ZM 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensional culture.

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ZM 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensional culture.

Cell Cycle. 2008 May 15;7(10):1473-9

Authors: Long ZJ, Xu J, Yan M, Zhang JG, Guan Z, Xu DZ, Wang XR, Yao J, Zheng FM, Chu GL, Cao JX, Zeng YX, Liu Q

Abstract
Mitotic Aurora kinases are essential for accurate chromosome segregation during cell division. Forced overexpression of Aurora kinase results in centrosome amplification and multipolar spindles, causing aneuploidy, a hallmark of cancer. ZM447439 (ZM), an Aurora selective ATP-competitive inhibitor, interferes with the spindle integrity checkpoint and chromosome segregation. Here, we showed that inhibition of Aurora kinase by ZM reduced histone H3 phosphorylation at Ser10 in Hep2 carcinoma cells. Multipolar spindles were induced in these ZM-treated G(2)/M-arrested cells with accumulation of 4N/8N DNA, similar to cells with genetically suppressed Aurora-B. Cells subsequently underwent apoptosis, as assessed by cleavage of critical apoptotic associated protein PARP. Hep2 cells formed a tumor-like cell mass in 3-dimensional matrix culture; inhibition of Aurora kinase by ZM either destructed the preformed cell mass or prevented its formation, by inducing apoptotic cell death as stained for cleaved caspase-3. Lastly, ZM inhibition of Aurora kinase was potently in association with decrease of Akt phosphorylation at Ser473 and its substrates GSK3alpha/beta phosphorylation at Ser21 and Ser9. Together, we demonstrated that Aurora kinase served as a potential molecular target of ZM for more selective therapeutic cancer treatment.

PMID: 18418083 [PubMed - indexed for MEDLINE]

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Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase.

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Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase.

Nat Cell Biol. 2011 Oct;13(10):1265-71

Authors: Foley EA, Maldonado M, Kapoor TM

Abstract
Error-free chromosome segregation depends on the precise regulation of phosphorylation to stabilize kinetochore-microtubule attachments (K-fibres) on sister chromatids that have attached to opposite spindle poles (bi-oriented). In many instances, phosphorylation correlates with K-fibre destabilization. Consistent with this, multiple kinases, including Aurora B and Plk1, are enriched at kinetochores of mal-oriented chromosomes when compared with bi-oriented chromosomes, which have stable attachments. Paradoxically, however, these kinases also target to prometaphase chromosomes that have not yet established spindle attachments and it is therefore unclear how kinetochore-microtubule interactions can be stabilized when kinase levels are high. Here we show that the generation of stable K-fibres depends on the B56-PP2A phosphatase, which is enriched at centromeres/kinetochores of unattached chromosomes. When B56-PP2A is depleted, K-fibres are destabilized and chromosomes fail to align at the spindle equator. Strikingly, B56-PP2A depletion increases the level of phosphorylation of Aurora B and Plk1 kinetochore substrates as well as Plk1 recruitment to kinetochores. Consistent with increased substrate phosphorylation, we find that chemical inhibition of Aurora or Plk1 restores K-fibres in B56-PP2A-depleted cells. Our findings reveal that PP2A, an essential tumour suppressor, tunes the balance of phosphorylation to promote chromosome-spindle interactions during cell division.

PMID: 21874008 [PubMed - indexed for MEDLINE]

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Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit.

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Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit.

Mol Cancer Ther. 2009 Jun;8(6):1646-54

Authors: Bekier ME, Fischbach R, Lee J, Taylor WR

Abstract
Cell death induced by agents that disrupt microtubules can kill cells by inducing a prolonged mitotic block. This mitotic block is dependent on the spindle assembly checkpoint, a surveillance system that ensures the bipolar attachment of chromosomes to the mitotic spindle before the onset of anaphase. Under some conditions, the spindle assembly checkpoint can become weakened, allowing cells to exit mitosis despite the presence of chromosomes that are not properly attached to the mitotic spindle. Here, we use an Aurora kinase inhibitor to drive mitotic exit and test the effect of mitotic arrest length on death in the subsequent interphase. Cells that are blocked in mitosis for >15 h die shortly after exiting from mitosis, whereas cells that exit after being blocked for <15 h show variable fates, with some living for days after exiting mitosis. Cells blocked in mitosis by either Taxol or epothilone B are acutely sensitive to the death ligand tumor necrosis factor-related apoptosis-inducing ligand, suggesting that prolonged mitosis allows the gradual accumulation of internal death signals, rendering cells hypersensitive to additional prodeath cues. Death under these conditions is initiated while cyclin B1 is still present, indicating that cells are in mitosis. Our experiments suggest that there is a point of no return during prolonged mitotic block after which mitotic exit can no longer block death.

PMID: 19509263 [PubMed - indexed for MEDLINE]

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Frequent overexpression of aurora B kinase, a novel drug target, in non-small cell lung carcinoma patients.

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Frequent overexpression of aurora B kinase, a novel drug target, in non-small cell lung carcinoma patients.

Mol Cancer Ther. 2006 Nov;5(11):2905-13

Authors: Vischioni B, Oudejans JJ, Vos W, Rodriguez JA, Giaccone G

Abstract
The serine/threonine protein kinase aurora B, a key regulator of mitosis, is emerging as a novel drug target for cancer treatment. Aurora B overexpression has been previously documented by immunohistochemistry in several types of human tumors. We assessed aurora B expression in a series of 160 non-small cell lung cancer (NSCLC) samples (60% stage I, 21% stage II, 11% stage III, and 8% stage IV). In addition, we determined the expression of survivin and p16, two molecules also involved in cell cycle control. Aurora B was expressed selectively in tumor cells compared with normal epithelium. Aurora B expression was significantly correlated with expression of survivin in the nucleus (P < 0.0001), but not with expression of p16 (P = 0.134). High aurora B expression levels were significantly associated with older age (P = 0.012), male sex (P = 0.013), squamous cell carcinoma histology (P = 0.001), poor tumor differentiation grade (P = 0.007), and lymph node invasion (P = 0.037), in the subset of radically resected patients in our series. In addition, aurora B expression predicted shorter survival for the patients with adenocarcinoma histology, at both univariate (P = 0.020) and multivariate (P = 0.012) analysis. Survivin expression levels were neither associated with patient clinicopathologic characteristics nor with survival. However, expression of survivin in the nucleus was preferentially detected in stage I and II than in stage III and IV (P = 0.007) in the overall series of NSCLC samples. Taken together, our results suggest that aurora B may represent a valid target in NSCLC.

PMID: 17121938 [PubMed - indexed for MEDLINE]

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Effectiveness of statins in chronic kidney disease.

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Effectiveness of statins in chronic kidney disease.

QJM. 2012 Jul;105(7):641-8

Authors: Sheng X, Murphy MJ, Macdonald TM, Wei L

Abstract
BACKGROUND: Previous studies show that statins reduce total cholesterol (TC) concentration by both 21% in primary prevention (PP) and secondary prevention (SP) in clinical trials and by ?24% in the general population. There are few data about the efficacy of statins on TC concentration and cardiovascular (CV) outcome in patients with chronic kidney disease (CKD). We evaluated the reduction of TC concentration and subsequent risk of CV morbidity and mortality with statins in CKD patients.
METHODS: A population-based cohort study using a record-linkage database in Tayside, Scotland. A total of 2369 patients who had a primary diagnosis of CKD from Scottish Morbidity Record data or biochemistry database (serum creatinine of 220??mol/l or higher) and who had at least two separate TC measurements between 1993 and 2007 were studied. Patients were categorized into statin-exposed and statin-unexposed groups according to statin use status during the follow-up. They were also classified into PP (n?=?1325) and SP (n?=?1044) cohorts at the entry date. The main outcomes were TC concentration change from baseline, CV events [Antiplatelet Trialist's Collaboration (APTC)] and all-cause mortality during the follow-up. Cox regression models, in which statin use was a time-dependent variable, were employed to assess the risk of outcome and adjusted for other known confounders.
RESULTS: Statin-associated TC concentrations decreased by 0.59?mmol/l (12%) in PP cohort and 0.56?mmol/l (13%) in SP cohort from 4.77 and 4.48?mmol/l at baselines, respectively. Statin use was associated with a reduced risk of APTC events, CV mortality or all-cause mortality in PP {adjusted hazard ratio (HR), 0.65 [95% confidence interval (CI) 0.48-0.88]; 0.73 (95% CI 0.52-0.98); 0.59 (95% CI 0.48-0.73)} and SP [adjusted HR, 0.66 (95% CI 0.52-0.84); 0.60 (95% CI 0.47-0.77); 0.56 (95% CI 0.47-0.68)], respectively.
CONCLUSION: Statin use reduced TC concentrations by ?13% in patients with CKD. Statins were protective of APTC events, CV mortality and all-cause mortality in patients with or without established CV disease.

PMID: 22383690 [PubMed - indexed for MEDLINE]

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Aurora B confers cancer cell resistance to TRAIL-induced apoptosis via phosphorylation of survivin.

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Aurora B confers cancer cell resistance to TRAIL-induced apoptosis via phosphorylation of survivin.

Carcinogenesis. 2012 Mar;33(3):492-500

Authors: Yoon MJ, Park SS, Kang YJ, Kim IY, Lee JA, Lee JS, Kim EG, Lee CW, Choi KS

Abstract
Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) induces apoptosis selectively in cancer cells while sparing normal cells. However, many cancer cells are resistant to TRAIL-induced cell death. In this study, we examined whether Aurora B, which is frequently overexpressed in cancer cells, is associated with TRAIL resistance. The protein levels of Aurora B were higher in TRAIL-resistant cancer cell lines than in TRAIL-sensitive cancer cell lines. Exogenously expressed Aurora B attenuated TRAIL-induced apoptosis in the tested TRAIL-sensitive cancer cell lines, whereas the small interfering RNA-mediated suppression of Aurora B expression stimulated TRAIL-mediated apoptosis in the tested TRAIL-resistant cancer cell lines. Furthermore, combined treatment with TRAIL and ZM447439, a specific inhibitor of Aurora B, synergistically induced apoptosis in various TRAIL-resistant cancer cells, suggesting that this combined regimen may represent an attractive strategy for effectively treating TRAIL-resistant malignant cancers. Mechanistically, the inhibition of Aurora B activity in various cancer cells commonly downregulated survivin protein levels and potentiated the activation of caspase-3. In addition, Aurora B inhibition induced mitotic catastrophe, which also contributed to the sensitization of cells to TRAIL-mediated apoptosis. Interestingly, forced overexpression of Aurora B increased the protein levels of survivin, but not those of a non-phosphorylatable survivin mutant in which threonine 117 was replaced by alanine, indicating that phosphorylation of survivin is required for this effect. Furthermore, TRAIL-induced apoptosis in MDA-MB-435S cells was attenuated by wild-type survivin but not by the non-phosphorylatable survivin mutant. Collectively, our results demonstrate that Aurora B confers TRAIL resistance to cancer cells via phosphorylation of survivin.

PMID: 22159225 [PubMed - indexed for MEDLINE]

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Molecular basis of drug resistance in aurora kinases.

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Molecular basis of drug resistance in aurora kinases.

Chem Biol. 2008 Jun;15(6):552-62

Authors: Girdler F, Sessa F, Patercoli S, Villa F, Musacchio A, Taylor S

Abstract
Aurora kinases have emerged as potential targets in cancer therapy, and several drugs are currently undergoing preclinical and clinical validation. Whether clinical resistance to these drugs can arise is unclear. We exploited a hypermutagenic cancer cell line to select mutations conferring resistance to a well-studied Aurora inhibitor, ZM447439. All resistant clones contained dominant point mutations in Aurora B. Three mutations map to residues in the ATP-binding pocket that are distinct from the "gatekeeper" residue. The mutants retain wild-type catalytic activity and were resistant to all of the Aurora inhibitors tested. Our studies predict that drug-resistant Aurora B mutants are likely to arise during clinical treatment. Furthermore, because the plasticity of the ATP-binding pocket renders Aurora B insensitive to multiple inhibitors, our observations indicate that the drug-resistant Aurora B mutants should be exploited as novel drug targets.

PMID: 18559266 [PubMed - indexed for MEDLINE]

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