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Role of Senescence and Mitotic Catastrophe in Cancer Therapy Richa Singh, Jasmine George, Yogeshwer Shukla*

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Role of Senescence and Mitotic Catastrophe in Cancer Therapy Richa Singh, Jasmine George, Yogeshwer Shukla* Singh et al. Cell Division 2010, 5:4 http://www.celldiv.com/content/5/1/4 REVIEW Open Access Role of senescence and mitotic catastrophe in cancer therapy Richa Singh, Jasmine George, Yogeshwer Shukla* Abstract Senescence and mitotic catastrophe (MC) are two distinct crucial non-apoptotic mechanisms, often triggered in cancer cells and tissues in response to anti-cancer drugs. Chemotherapeuticals and myriad other factors induce cell eradication via these routes. While senescence drives the cells to a state of quiescence, MC drives the cells towards death during the course of mitosis. The senescent phenotype distinguishes tumor cells that survived drug expo- sure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senes- cent cells do not proliferate, they are metabolically active and may secrete proteins with potential tumor- promoting activities. The other anti-proliferative response of tumor cells is MC that is a form of cell death that results from abnormal mitosis and leads to the formation of interphase cells with multiple micronuclei. Different classes of cytotoxic agents induce MC, but the pathways of abnormal mitosis differ depending on the nature of doi: 10.1186/1747-1028-7-15 the inducer and the status of cell-cycle checkpoints. In this review, we compare the two pathways and mention that they are activated to curb the growth of tumors. Altogether, we have highlighted the possibilities of the use of senescence targeting drugs, mitotic kinases and anti-mitotic agents in fabricating novel strategies in cancer control. Introduction MC therefore, refers to the process when cells attempt The incidence of cancer worldwide is on a rise, making it to divide without proper repair of DNA damage due to only second to coronary heart disease [1]. Unifying prop- faulty cell cycle checkpoint functioning consequently erty of cancer includes six canonical characteristics: self resulting in formation of giant, multinucleated cells with sufficiency in growth signals, insensitivity to growth inhibi- condensed chromosomes, distinguishing MC morpholo- tory signals (anti-growth), evasion of programmed cell gically from other modes of cell deaths. death (apoptosis), unlimited proliferation of diseased cells, Abundant data amassed from several laboratories have sustained angiogenesis, intrusion of adjacent cells and tis- provided innumerable instances to show that it is better sues and metastasis to distant niches in the body [2]. to cure this dreadful disease at preventable stage by Genetic instability associated with telomere attrition early diagnosis and consequent therapeutic intervention. or cell cycle checkpoint dysfunction is an early event in Strategies for cancer treatment has generated significant tumorigenesis. Telomeres are guanine rich tandem interest in the recent past and therefore, the focus of nucleotide repeats flanking the ends of chromosomes in research endeavors on understanding the mechanism of all eukaryotic cells responsible for maintaining genetic cell death pathways applicable in treatment of cancer RETRACTED 15integrity MAY 2012 and implicated in aging (senescence) and can- which include not only apoptosis but necrosis, autop- cer [3]. Cell cycle checkpoints or mitotic kinases (MKs) hagy, MC and in context of cancer therapy, senescence are the rigorous quality control steps of mitosis [4] that has always been there [5]. function in preserving the fidelity and integrity of DNA This review will explore major highlights on the role and allow mitosis to continue with accurately function- of senescence and MC triggered in various cancers by ing DNA, spindle assembly, centrosome and kinetochore chemotherapeutic intrusion and opens avenues for thus preventing cell death via mitotic catastrophe (MC). expanding research work by comparing the results obtained so far. * Correspondence: [email protected] Proteomics Laboratory, Indian Institute of Toxicology Research, (Council of Scientific & Industrial Research), PO Box 80, MG Marg, Lucknow-226001, India © 2010 Singh et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Singh et al. Cell Division 2010, 5:4 Page 2 of 12 http://www.celldiv.com/content/5/1/4 Senescence: Terminal growth arrest in dividing cells situ hybridization assay [22]. Telomerase and p53 play The term senescence is derived from the Latin word critical roles in tumorigenesis and senescence. Senescent senex, meaning “old age” or “advanced in age”.Senes- cells exhibit distinct morphology in culture. They are cence at the cellular level is a physiological program of enlarged and flattened with increased granularity [23] cellular growth arrest that is triggered by the shortening exhibit SA-b-gal staining and a characteristic senescence of telomeres or by stress [6]. This permanent growth associated heterochromatin foci (SAHF) formation [24] arrest is also considered a type of cell death in the con- and comparatively less dense culture than a confluent text of cancer therapy by some researchers [7,8] and young culture probably because they are more sensitive some consider it similar to the programmed cell death to cell-cell contact inhibition [12,13]. Even though they by ‘apoptosis’ [9]. Senescence can be broadly categorized cannot divide under mitogenic stimulation yet they into two classes: accelerated or stress induced premature remain metabolically and synthetically active in in vitro senescence (SIPS) and replicative senescence (RS) and conditions for several years [24] but can not resume cell both are believed to be essential anti-carcinogenic pro- growth after drug withdrawal. SA-b-gal, the most widely grams in normal cells. Accelerated senescence occurs in used surrogate marker with considerable specificity to response to the activation of Ras/Raf pathways [10] and senescent cells appears to reflect an increased lysosomal by supra-physiological mitogenic signaling [11]. The mass [23]. Another marker is clusterin/apolipopterin J, phenomenon of RS was first described in the context of is a highly conserved ubiquitously expressed secreted normal human cells explanted in culture that failed to glycoprotein has been implicated in many physiological divide beyond a finite number of fifty divisions [12] and processes, gets upregulated during stress induced pre- it is a well-known defining property of euploid mamma- mature senescence, in vivo aging, RS, in several age lian cells [13]. Telomere dynamics has been shown to be linked deformities, neuropathological disorders like Alz- doi: 10.1186/1747-1028-7-15 a critical component of both aging and cancer [14]. Tel- hiemers disease and dementia and has a direct relation- omeres, the highly repetitive DNA (TTAGGG sequence) ship with human longevity [25]. Cellular senescence is a which camouflages chromosome ends [15] prevent potent anti-cancer mechanism controlled by tumor sup- nucleolytic degradation, end-to-end fusion, irregular pressor genes, particularly p53 and pRb. recombination, and other events that are normally lethal Role of p53 to a cell [15]. With each cell division a part of telomere Telomere-induced senescence has been proved to be as gets eroded [16,17] and the chromosome being passed effective as apoptosis in reducing cancer incidence and to the progeny gets the clipped off telomere. is mediated by the tumor suppressor gene, p53 [26]. Thus genetic integrity is gradually lost with telomeres Mutations in the p53 gene frequently appear in human progressively shortening after each division as a result of tumors conferring aggressive oncogenic properties such end-replication problems and hence, is a conspicuous as exacerbated malignant transformation and metastatic feature in almost all dividing cells which do not express phenotype when over-expressed in p53-null cells. P53 or maintain sufficient telomerase activity to maintain gets activated upon genotoxic and non genotoxic stres- the telomeres. Telomerase reverse transcriptase ses like oxidative damage and activates p21 and ulti- (hTERT), whose amount is lessened after birth, func- mately culminates the cell to senescence. Mice with a tions by replenishing telomere by adding TTAGGG point mutation (p53(R172H)) in their endogenous p53 sequence at the 3’end of DNA. Telomerase activity is loci act as a model for the human Li-Fraumeni syn- measured by TRAP assay or RT-PCR. Less frequently drome. Genetic alterations at chromosomes 3p, 6p, and other alternative mechanism of telomere maintenance 1lq were frequently found early in tumor development namely Alternative Lengthening of Telomeres (ALT) is and showed additional allelic losses at chromosome RETRACTED 15opted MAY 2012 [18]. Telomere dysfunction (short telomeres) has arms 6q, 17p and 18q. Genes for telomerase suppression been associated with the initiation and progression of are presumably located on chromosomes 3, 4 and 6 [27]. mouse and human intestinal neoplasia [19] and may P53 over expression has been directly associated with also increase the risk of developing epithelial cancers by unfavorable clinico-pathologic factors such as advanced a process of breakage-fusion-bridge that leads to the for- stage, histologic subtype, advanced patient age and mation of complex nonreciprocal translocations (a clas- nodal metastasis in endometrial
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