telomerase inhibitors, such as 3'-azido-3'-deoxythymidine (AZT) [75,76]. More recently, using telomerase-deficient cells derived from mTERC−/− (mouse telomerase RNA componentminus) mice, Park et al demonstrated that, upon telomere erosion, paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres [77]. Chromosomal fusions promoted by paclitaxel involve both q-and p-chromosome arms, being the q-arm fusions both unstable and lethal [77].…”

Section: Paclitaxelmentioning

confidence: 99%

“…More recently, using telomerase-deficient cells derived from mTERC−/− (mouse telomerase RNA componentminus) mice, Park et al demonstrated that, upon telomere erosion, paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres [77]. Chromosomal fusions promoted by paclitaxel involve both q-and p-chromosome arms, being the q-arm fusions both unstable and lethal [77]. These chromosomal fusions occur in response to microtubule disruption induced by paclitaxel in cells with dysfunctional telomeres [77].…”

Section: Paclitaxelmentioning

confidence: 99%

“…Chromosomal fusions promoted by paclitaxel involve both q-and p-chromosome arms, being the q-arm fusions both unstable and lethal [77]. These chromosomal fusions occur in response to microtubule disruption induced by paclitaxel in cells with dysfunctional telomeres [77]. Thus, telomere dysfunction, rather than telomerase inhibition seems to be essential to sensitize transformed cells to paclitaxel.…”

Section: Paclitaxelmentioning

confidence: 99%

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Telomere Instability Induced by Anticancer Drugs in Mammalian Cells

Bolzán¹

2016

Telomere - A Complex End of a Chromosome

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Telomere instability results from chromosome end loss due to chromosome breakage at one or both ends or, more frequently, telomere dysfunction. Dysfunctional telomeres arise when they lose their end-capping function or become critically short, which causes chromosomal termini to behave like a DN" double-strand break. "t the chromosomal level, this phenomenon is visualized by using Fluorescence In Situ Hybridization FISH , as chromosomal aberrations directly involving terminal telomeric repeats loss or duplication of telomeric signals, association or fusion of telomeres of different chromosomes, telomere sister chromatid exchanges, translocation or amplification of telomeric sequences, and extrachromosomal telomeric signals. "t the molecular level, telomere instability arises due to the loss or modification of any of the components of the telomere telomere DN", telomere-associated proteins or telomere RN" . Since telomeres play a fundamental role in maintaining genomic stability, the study of telomere instability in cells exposed to anticancer drugs is of great importance to understand the genomic instability associated with chemotherapy regimens. In this chapter, we will summarize our current knowledge about telomere instability induced by anticancer drugs on mammalian cells. Keywords:Telomere, telomere instability, telomere loss, telomere dysfunction, telomere erosion, chemotherapy, anticancer drugs . Introduction . . What are telomeres?Classically defined as the chromosome ends, telomeres from the Greek, telo = end, and mere = part [ ] are nowadays defined as specialized nucleoprotein complexes localized at the physical ends of linear eukaryotic chromosomes, that maintain their stability and integrity [ , ]. They protect chromosomes from degradation, recombination or fusion, by preventing the © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.ends of linear chromosomes from being recognized as DN" double-strand breaks DS" by the DN" repair machinery, i.e., they distinguish natural DN" ends from DN" ends resulting from breakage events [ , ].In all vertebrates, telomeres are composed of tandem arrays of short, repetitive G-rich sequences TT"GGG n, oriented ′ → ′ towards the end of the chromosome, ending in an essential ′ single-stranded overhang that ranges in length from ~ to nt [ -], bound by a specialised multiprotein complex known as shelterin or telosome [ -]. The length of the double-stranded telomeric repeat varies greatly among species [ ]. In normal human cells, the DN" at each chromosome terminus spans -kb in length [ , , ], terminating in a " single-stranded overhang -nt in length [ ], whereas in human tumor cells, telomere length varies from to kb [ -].The telosome is constituted by proteins POT , TPP . TIN , TRF , TRF and R"P and is charged with prot...

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Paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres: Implication in multinucleation and chemosensitization

Cited by 15 publications

References 20 publications

Deregulation of the Replisome Factor MCMBP Prompts Oncogenesis in Colorectal Carcinomas through Chromosomal Instability

Deregulation of the Replisome Factor MCMBP Prompts Oncogenesis in Colorectal Carcinomas through Chromosomal Instability

Association between hTERT rs2736100 polymorphism and sensitivity to anti-cancer agents

Telomere Instability Induced by Anticancer Drugs in Mammalian Cells

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