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 exposure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senescent 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 carcinomas while bcl-2 sical cytogenetic feature of human carcinoma) [20]. expression was related with younger age, favorable grade Blood relative telomere length was found to represent a and PR expression by tumor cells. Patient survival is strong independent prognostic indicator in patients with however not related to the tested biomarkers [28]. In advanced breast cancer [21]. Similarly mean telomere humans, TP53 codon 72 Arginine to Proline poly- length was statistically shorter in case patients with head morphism was found to affect both cancer incidence and neck cancer as compared with control as measured and longevity as well [29]. The senescence-associated with the southern blot and quantitative-fluorescent in signature of p53 isoform expression (that is, elevated Singh et al. Cell Division 2010, 5:4 Page 3 of 12 http://www.celldiv.com/content/5/1/4

p53beta and reduced Delta133p53) was observed in vivo become permanently growth-arrested as a result of so- in colon adenomas with senescent phenotypes. The called drug-induced premature senescence (pseudo- increased Delta133p53 and decreased p53beta isoform senescence) or SIPS. Similarly, lowered efficacy of anti- expression found in colon carcinoma may signal an cancer doxorubicin (due to dose dependent toxicity) escape from the senescence barrier during the progres- against breast cancer cells can be increased when used sion from adenoma to carcinoma [30]. in conjunction with siRNA inhibitor of telomerase [39]. Other tumor suppressor genes Yet another study advocated the use of GRN163L (novel P107 is required for the initiation of accelerated cellular telomerase template antagonist) in the treatment of senescence in the absence of Rb and p130 may be breast cancer by augmenting the effects of paclitaxel required to prevent the onset of this phenomenon in un- [40]. Hence clearly proposing that inhibition of telomer- stimulated prostate cancer cells lacking a functional Rb ase is a potential treatment strategy for inducing senes- allele [31]. Cell cycle regulatory proteins are more sensi- cence. It has also been shown that caveolin-1 targets tive to exogenous hormone treatment in postm-HBT Mdm2/p53-mediated pathway and causes senescence in (postmenopausal human breast tissue) than in pre-HBT breast cancer cells [41]. Another study reported that (premenopausal human breast tissue) [32]. Olsson et al bleomycin, a widely used anti-tumor agent, causes advocates that bfl-1 (tumor suppressor bcl-2 family senescence of lung cancer cells by modulating the roles member) contributes to chemo resistance and might be a of caveolin-1, a protein abundant in lung fibroblasts and therapeutic target in B-cell chronic lymphocytic leukae- smooth muscle and endothelial cells [42]. mia [33]. The activation of PI3K/Akt pathway is involved A recent study showed that the activation of the p53- in the late-stage progression and metastasis of gastric p21(Cip1/WAF1) pathway acts as a major mediator of cel- cancer and attenuation of p-Akt by 2-ME suppresses lular senescence induced by CKII inhibition in HCT116

doi: 10.1186/1747-1028-7-15 metastasis [34]. Yet another tumor suppressor Promyelo- colon carcinoma cells [43]. A senescence-inducing effect lytic leukemia (PML) regulates p53 acetylation in both of doxorubicin on the same cells, in another study, had a RS as well as Ras induced accelerated senescence [35]. dual effect-it stopped the proliferation of the majority of Senescence in cancer cells: In vitro studies the cells and led to the appearance of proliferating aneu- A large number of in vitro studies have been reported ploid cells [44]. Likewise, while characterizing ashwa- where a wide range of chemotherapeutical antidotes gandha and its molecular mechanisms Wadhwa et al induce senescence like morphological changes and SA- provided the first example that phytochemical(s) have b-gal expression in cancer cells activating the pathway both anti-cancer and anti senescent activities and pointed of senescence. Research into the induction of cellular towards the molecular link between aging and cancer senescence as cancer therapy has however, been hin- using normal human fibroblasts through decreased accu- dered by a lack of compounds that efficiently induce mulation of molecular damage, down-regulation of the this response. To overcome this, Ewald et al (2009) by SA-b gal activity and the senescence marker protein, p21 using dual Hoechst 33342 and SA-b gal staining identi- (WAF-1), protection against oxidative damage, and induc- fied library compounds that induce senescence in pros- tion of proteasomal activity [45]. In one of the studies, by tate cancer cells [36]. It is well acknowledged that silencing BRCA1 expression at different levels through telomerase and the maintenance of telomeres are key RNA interference technology in a series of partially trans- players in the ability of stem and cancer cells to bypass formed (HBL100) and tumorigenic (MCF7 and T47D) senescence and be immortal. Proliferation of telomerase breast cancer cell lines, cell models were probed by clono- (-) pre-malignant cells leads to telomere dysfunction genic assay for their response to several DNA-damaging and increased genomic instability suggesting one possi- agents (mitomycin C, cisplatin, doxorubicin, and etopo-

RETRACTED 15ble MAY 2012 sequence of events leading to immortalization of side) commonly used in cancer therapy [46]. The breast epithelial cells during cancer progression [37]. increased sensitivity to these compounds displayed by Theincreasedh-TERTexpressionmaybeacellular BRCA1-defective cells was correlated to an increased frac- response to genomic insults by various metal toxicants tion of growth-arrested, enlarged, multinucleated SA-b- like arsenic that may also act as a tumor promoter in galactosidase-positive senescent cells [46]. Melanocytic mammalian carcinogenesis as studied in blood cells by nevi frequently harbor oncogenic BRAF mutations and Mumford et al hTERT-specific T cells could contribute recently it was found that a subpopulation of melanocytes to the immunosurveillance of breast cancer suggests possess the ability to survive BRAF induced senescence, novel opportunities for both therapeutic and prophylac- and suggest that p53 inactivation may promote malignant tic vaccine strategies for cancer [38]. transformation of these cells [47] and thus have implica- In one of the studies, using non-small lung adenocar- tions in skin cancer treatment. In vitro experiments with cinoma A549 cells, it was shown that after treatment therapeutic nucleic acids successfully inhibited E6/E7 with DNA damaging anti-tumor drugs like caffeine, cells oncogene expression and caused induction of apoptosis Singh et al. Cell Division 2010, 5:4 Page 4 of 12 http://www.celldiv.com/content/5/1/4

and/or senescence in cervical carcinoma cells. A useful al using p38-null mice skin carcinogenesis model assay was described by Lau et al [48] to predict the strongly suggests a role for p38delta (key regulator in response of the patient to a set of medicines without senescence, tumorigenesis, survival, inflammation etc) in administering them by testing the susceptibility of a sam- promoting cell proliferation and tumor development in ple of cancer cells in vitro and comparing it to the stan- epidermis and may have therapeutic implication for skin dard regimen. cancer [58]. Three xenograft breast cancer mouse mod- Apart from these, it has been observed that cells’ pas- els, 2 of them with a TP53 mutation and one without it, sage number controls the appearance of senescence. were studied for their immediate response to high doses Normal human diploid fibroblasts approach senescence of epirubicin-cyclophosphamide. TP53 wild type stained near passage 64 through RNaseT2 expression, which positive for SA-b-galactosidase staining and also over however fails to induce senescence in SV40 immorta- expressed P21 but TP53 mutant did not succumb to lized cell lines [49]. Rat chondrocytes show the onset of senescence suggesting that treatment induced senes- senescence in the 4th passage [50] while human rheuma- cence is mediated via functional p53 in breast cancer toid arthritis fibroblast-like synoviocytes exhibit ageing [59]. More in vivo studies are however, needed to eluci- at 10th passage [51]. Stable clones derived from hTERT- date the role of senescence in cancer. Although these expressing normal and G6PD-deficient fibroblasts have concepts are well supported in these models, translating normal karyotypes, and display no sign of senescence them to clinical oncology remains a challenge. beyond 145 and 105 passages, respectively, suggesting Neosis - Achilles heel of cancer cells evading senescence that ectopic expression of hTERT, in addition to telo- The physiological phenomenon of senescence serves as a mere length maintenance by activating telomerase, also lucrative pathway to annihilate deleterious cancer cells functions in regulating senescence induction [52]. and tissues. This program of senescence is activated upon

doi: 10.1186/1747-1028-7-15 Recently, a study explored the self-renewal potential of the administration of various anti-cancer regimens. Even human breast stem cells and found that it gets though this is not a universal mechanism of curbing exhausted within five in vitro passages of mammo- tumor cell growth, yet a considerable number of instances spheres, suggesting the need for further improvisation in of in vitro as well as in vivo studies have been cited to culture conditions for their long-term maintenance [53]. decipher the metabolic pathway it targets and these stu- Senescence in animal models: In vivo studies dies have produced useful results that have enhanced and Induction of senescence upon drug administration has refined our knowledge about these pathways (Figure 1) been proposed as a possible anti-cancer treatment in and will be helpful in delineating new treatment strategies various animal models. The finite proliferative potential for curtailing cancer. Several studies [60,61], however pro- of normal human cells leads to RS, which is a critical vide compelling evidence that some cancer cells which are barrier to tumor progression in vivo.Bystudying mitotically non-viable escape cell death, due to the accu- embryonic fibroblast-derived cells with loss-of-senes- mulation of some genetic and epigenetic mutations and cence or H-RasV12/E1A-transformed phenotypes at dif- p53/pRB/p53Ink4a-dependent senescence checkpoint mal- ferent stages of oncogenic progression in nude mice, it functioning resulting in telomerase dysfunction [61,62] was postulated that they may escape therapies aimed at and finally evade cell death via continued progression metabolic inhibition of tumors with a fully developed through neosis. Such cells acquire so called’ immortality’ Warburg phenotype [54]. b-carotene provides protection and to eliminate them, different strategies need to be against O3-induced skin oxidative stress in female SKH- designed. These cells multiply by a unique route called 1 mice skin, which is consistent with a protective role ‘neosis’ that facilitates in its progression and existence for beta-carotene in the skin hence has implications in thereby evading the program of senescence. It has been

RETRACTED 15skin MAY 2012 cancer and aging or senescence of skin [55]. A described as a parasexual, somatic, reduction division in novel target of NESH-SH3 (TARSH), cellular senescence cancer [62]. Although neosis-like events have been related gene in mouse embryonic fibroblasts may sup- reported in the literature sporadically for more than a cen- press tumor development in pulmonary tumorigenesis tury [63] under different names, they have been neglected mouse model by causing an increase in SA-b-gal activity due to the lack of appreciation of the significance of this and this was attributed to p53-dependent p21(Cip1) accu- process in cancer biology. Neosis may be a fundamental mulation [56]. Pituitary tumor transforming gene dele- step in current concept of multi step carcinogenesis. tion results in pituitary p21 induction and abrogates Studying the behavior of individual neotic clones has tumor development in Rb(+/-)Pttg(-/-) mice. Senescence revealed the significance of their central role in cancer was evidenced by increased p21 and SA-b-galactosidase. [64]. Non-synchronous occurrence of secondary/tertiary- Aneuploid pituitary cell p21 may constrain pituitary neosis (Figure 2) creates the illusion of the existence of tumor growth, thus accounting for the very low inci- cancer stem cells and the ‘mirage’ of immortality of cancer dence of pituitary carcinomas [57]. Work by Efimova et cells. Singh et al. Cell Division 2010, 5:4 Page 5 of 12 http://www.celldiv.com/content/5/1/4 doi: 10.1186/1747-1028-7-15 RETRACTED 15 MAY 2012

Figure 1 Genes involved in senescence. Singh et al. Cell Division 2010, 5:4 Page 6 of 12 http://www.celldiv.com/content/5/1/4 doi: 10.1186/1747-1028-7-15

Figure 2 Prerequisites for the onset of neosis and step-wise depiction of primary neosis (P/neosis) and secondary and tertiary neosis (S/T neosis). When a normal diploid cell accumulates genetic mutation owing to exposure, either dies following apoptosis or necrosis or may enter mitotic crisis and after repair again re-enters cell cycle or may become tetraploid after few hours or become polyploidy and succumb to senescence or may circumvent senescence and divide by neosis. Neosis of non-viable NMCs may give rise to genetically viable daughter cells ‘Raju cells’ by P/neosis and further divide and re-divide by S/T neosis. The number of progenies may vary from one to infinite and differ from NMCs and other daughter cells unlike conventional mode of division, mitosis. Number of surviving progenies depends on the ‘survival of the fittest’.

Some of the genetic and epigenetic alterations become design anti-neotic agents or neosicides that will be more

RETRACTED 15the MAY 2012 achilles heel of the mutated tumors that bypass the specific in their action and do less harm to non diseased effect of certain classes of anti-cancer agents. That is, cells. A judicial combination of senescent drugs with patients whose tumors carry such defects can be strati- efficient neosicides could further improve the status of fied for respective therapy rendering some classic DNA cancer control. damaging agents called neosicides into “targeted thera- MC and role of MKs in cancer pies.” Development of novel strategies to improve cur- According to the tenets of cancer biology, tumor cells rent status of cancer therapy will require identification arise after about 13 mitotic divisions of the initiated cell and exploitation of yet unrecognized differences between [66]. MKs, are rigorous quality control steps of mitosis normal and tumor cells with respect to propagation, and function in preserving the fidelity and integrity of evolution and development of resistance to conventional DNA and allow mitosis to continue only with accurately treatments [65]. The discovery of neosis has identified functioning DNA, spindle assembly, centrosome and novel cellular targets, against which one can identify kinetochore thus preventing MC [67]. Malfunctioning of novel neosis-specific molecular targets in order to MKs are intimately involved in the development of Singh et al. Cell Division 2010, 5:4 Page 7 of 12 http://www.celldiv.com/content/5/1/4

errors in a vast majority of solid tumors and hematolo- of various members of the MK families, including Aur- gical malignancies. MC is an event in which a cell is ora kinases (A, B, C), Polo-like (Plk1-4), and Nek destroyed during mitosis. This is believed to be caused (NIMA1-11) in diverse human tumors strongly indicate through apoptosis as a result of an attempt at aberrant that these entities are closely involved in the develop- chromosome segregation early in mitosis, or as a result ment of errors in centrosome duplication, chromosome of DNA damage later, during the metaphase/anaphase segregation, and cytokinesis. transition. Cells which fail to go through a MC after MKs families mitotic failures are likely to create aneuploid cells when The focus of this section is on the different MKs they later reproduce, posing a risk of oncogenesis, families. These kinases are modulated by de-novo synth- potentially leading to cancer [67]. Hence MC is also in esis, stability factors, phosphorylation, and ubiquitin- the league of processes which participate in prevention dependent proteolysis. They, in turn, phosphorylate of cancer. MC which has been described as ‘Death innumerable centrosomal/mitotic protein substrates, and through a tragedy’ [68] is stimulated by ionizing radia- have the ability to behave as oncogenes (i.e. Aurora-A, tions (IR), chemotherapeutic drugs or hyperthermia and Plk-1), providing a compelling link between errors in is caused by malfunctioning of cell cycle checkpoints mitosis and oncogenic processes [73]. Additionally, dys- and MKs. The normal choreography of the events in the regulation of MKs have been linked with improper cell mitotic cell cycle gets disturbed and aneuploidy follows. cycle progression both in vitro and in vivo. Without get- An aneuploid cell can be hyperaneuploid and may con- ting into the basics of MKs, the main pre-clinical and tribute to tumorigenesis by an enhanced expression of clinical studies concerning MK inhibitors currently oncogenes or may be hypo-aneuploid and be liable for under investigation are reported and important consid- tumorigenesis by a loss of heterozygosity of various erations for their future development are discussed.

doi: 10.1186/1747-1028-7-15 tumor suppressor genes [69]. Here is given a representation of kinases in different MC shares several biochemical hallmarks of apoptosis, phases of cell cycle (Additional File 1: Table S1). in particular mitochondrial membrane permeabilization Cyclin dependent kinases 1 (Cdk1) and caspase activation [70] but is proposed to be funda- Cdk1 is vital participant in the mitotic cell cycle. Mitosis mentally different from apoptosis [71]. Both senescence begins and ends with the activity of cdk1 with binding and MC are important pathways that cause cell annihi- partner cyclin B1. First studied in fission yeast (Sacchar- lation upon chemotherapeutic intervention. The omyces cerevesiae), Nurse [74] identified a gene that mechanism and morphology of the deceased cells is controlled mitosis and named it cdk1 or cdc2. Studies however different in both the cases. A tabular represen- have revealed that functional p53 protein may enhance tation of the differences between MC and senescence is the anti-cancer activity of roscovitine (known cdk1 inhi- given in Table 1. bitor) that could be beneficial for anti-cancer therapy Genetic checkpoint defects lead to syndromes that [75]. Tumorigenecity mediated by p53 loss does not demonstrate chromosomal instability, increased sensitiv- require either Cdk2 or Cdk4, which necessitates consid- ity to genotoxic stress and consequently cancer predis- eration of the use of broad spectrum cell cycle inhibitors position. The detection of persistent MK over- as a means of effective anti-Cdk cancer therapy [76]. expression, particularly the Aurora kinase family, and Gartner et al have reported for the first time reported centrosome amplification in precursor/pre-malignant an association of cyclins and Cdks with the microtubule stages, strongly correlate these molecular changes in network by immunoelectron microscopy and immuno- precipitating the aneuploidy seen in many human neo- biochemical methods. Cyclins D, E, A and B as well as plasms [72]. The sustained over-expression and activity Cdks 1, 2 and 4 were also found to be associated and RETRACTED 15 MAY 2012

Table 1 Comparison between senescence and mitotic catastrophe Characteristics Mitotic catastrophe Senescence Definition Synonymous with ‘Terminal proliferation arrest’ may proceed with Synonymous with ‘Terminal growth arrest’ Cell apoptosis or necrosis depending on molecular profile of the cell death in context of cancer Biomarker Multinucleated giant cells, no specific in vitro and in vivo assay available SA-b galactosidase expression, detected by X- gal staining Morphology Aneuploidy, disrupted DNA index, micronuclei formation, nuclear envelope Flattened enlarged cells, granular cytoplasm, lacking, nuclear fragmentation and uncondensed chromatin exhibit SAHF formation Genotype implicated Accelerated by G1, G2 and prophase checkpoint proteins (ATM, ATR, p53, Accelerated by telomere attrition, ras in carcinogenesis Chk2, Cdc25A, Cdc25B, Plk1 & 3) mutations, inhibited by ALT or p53 Inducing agents Hyperthermia, IR, anti-cancer drugs interfering with DNA or microtubule Spontaneous as a result of cumulative divisions assembly or challenged by oncogenic stimulus Singh et al. Cell Division 2010, 5:4 Page 8 of 12 http://www.celldiv.com/content/5/1/4

exhibit kinase activity towards the microtubule-asso- Plk1 gene expression is tightly regulated with mRNA ciated protein tau [77]. Bailet et al [78] have highlighted increase beginning in S phase and peak mRNA levels a new role for spleen tyrosine kinase (Syk) in regulating detected at G2-M transitions and through mitosis [88]. cellular senescence and identify Syk-mediated senes- RNA-interference -mediated depletion of Plk1 to deter- cence as a novel tumor suppressor pathway, the inacti- mine its potential for sensitizing pancreatic tumor cells vation of which may contribute to melanoma to gemcitabine showed that small interfering RNA- tumorigenicity. Study by Buchanan et al [79] on murine mediated knockdown of Plk1 caused cell cycle arrest at adenocarcinoma mammary cells provided new clues G2/M and the reduction of cellular proliferation and regarding the mechanism involved in the modulation of decreased cell viability and increased cellular apoptosis mammary tumor cell growth and survival induced by [89]. Transcription of Plk1 is inhibited along with other glypican-3. Gene expression profiling has generated G2/M specific genes like cyclin B1, cyclin B2 and hypotheses that led to an increase in our knowledge of cdc25B by inhibition of Nuclear Factor kappa B at G2- the cellular effects of seliciclib (cdk inhibitor) and could M phases [90]. Studies define and illuminate a late mito- provide potential pharmacodynamic or response biomar- tic function of Plk1 that it is obligatory in the position- kers for use in animal models and clinical trials [80]. ing and recruitment of Rho guanine nucleotide Another Cdk inhibitor SU9516 is over expressed in exchange factor (RhoGEF) Ect2 to the central spindle HCT116 cells by the knockout of the p21WAF1/CIP1 gene and abolishing RhoA GTPase localization to the equa- which suppresses thymidylate synthase and enhances torial cortex, and suppressing cleavage furrow formation chemosensitivity to 5-Flurouracil [81]. and cell division [91]. Increased plk-1 gene and protein Check point kinases 1 (Chk1) and 2 (Chk2) perhapsplayakeyroleinabnormalproliferationof Chk1 and Chk2 are effector kinases in the cellular DNA acute leukemia cells and correlate with the malignancy

doi: 10.1186/1747-1028-7-15 damage response and impairment of their function is of leukemia [92] prostate carcinoma, [93] and gastric closely related to tumorigenesis. If DNA damage is carcinoma [94]. Snk/Plk2 is transcriptionally down-regu- detected after S and before G2/M transition, ATM/ATR lated in B-cell neoplasms [95] and consequently pro- is activated and phosphorylation of Chk1 and Chk2 vides a potential mechanistic basis underlying the strong occurs [82] leading to cell death during mitosis or MC. selective pressure for abrogation of Plk2 function in B- Experiments have demonstrated that there are alternate cell neoplasia. Plk3 has been shown to catalyse the mechanisms for activating ATM that are both stress- priming of Cdc25A by phosphorylated glycogen synthase specific and independent of the presence of DNA breaks kinase-3b (GSK-3b) and observations indicate that GSK- [83]. The activation of the ATR-Chk1 pathway in 3b inactivation may account for Cdc25A overproduction response to bifunctional DNA alkylator 1,3-bis(2-chlor- in a subset of human tumors [96]. LFM-A13 (alpha- oethyl)-1-nitrosourea (BCNU) treatment and the depen- cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) dency of this response on the DNA mismatch repair propenamide) has recently been identified as an inhibi- capacity were investigated. Chk1 was found to be phos- tor of Plks and markedly enhances the anti-cancer activ- phorylated at serine 345 and exhibited increased kinase ity of paclitaxel [97] with anti-proliferative activity activity. Si-RNA knockdown of ATR also reduced Chk1 against human breast cancer [98]. phosphorylation following exposure to BCNU. However, Aurora kinases knockdown of ATM had no effect on the observed Aurora kinases namely, Aurora A(Aurora 2), Aurora B Chk1 phosphorylation, suggesting that ATR was primar- (Aurora 1) and Aurora C(Aurora 3) are serine/threonine ily responsible for Chk1 activation [84]. kinases also known as tubulin-associated proteins [99] Polo like kinases (Plk) which are expressed only in actively dividing cells and

RETRACTED 15A MAY 2012 family of serine/threonine kinases also designated as their increase is a factor of bad prognosis in cancer. tubulin-associated proteins actively participate during Side effects, dosing and tolerability of inhibitors have mitosis and comprises four distinct members: Plk1 been discussed in great length by Pinel et al [100] and (Plk), Plk2 (Snk), Plk3 (Prk or Fnk) and Plk4 (Sak) [85] enzymatic characterization of GSK1070916, a potent each carrying out a multitude of distinct roles. Plk1 is and selective Aurora-B/Aurora-C inhibitor was done the most extensively characterized among the family and compared with other Aurora inhibitors AZD1152 members, suggesting that the polo box domain of it and VX-680 [101], GSK1070916 was found to exert a can provide an additional structural basis for discovery more prevailing inhibitory effect due to a slow rate of of new anti-cancer drugs. It was also found out that dissociation from the Aurora-B & C enzymes. Detailed Plk1 is required for chromosomal DNA replication kinetic analyses of two isogenic cell lines differing in under stressful conditions [86] and Plk3 is more potent p53 function and have been compared with the effects in inhibiting cell proliferation and inducing apoptosis of ZM447439 and VE-465 to describe several mechan- [87]. isms explaining how cells may evade killing by Aurora Singh et al. Cell Division 2010, 5:4 Page 9 of 12 http://www.celldiv.com/content/5/1/4

kinase inhibitors [102]. It has been proposed that periki- to understand the role of MKs and their utility as tar- netochoric rings of MCAK and Aurora-B define a novel gets before we can actually embark on translational stu- transient centromere domain at least in mouse chromo- dies in human. somes during meiosis and also its functions have been illustrated by Parra et al [103]. Conclusions and future connotations Bub related kinases (Bub family) Cancer is a global health problem and various treatment The Bub family of kinases constitutes members that are strategies are premeditated for curbing this deadly bio- concerned with spindle assembly functioning and APC/ medical manifestation. Cells continuously encounter C regulation. In one of the studies p53 was sustained to DNA damage caused either by damaging agents, includ- express in K562 leukemic cells after being infected by ing oxygen radicals and DNA replication errors caused recombinant adenoviruses carrying the wt-p53 gene and by stalled replication forks, or by extracellular environ- it was shown that wt-p53 can suppress excessive replica- ments such as ultraviolet or IR. The cellular response to tion of centrosomes and may contribute to the upregu- radiation or chemicals is complex and may lead to dif- lation of Gadd45a and BubR1 protein expression as well ferent biological outcomes. Senescence, MC, necrosis, as the downregulation of Aurora A protein expression apoptosis and autophagy are such mechanisms out of [104]. A novel study reports that Ajuba, a microtubule- which the two former mechanisms have been discussed associated protein collaborates with Aurora B and in this review. BubR1 at the metaphase-anaphase transition and The physiological phenomenon of senescence is sti- ensures proper chromosome segregation[105]. mulated by ras/raf activity, telomere attrition and p53. Never in mitosis A- Related kinase (NIMA, Nek, Nrk) Cellular senescence is a persistently growth-arrested The Nek or Nrk related kinase family are essential MKs phenotype in normal and transformed cells which may

doi: 10.1186/1747-1028-7-15 first described in the filamentous fungus Aspergillus be beneficial when used to target the proliferation of nidulans [106] containing 11 members (Nek1, 2, 3, 6, 7, tumor cells or during organogenesis or wound healing. 8, 9, and 11 are prominent) [107]. Nek1 is involved It is well known that cancer risk rises exponentially with early in the DNA damage sensing/repair pathway after age fuelled by somatic mutations. Senescence leads to IR and G(1)-S-phase checkpoint control can be rescued altered expression of genes (cell division control, cell by ectopically over-expressing wild-type Nek1. More- structure and metabolism) and imparts resistance to over, in cells without functional Nek1, DNA is not cells towards apoptosis apart from actively secreting repaired properly, double-stranded DNA breaks persist inflammatory cytokines, proteinases and growth factors. long after low dose IR, and excessive numbers of chro- Keeping all these aspects about this mechanism in mosome breaks are observed [108]. Recently, studies mind, we can design novel treatment tactics in curbing have explicated that ciliary localization of Nek8 in a cancer. The discovery of neosis has identified novel cel- subset of ureteric-bud-derived kidney tubules is essential lular targets, against which one can identify novel neo- for maintaining the integrity of those tubules in the sis-specific molecular targets in order to design anti- mammalian kidney [109]. neotic agents or neosicides that will be effective against MKs and their role in cancer control- In a nutshell many tumor types and theoretically be expected to have As current cancer therapies are still in their infancy and a prophylactic action against multiple primary cancer are not able to fulfill the expectations of cancer control, growths. strategies targeting mitotic regulators could be a poten- Discussing the regulation of MKs, we open promising tially pragmatic option, which may improve the thera- avenues in designing novel biomarkers for novel unex- peutic index when used either alone or in combination plored targets and present the rationale for these kinases

RETRACTED 15with MAY 2012 current anti-cancer antidotes. The uniqueness of as an anti-cancer target. More in vivo work needs to be MKs lies in the fact that they are expressed in actively undertaken to understand the role of MKs and their duplicating cells and not in differentiated cells further prospective as cellular targets before translational stu- make it important targets against cancer cells. Targeting dies can be performed in humans. Several key works MKs would aid us in understanding the mechanism of using clinical samples strongly suggest that point muta- chemo-resistance. The research efforts to examine the tions of the checkpoint genes contribute to malignant role of MKs and mitotic signaling pathways are, how- transformation and genetic instability in cancer cells. ever, in its beginning. By presenting an overview of reg- However, the exact role of DNA damage checkpoints in ulation of MKs in this review, we open promising the prevention of human carcinogenesis should be re- avenues in designing novel therapeutic approaches in evaluated. The spindle checkpoint inhibits the ubiquitin curbing cancer. Simultaneously, we also present the ligase activity of the anaphase-promoting complex or rationale for these kinases as an anti-cancer target. cyclosome (APC/C), which is essential for mitotic pro- Hence, more concern needs to be laid on in vivo work gression, until spindles are properly attached to all Singh et al. Cell Division 2010, 5:4 Page 10 of 12 http://www.celldiv.com/content/5/1/4

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