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Combining an Aurora Kinase Inhibitor and a Death Receptor Ligand/Agonist Antibody Triggers Apoptosis in Melanoma Cells and Prevents Tumor Growth in Preclinical Mouse Models.
Liu Y, Hawkins OE, Vilgelm AE, Pawlikowski JS, Ecsedy JA, Sosman JA, Kelley MC, Richmond A
(2015) Clin Cancer Res 21: 5338-48
MeSH Terms: Animals, Antibodies, Monoclonal, Antineoplastic Agents, Apoptosis, Aurora Kinases, Azepines, Caspases, Cell Line, Tumor, Cellular Senescence, Disease Models, Animal, Drug Evaluation, Preclinical, Female, Humans, Melanoma, Mice, Protein Kinase Inhibitors, Pyrimidines, Receptors, Death Domain, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor, Member 10c, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Show Abstract · Added August 21, 2015
PURPOSE - Preclinical studies show that inhibition of aurora kinases in melanoma tumors induces senescence and reduces tumor growth, but does not cause tumor regression. Additional preclinical models are needed to identify agents that will synergize with aurora kinase inhibitors to induce tumor regression.
EXPERIMENTAL DESIGN - We combined treatment with an aurora kinase A inhibitor, MLN8237, with agents that activate death receptors (Apo2L/TRAIL or death receptor 5 agonists) and monitored the ability of this treatment to induce tumor apoptosis and melanoma tumor regression using human cell lines and patient-derived xenograft (PDX) mouse models.
RESULTS - We found that this combined treatment led to apoptosis and markedly reduced cell viability. Mechanistic analysis showed that the induction of tumor cell senescence in response to the AURKA inhibitor resulted in a decreased display of Apo2L/TRAIL decoy receptors and increased display of one Apo2L/TRAIL receptor (death receptor 5), resulting in enhanced response to death receptor ligand/agonists. When death receptors were activated in senescent tumor cells, both intrinsic and extrinsic apoptotic pathways were induced independent of BRAF, NRAS, or p53 mutation status. Senescent tumor cells exhibited BID-mediated mitochondrial depolarization in response to Apo2L/TRAIL treatment. In addition, senescent tumor cells had a lower apoptotic threshold due to decreased XIAP and survivin expression. Melanoma tumor xenografts of one human cell line and one PDX displayed total blockage of tumor growth when treated with MLN8237 combined with DR5 agonist antibody.
CONCLUSIONS - These findings provide a strong rationale for combining senescence-inducing therapeutics with death receptor agonists for improved cancer treatment.
©2015 American Association for Cancer Research.
2 Communities
3 Members
0 Resources
24 MeSH Terms
Aurora kinase inhibition induces PUMA via NF-κB to kill colon cancer cells.
Sun J, Knickelbein K, He K, Chen D, Dudgeon C, Shu Y, Yu J, Zhang L
(2014) Mol Cancer Ther 13: 1298-308
MeSH Terms: Animals, Apoptosis, Apoptosis Regulatory Proteins, Aurora Kinases, Cell Line, Tumor, Cell Survival, Colonic Neoplasms, Disease Models, Animal, Drug Resistance, Neoplasm, Female, Humans, Mice, NF-kappa B, Polyploidy, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, RNA Interference, Signal Transduction, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Show Abstract · Added July 28, 2015
Aurora kinases play a key role in mitosis and are frequently overexpressed in a variety of tumor cells. Inhibition of aurora kinases results in mitotic arrest and death of cancer cells, and has been explored as an anticancer strategy. However, how aurora inhibition kills cancer cells is poorly understood. In this study, we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, in colorectal cancer cells irrespective of p53 status. Deficiency in PUMA increased polyploidy, improved cell survival, and abrogated mitochondria-mediated apoptosis induced by aurora kinase inhibitors. In response to aurora kinase inhibition, PUMA was directly activated by p65 through the canonical NF-κB pathway following AKT inhibition. Furthermore, PUMA was necessary for the chemosensitization and in vivo antitumor effects of aurora kinase inhibitors in colon cancer cells. These results suggest that PUMA induction mediates the apoptotic response to mitotic arrest imposed by aurora kinase inhibition, and may be a useful indicator for the anticancer activity of aurora kinase inhibitors.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.
Liu Y, Hawkins OE, Su Y, Vilgelm AE, Sobolik T, Thu YM, Kantrow S, Splittgerber RC, Short S, Amiri KI, Ecsedy JA, Sosman JA, Kelley MC, Richmond A
(2013) EMBO Mol Med 5: 149-66
MeSH Terms: Animals, Antineoplastic Agents, Ataxia Telangiectasia Mutated Proteins, Aurora Kinases, Azepines, Benzazepines, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Cellular Senescence, Checkpoint Kinase 2, DNA Damage, DNA-Binding Proteins, Humans, Melanoma, Experimental, Mice, Mice, Nude, NF-kappa B, Polyploidy, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Pyrimidines, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays
Show Abstract · Added June 14, 2013
Oncogene-induced senescence can provide a protective mechanism against tumour progression. However, production of cytokines and growth factors by senescent cells may contribute to tumour development. Thus, it is unclear whether induction of senescence represents a viable therapeutic approach. Here, using a mouse model with orthotopic implantation of metastatic melanoma tumours taken from 19 patients, we observed that targeting aurora kinases with MLN8054/MLN8237 impaired mitosis, induced senescence and markedly blocked proliferation in patient tumour implants. Importantly, when a subset of tumour-bearing mice were monitored for tumour progression after pausing MLN8054 treatment, 50% of the tumours did not progress over a 12-month period. Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-κB-related, senescence-associated secretory phenotype (SASP). Blockade of IKKβ/NF-κB led to reversal of MLN8237-induced senescence and SASP. Results demonstrate that removal of senescent tumour cells by infiltrating myeloid cells is crucial for inhibition of tumour re-growth. Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.
Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.
2 Communities
7 Members
0 Resources
25 MeSH Terms
The combination of alisertib, an investigational Aurora kinase A inhibitor, and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas.
Sehdev V, Katsha A, Ecsedy J, Zaika A, Belkhiri A, El-Rifai W
(2013) Cancer 119: 904-14
MeSH Terms: Adenocarcinoma, Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Aurora Kinase A, Aurora Kinases, Azepines, Cell Cycle Checkpoints, Cell Survival, Docetaxel, Female, Gastrointestinal Neoplasms, Humans, Mice, Mice, Nude, Polyploidy, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Pyrimidines, Taxoids, Xenograft Model Antitumor Assays
Show Abstract · Added September 3, 2013
BACKGROUND - Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. The authors and others have previously reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and protein overexpression in UGCs. The objective of the current study was to determine the therapeutic potential of alisertib (MLN8237) alone and in combination with docetaxel in UGCs.
METHODS - After treatment with alisertib and/or docetaxel, clonogenic cell survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth assays were carried out to measure cell survival, cell cycle progression, apoptotic protein expression, and tumor xenograft volumes, respectively.
RESULTS - By using the AGS, FLO-1, and OE33 UGC cell lines, which have constitutive AURKA overexpression and variable tumor protein 53 (p53) status, significantly enhanced inhibition of cancer cell survival was observed with alisertib and docetaxel treatment in combination (P < .001), compared with single-agent treatments. Cell cycle analyses, after 48 hours of treatment with alisertib, produced a significant increase in the percentage of polyploidy in UGC cells (P < .01) that was further enhanced by docetaxel (P < .001). In addition, an increase in the percentage of cells in sub-G1-phase observed with alisertib (P < .01) was significantly enhanced with the combination treatment (P < .001). Western blot analysis demonstrated higher induction of cleaved caspase 3 protein expression with the combined treatment compared with single-agent treatments. In addition, FLO-1 and OE33 cell xenograft models demonstrated enhanced antitumor activity for the alisertib and docetaxel combination compared with single-agent treatments (P < .001).
CONCLUSIONS - The current study demonstrated that alisertib combined with docetaxel can mediate a better therapeutic outcome in UGC cell lines.
Copyright © 2012 American Cancer Society.
0 Communities
3 Members
0 Resources
21 MeSH Terms
The aurora kinase A inhibitor MLN8237 enhances cisplatin-induced cell death in esophageal adenocarcinoma cells.
Sehdev V, Peng D, Soutto M, Washington MK, Revetta F, Ecsedy J, Zaika A, Rau TT, Schneider-Stock R, Belkhiri A, El-Rifai W
(2012) Mol Cancer Ther 11: 763-74
MeSH Terms: Adenocarcinoma, Animals, Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Aurora Kinase A, Aurora Kinases, Azepines, Blotting, Western, Cell Cycle Checkpoints, Cell Line, Cell Line, Tumor, Cell Survival, Cisplatin, Drug Synergism, Esophageal Neoplasms, Esophagus, Female, Gene Expression, Humans, Mice, Mice, Nude, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Pyrimidines, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays
Show Abstract · Added September 3, 2013
Esophageal adenocarcinomas are poorly responsive to chemotherapeutics. This study aimed to determine the levels of Aurora kinase A (AURKA) and the therapeutic potential of MLN8237, an investigational AURKA inhibitor, alone and in combination with cisplatin. Using quantitative real-time PCR, we detected frequent AURKA gene amplification (15 of 34, 44%) and mRNA overexpression (37 of 44, 84%) in esophageal adenocarcinomas (P < 0.01). Immunohistochemical analysis showed overexpression of AURKA in more than two-thirds of esophageal adenocarcinoma tissue samples (92 of 132, 70%; P < 0.001). Using FLO-1, OE19, and OE33 esophageal adenocarinoma cell lines, with constitutive AURKA overexpression and mutant p53, we observed inhibition of colony formation with a single treatment of 0.5 μmol/L MLN8237 (P < 0.05). This effect was further enhanced in combination with 2.5 μmol/L cisplatin (P < 0.001). Twenty-four hours after treatment with the MLN8237 or MLN8237 and cisplatin, cell-cycle analyses showed a sharp increase in the percentage of polyploid cells (P < 0.001). This was followed by an increase in the percentage of cells in the sub-G(1) phase at 72 hours, concordant with the occurrence of cell death (P < 0.001). Western blot analysis showed higher induction of TAp73β, PUMA, NOXA, cleaved caspase-3, and cleaved PARP with the combined treatment, as compared with a single-agent treatment. Using xenograft models, we showed an enhanced antitumor role for the MLN8237 and cisplatin combination, as compared with single-agent treatments (P < 0.001). In conclusion, this study shows frequent overexpression of AURKA and suggests that MLN8237 could be an effective antitumor agent, which can be combined with cisplatin for a better therapeutic outcome in esophageal adenocarcinomas.
1 Communities
4 Members
0 Resources
29 MeSH Terms
Conditional ablation of Ikkb inhibits melanoma tumor development in mice.
Yang J, Splittgerber R, Yull FE, Kantrow S, Ayers GD, Karin M, Richmond A
(2010) J Clin Invest 120: 2563-74
MeSH Terms: Animals, Apoptosis, Aurora Kinase A, Aurora Kinase B, Aurora Kinases, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Genes, ras, I-kappa B Kinase, Melanocytes, Melanoma, Mice, Mice, Knockout, Mice, Transgenic, NF-kappa B, Neoplasms, Phosphorylation, Protein-Serine-Threonine Kinases, Transcription Factor RelA, Transcription, Genetic, Tumor Suppressor Protein p53
Show Abstract · Added June 14, 2013
Several lines of evidence suggest that tumor cells show elevated activity of the NF-kappaB transcription factor, a phenomenon often resulting from constitutive activity of IkappaB kinase beta (IKKbeta). However, others have found that loss of NF-kappaB activity or IKKbeta is tumor promoting. The role of NF-kappaB in tumor progression is therefore controversial and varies with tumor type. We sought to more extensively investigate the role IKKbeta in melanoma tumor development by specifically disrupting Ikkb in melanocytes in an established mouse model of spontaneous melanoma, whereby HRasV12 is expressed in a melanocyte-specific, doxycycline-inducible manner in mice null for the gene encoding the tumor suppressor inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf). Our results show that Ink4a/Arf-/- mice with melanocyte-specific deletion of Ikkb were protected from HRasV12-initiated melanoma only when p53 was expressed. This protection was accompanied by cell cycle arrest, with reduced cyclin-dependent kinase 2 (Cdk2), Cdk4, Aurora kinase A, and Aurora kinase B expression. Increased p53-mediated apoptosis was also observed, with decreased expression of the antiapoptotic proteins Bcl2 and survivin. Enhanced stabilization of p53 involved increased phosphorylation at Ser15 and reduced phosphorylation of double minute 2 (Mdm2) at Ser166. Together, our findings provide genetic and mechanistic evidence that mutant HRas initiation of tumorigenesis requires Ikkbeta-mediated NF-kappaB activity.
3 Communities
3 Members
0 Resources
21 MeSH Terms
Esophageal adenocarcinoma: treatment modalities in the era of targeted therapy.
Mukherjee K, Chakravarthy AB, Goff LW, El-Rifai W
(2010) Dig Dis Sci 55: 3304-14
MeSH Terms: Adenocarcinoma, Angiogenesis Inhibitors, Antineoplastic Agents, Aurora Kinases, Barrett Esophagus, Clinical Trials as Topic, Combined Modality Therapy, Disease Progression, ErbB Receptors, Esophageal Neoplasms, Esophagectomy, Humans, Molecular Targeted Therapy, Protein-Serine-Threonine Kinases, Treatment Outcome
Show Abstract · Added March 11, 2014
Esophageal adenocarcinoma is an aggressive malignancy with a poor outcome, and its incidence continues to rise at an alarming rate. Current treatment strategies combining chemotherapy, radiation, and surgery are plagued with high rates of recurrence and metastasis. Multiple molecular pathways including the epidermal growth factor receptor, vascular endothelial growth factor, v-erb-b2 erythroblastic leukemia viral oncogene homolog (ERBB2), and Aurora kinase pathways are activated in many esophageal adenocarcinomas. In many cases, these pathways have critical roles in tumor progression. Research on the mechanisms by which these pathways contribute to disease progression has resulted in numerous biologic agents and small molecules with the potential to improve outcome. The promise of targeted therapy and personalized medicine in improving the clinical outcome is now closer than it has ever been.
0 Communities
2 Members
0 Resources
15 MeSH Terms
Aurora kinase inhibitors--rising stars in cancer therapeutics?
Dar AA, Goff LW, Majid S, Berlin J, El-Rifai W
(2010) Mol Cancer Ther 9: 268-78
MeSH Terms: Antineoplastic Agents, Aurora Kinase A, Aurora Kinases, Clinical Trials as Topic, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Models, Biological, Neoplasms, Protein-Serine-Threonine Kinases, Signal Transduction
Show Abstract · Added March 11, 2014
Standard therapeutic approaches of cytotoxics and radiation in cancer are not only highly toxic, but also of limited efficacy in treatment of a significant number of cancer patients. The molecular analysis of the cancer genomes have shown a remarkable complexity and pointed to key genomic and epigenomic alterations in cancer. These discoveries are paving the way for targeted therapy approaches. However, although there are a large number of potential targets, only a few can regulate key cellular functions and intersect multiple signaling networks. The Aurora kinase family members (A, B, and C) are a collection of highly related and conserved serine-threonine kinases that fulfill these criteria, being key regulators of mitosis and multiple signaling pathways. Alterations in Aurora kinase signaling are associated with mitotic errors and have been closely linked to chromosomal aneuploidy in cancer cells. Several studies have shown amplification and/or overexpression of Aurora kinase A and B in hematologic malignancies and solid tumors. Over the past several years, Aurora kinases have become attractive targets. Several ongoing clinical trials and bench-based research are assessing the unique therapeutic potential of Aurora-based targeted therapy.
0 Communities
3 Members
0 Resources
12 MeSH Terms
A link between aurora kinase and Clp1/Cdc14 regulation uncovered by the identification of a fission yeast borealin-like protein.
Bohnert KA, Chen JS, Clifford DM, Vander Kooi CW, Gould KL
(2009) Mol Biol Cell 20: 3646-59
MeSH Terms: Amino Acid Sequence, Aurora Kinases, Cell Cycle Proteins, Chromosomes, Fungal, Cytokinesis, Humans, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Phosphoprotein Phosphatases, Protein Structure, Secondary, Protein Subunits, Protein Tyrosine Phosphatases, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 5, 2014
The chromosomal passenger complex (CPC) regulates various events in cell division. This complex is composed of a catalytic subunit, Aurora B kinase, and three nonenzymatic subunits, INCENP, Survivin, and Borealin. Together, these four subunits interdependently regulate CPC function, and they are highly conserved among eukaryotes. However, a Borealin homologue has never been characterized in the fission yeast, Schizosaccharomyces pombe. Here, we isolate a previously uncharacterized S. pombe protein through association with the Cdc14 phosphatase homologue, Clp1/Flp1, and identify it as a Borealin-like member of the CPC. Nbl1 (novel Borealin-like 1) physically associates with known CPC components, affects the kinase activity and stability of the S. pombe Aurora B homologue, Ark1, colocalizes with known CPC subunits during mitosis, and shows sequence similarity to human Borealin. Further analysis of the Clp1-Nbl1 interaction indicates that Clp1 requires CPC activity for proper accumulation at the contractile ring (CR). Consistent with this, we describe negative genetic interactions between mutant alleles of CPC and CR components. Thus, this study characterizes a fission yeast Borealin homologue and reveals a previously unrecognized connection between the CPC and the process of cytokinesis in S. pombe.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Spindle assembly in the absence of a RanGTP gradient requires localized CPC activity.
Maresca TJ, Groen AC, Gatlin JC, Ohi R, Mitchison TJ, Salmon ED
(2009) Curr Biol 19: 1210-5
MeSH Terms: Animals, Aurora Kinases, Cell Division, Centrosome, Chromatin, Kinetics, Kinetochores, Microscopy, Fluorescence, Microspheres, Microtubules, Multiprotein Complexes, Protein-Serine-Threonine Kinases, Spindle Apparatus, Xenopus laevis, ran GTP-Binding Protein
Show Abstract · Added March 5, 2014
During animal cell division, a gradient of GTP-bound Ran is generated around mitotic chromatin. It is generally accepted that this RanGTP gradient is essential for organizing the spindle, because it locally activates critical spindle assembly factors. Here, we show in Xenopus laevis egg extract, where the gradient is best characterized, that spindles can assemble in the absence of a RanGTP gradient. Gradient-free spindle assembly occurred around sperm nuclei but not around chromatin-coated beads and required the chromosomal passenger complex (CPC). Artificial enrichment of CPC activity within hybrid bead arrays containing both immobilized chromatin and the CPC supported local microtubule assembly even in the absence of a RanGTP gradient. We conclude that RanGTP and the CPC constitute the two major molecular signals that spatially promote microtubule polymerization around chromatin. Furthermore, we hypothesize that the two signals mainly originate from discreet physical sites on the chromosomes to localize microtubule assembly around chromatin: a RanGTP signal from any chromatin and a CPC-dependent signal predominantly generated from centromeric chromatin.
0 Communities
1 Members
0 Resources
15 MeSH Terms