Inhibition of Aurora B kinase sensitizes a subset of human glioma cells to TRAIL concomitant with induction of TRAIL-R2

Li, J; Anderson, Mark G.; Tucker, Lora; Shen, Yu; Glaser, Keith B.; Shah, O. Jameel

doi:10.1038/cdd.2008.174

Cited by 32 publications

(20 citation statements)

References 33 publications

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“…Because Aurora kinase A, Aurora kinase B and survivin are essential for successful mitotic transition, particularly in cytokinesis, [65][66][67][68] and mitotic catastrophe is characterized by the appearance of enlarged micro-and/or multinucleated cells, we examined the morphology of nuclei of cucurbitacin and ABT-737-treated cells. At least 100 cells were analyzed and the results are presented in Figure 4G.…”

Section: Resultsmentioning

confidence: 99%

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Premkumar¹,

Jane

Pollack

2014

Cancer Biology & Therapy

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Abbreviations: BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; EGFR, epidermal growth factor receptor; MTS,[3][4]]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium; FITC, fluorescein isothiocyanate; NF-kB, nuclear factor kB; PI3K, Phosphatidylinositol 3-Kinase; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophoresis; PDGFR, platelet derived growth factor receptor; TBS, Tris-buffered saline; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; PI, propidium iodide.Because STAT signaling is commonly activated in malignant gliomas as a result of constitutive EGFR activation, strategies for inhibiting the EGFR/JAK/STAT cascade are of significant interest. We, therefore, treated a panel of established glioma cell lines, including EGFR overexpressors, and primary cultures derived from patients diagnosed with glioblastoma with the JAK/STAT inhibitor cucurbitacin-I. Treatment with cucurbitacin-I depleted p-STAT3, p-STAT5, p-JAK1 and p-JAK2 levels, inhibited cell proliferation, and induced G2/M accumulation, DNA endoreduplication, and multipolar mitotic spindles. Longer exposure to cucurbitacin-I significantly reduced the number of viable cells and this decrease in viability was associated with cell death, as confirmed by an increase in the subG1 fraction. Our data also demonstrated that cucurbitacin-I strikingly downregulated Aurora kinase A, Aurora kinase B and survivin. We then searched for agents that exhibited a synergistic effect on cell death in combination with cucurbitacin-I. We found that cotreatment with cucurbitacin-I significantly increased Bcl -2/Bcl -xL family member antagonist ABT-737-induced cell death regardless of EGFR/PTEN/p53 status of malignant human glioma cell lines. Although >50% of the cucurbitacin-I plus ABT-737 treated cells were annexin V and propidium iodide positive, PARP cleavage or caspase activation was not observed. Pretreatment of z-VAD-fmk, a pan caspase inhibitor did not inhibit cell death, suggesting a caspaseindependent mechanism of cell death. Genetic inhibition of Aurora kinase A or Aurora kinase B or survivin by RNA interference also sensitized glioma cells to ABT-737, suggesting a link between STAT activation and Aurora kinases in malignant gliomas.

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Section: Resultsmentioning

confidence: 99%

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Premkumar¹,

Jane

Pollack

2014

Cancer Biology & Therapy

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“…Consistently, Aurora B has been previously reported to be involved in cancer cell resistance to TRAIL. 40,41 Previous studies have shown that TRAIL can activate both NF-kB and the Ras/Raf/MEK/ERK mitogen-activated protein kinase cascade signaling pathways 5,6,42,43 and that Aurora A can be a downstream target of ERK. 44 The results of these studies, together with our findings of TRAIL-induced activation of both Aurora and IKK kinases, define an important role for Aurora kinases in connecting mitogen-activated protein kinase signaling to NF-kB activity.…”

Section: Discussionmentioning

confidence: 99%

Aurora and IKK kinases cooperatively interact to protect multiple myeloma cells from Apo2L/TRAIL

Mazzera

Lombardi

Abeltino

et al. 2013

Blood

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Constitutive activation of the canonical and noncanonical nuclear factor-kB (NF-kB) pathways is frequent in multiple myeloma (MM) and can compromise sensitivity to TRAIL. In this study, we demonstrate that Aurora kinases physically and functionally interact with the key regulators of canonical and noncanonical NF-kB pathways IkB kinase b (IKKb) and IKKa to activate NF-kB in MM, and the pharmacological blockade of Aurora kinase activity induces TRAIL sensitization in MM because it abrogates TRAIL-induced activation of NF-kB. We specifically found that TRAIL induces prosurvival signaling by increasing the phosphorylation state of both Aurora and IKK kinases and their physical interactions, and the blockade of Aurora kinase activity by pan-Aurora kinase inhibitors (pan-AKIs) disrupts TRAIL-induced survival signaling by effectively reducing Aurora-IKK kinase interactions and NF-kB activation. Pan-AKIs consistently blocked TRAIL induction of the antiapoptotic NF-kB target genes A1/Bfl-1 and/or Mcl-1, both important targets for TRAIL sensitization in MM cells. In summary, these results identify a novel interaction between Aurora and IKK kinases and show that these pathways can cooperate to promote TRAIL resistance. Finally, combining pan-AKIs with TRAIL in vivo showed dramatic efficacy in a multidrug-resistant human myeloma xenograft model. These findings suggest that combining Aurora kinase inhibitors with TRAIL may have therapeutic benefit in MM. (Blood. 2013;122(15):2641-2653

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“…S2 C and D). MLN8054, a small-molecule inhibitor of aurora A, showed no synergy in combination with ABT-263 at aurora A-selective concentrations (<5 μM) (9,10). In contrast, synergy was observed when ABT-263 was combined with the aurora B-selective inhibitor, AZD1152 ( Fig.…”

mentioning

confidence: 92%

Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization

Shah¹,

Lin²,

Li³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This "addiction" can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility.apoptosis | aurora kinase | Bcl-XL | polyploidy

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Inhibition of Aurora B kinase sensitizes a subset of human glioma cells to TRAIL concomitant with induction of TRAIL-R2

Cited by 32 publications

References 33 publications

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Aurora and IKK kinases cooperatively interact to protect multiple myeloma cells from Apo2L/TRAIL

Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization

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