The Experts below are selected from a list of 11526 Experts worldwide ranked by ideXlab platform
Quentin Liu - One of the best experts on this subject based on the ideXlab platform.
-
apoptosis in Aurora-A-high acute myeloid leukemia Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces
2013Co-Authors: Xiang Bo Wan, Quentin Liu, Yi Xin Zeng, Xue Fei Huang, Shao Kai Luo, Fei Meng Zheng, Li Hui WangAbstract:Abstract Previously we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression of Aur-A was markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680-induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML ( P< .0001) or normal BMMCs ( P< .0001), suggesting the possible pharmacologic window in targeting Aurora kinase among Aur-A-high VX-680-sensitive leukemia patients. VX-680-induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G 2 /M phase arrest, decreased phosphorylated(p)-Akt-1 and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase (PARP). Notably, VX-680 increased Bax/Bcl-2 expression ratio, a favorable pro-apoptotic predictor for drug-response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and Aur-A-high expression may serve as a differential marker for selective treatment. From bloodjournal.hematologylibrary.org by guest on June 3, 2013. For personal use only.
-
Inhibition of mitotic kinase Aurora suppresses Akt-1 activation and induces apoptotic cell death in all-trans retinoid acid-resistant acute promyelocytic leukemia cells
Journal of translational medicine, 2011Co-Authors: Shan Huang, Zhengzhi Zou, Zijie Long, Jia-jie Chen, Dong Jun Lin, Quentin LiuAbstract:Background Aurora kinase ensures accurate chromosome segregation during cell cycle, maintaining genetic integrity in cell division. VX-680, a small-molecule Aurora kinase inhibitor, interferes with mitotic entry and formation of bipolar spindles. Here, we evaluated VX-680 as a potential agent for treatment of all-trans retinoid acid (ATRA)-resistant acute promyelocytic leukemia (APL) in vitro.
-
aurora kinase small molecule inhibitor destroys mitotic spindle suppresses cell growth and induces apoptosis in oral squamous cancer cells
Oral Oncology, 2008Co-Authors: Caobing Pan, Zijie Long, Min Yan, Jine Yao, Hongzhang Huang, Quentin LiuAbstract:Mitotic Aurora kinases are required for accurate chromosome segregation during cell division. Ectopic expression of Aurora-A (Aur-A) kinase results in centrosome amplification, aberrant spindles, and consequent aneuploidy. In the present study, we showed that Aurora kinase inhibitory small molecule VX-680 inhibited histone H3 phosphorylation at Ser10, a known in vivo substrate residue of Aurora kinase, in oral squamous cell carcinoma (OSCC) KB cells. In addition, monopolar spindle structures, typical abnormalities induced by inhibition of Aur-A, were generated in VX-680-treated cells. Inhibition of Aurora kinase led to reduced KB cell growth, as assessed by MTT assay. Western blot analysis revealed that VX-680 caused cleavage of two critical apoptotic associated proteins, PARP and caspase-3. In contrast, expression of cell survival factor Bcl-2 was reduced by VX-680 treatment in a dose-dependent manner. Subsequently, nuclear characteristic of DNA fragmentation, indicative of apoptotic cell death, was clearly observed in these OSCC cells with Aurora kinase inhibitory VX-680. Taken together, we showed that Aurora kinase inhibitory VX-680 led to apoptotic cell death in OSCC cells, suggesting a novel therapeutic target in oral cancer.
-
aurora kinase inhibitory vx 680 increases bax bcl 2 ratio and induces apoptosis in aurora a high acute myeloid leukemia
Blood, 2008Co-Authors: Xue Fei Huang, Min Yan, Xiang Bo Wan, Yi Xin Zeng, Shao Kai Luo, Li Hui Wang, Xian Ren Wang, Fei Meng Zheng, Quentin LiuAbstract:Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression ofAur-Awas markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680‐induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase amongAur-A-high VX-680‐ sensitive leukemia patients. VX-680‐ induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/ Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment. (Blood. 2008;111: 2854-2865)
Xiang Bo Wan - One of the best experts on this subject based on the ideXlab platform.
-
apoptosis in Aurora-A-high acute myeloid leukemia Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces
2013Co-Authors: Xiang Bo Wan, Quentin Liu, Yi Xin Zeng, Xue Fei Huang, Shao Kai Luo, Fei Meng Zheng, Li Hui WangAbstract:Abstract Previously we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression of Aur-A was markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680-induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML ( P< .0001) or normal BMMCs ( P< .0001), suggesting the possible pharmacologic window in targeting Aurora kinase among Aur-A-high VX-680-sensitive leukemia patients. VX-680-induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G 2 /M phase arrest, decreased phosphorylated(p)-Akt-1 and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase (PARP). Notably, VX-680 increased Bax/Bcl-2 expression ratio, a favorable pro-apoptotic predictor for drug-response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and Aur-A-high expression may serve as a differential marker for selective treatment. From bloodjournal.hematologylibrary.org by guest on June 3, 2013. For personal use only.
-
Inhibition of Aurora-A results in increased cell death in 3-dimensional culture microenvironment, reduced migration and is associated with enhanced radiosensitivity in human nasopharyngeal carcinoma.
Cancer biology & therapy, 2009Co-Authors: Xiang Bo Wan, Zijie Long, Xin Juan Fan, Ming Yuan Chen, Yi Jun Hua, Ming Huang Hong, Yi Xin ZengAbstract:Mitosis related Aurora-A kinase is amplified in a variety of carcinomas. Overexpression of Aurora-A contributes to tumorigenesis and disease progression, and has emerged as an attractive molecular target for the design of anticancer drugs. In this study, we investigated the function of Aurora-A selectively small molecule inhibitor VX-680 in nasopharyngeal carcinoma (NPC) CNE-2 cells. We found that VX-680 suppressed proliferation and induced apoptosis of 2-dimensional (2-D) cultured NPC CNE-2 cells. Moreover, CNE-2 cells formed a tumor-like cell mass in 3-dimensional (3-D) matrix culture microenvironment, and the tumor mass formation could be impaired when pretreated with VX-680 for indicated time. Similarly, when adding VX-680 to preformed 3-D CNE-2 tumor mass, the tight spatial tumor mass experienced apparent apoptotic cell death and consequently dissociated into individual dead cells, as detected by cleaved Caspase-3 immunofluorescence assay. The migration assay showed that VX-680 decreased NPC CNE-2 ce...
-
Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells.
Carcinogenesis, 2008Co-Authors: Xiang Bo Wan, Zijie Long, Min Yan, Xue Fei Huang, Xian Ren Wang, Liang Ping Xia, Yan Zhao, Xiao Feng ZhuAbstract:Mitotic serine/threonine kinase Aurora-A (Aur-A) plays a critical role in regulating centrosome segregation and spindle assemble. Aur-A overexpression causes excessive centrosome duplication and abnormal spindle structure, leading to tumor malignant progression. Here, we investigated Aur-A expression in nasopharyngeal carcinoma (NPC) and the association between Aur-A and NPC invasiveness. We showed that overexpression of Aur-A in tumor tissues was correlated with cranial bone invasion and clinical stage in NPC patients. Suppression of Aur-A by either selective Aurora inhibitory VX-680 or small-interfering RNA caused G(2)/M arrest and apoptotic cell death in NPC CNE-2 cells. Significantly, inhibition of Aur-A suppressed CNE-2 cell invasion and restored membrane expression of epithelial markers, E-cadherin and beta-catenin, suggesting a reversed epithelial-mesenchymal transition process in cancer cells. In addition, we found that Aur-A-regulated epithelial-mesenchymal transition and invasion were mediated by mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, suppression of MAP kinase by small-interfering RNA or its upstream MEK1/2-selective inhibitor U0126 abrogated cell invasion enhanced by Aur-A overexpression. On the other hand, forced overexpression of constitutively active form of MEK1/2, MEK2DD, in CNE-2 cancer cells rescued cell invasive ability suppressed by VX-680-imposed Aur-A inhibition. Our results indicated that Aur-A acted through a downstream MAP kinase pathway to promote epithelial-mesenchymal transition and invasiveness in nasopharyngeal tumorigenesis. Small chemical inhibitor VX-680 may offer as a promising molecular targeting agent in human NPC.
-
aurora kinase inhibitory vx 680 increases bax bcl 2 ratio and induces apoptosis in aurora a high acute myeloid leukemia
Blood, 2008Co-Authors: Xue Fei Huang, Min Yan, Xiang Bo Wan, Yi Xin Zeng, Shao Kai Luo, Li Hui Wang, Xian Ren Wang, Fei Meng Zheng, Quentin LiuAbstract:Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression ofAur-Awas markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680‐induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase amongAur-A-high VX-680‐ sensitive leukemia patients. VX-680‐ induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/ Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment. (Blood. 2008;111: 2854-2865)
-
Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia.
Blood, 2007Co-Authors: Xue Fei Huang, Min Yan, Xiang Bo Wan, Shao Kai Luo, Li Hui Wang, Xian Ren Wang, Fei Meng ZhengAbstract:Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression ofAur-Awas markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680‐induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase amongAur-A-high VX-680‐ sensitive leukemia patients. VX-680‐ induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/ Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment. (Blood. 2008;111: 2854-2865)
Zijie Long - One of the best experts on this subject based on the ideXlab platform.
-
aurora kinase a inhibition induced autophagy triggers drug resistance in breast cancer cells
Autophagy, 2012Co-Authors: Zhengzhi Zou, Zhongyu Yuan, Qiongxia Zhang, Zijie Long, Jinna Chen, Zhiping Tang, Yuliang Zhu, Shupeng Chen, Min Yan, Jing WangAbstract:We have previously shown that elevated expression of mitotic kinase aurora kinase A (AURKA) in cancer cells promotes the development of metastatic phenotypes and is associated clinically with adverse prognosis. Here, we first revealed a clinically positive correlation between AURKA and autophagy-associated protein SQSTM1 in breast cancer and further demonstrated that AURKA regulated SQSTM1 through autophagy. Indeed, depletion by siRNA or chemical inhibition of AURKA by the small molecule VX-680 increased both the level of microtubule-associated protein 1 light chain 3-II (LC3-II) and the number of autophagosomes, along with decreased SQSTM1. Conversely, overexpression of AURKA inhibited autophagy, as assessed by decreased LC3-II and increased SQSTM1 either upon nutrient deprivation or normal conditions. In addition, phosphorylated forms of both RPS6KB1 and mechanistic target of rapamycin (MTOR) were elevated by overexpression of AURKA whereas they were suppressed by depletion or inhibition of AURKA. Moreover, inhibition of MTOR by PP242, an inhibitor of MTOR complex1/2, abrogated the changes in both LC3-II and SQSTM1 in AURKA-overexpressing BT-549 cells, suggesting that AURKA-suppressed autophagy might be associated with MTOR activation. Lastly, repression of autophagy by depletion of either LC3 or ATG5, sensitized breast cancer cells to VX-680-induced apoptosis. Similar findings were observed in cells treated with the autophagy inhibitors chloroquine (CQ) and bafilomycin A 1 (BAF). Our data thus revealed a novel role of AURKA as a negative regulator of autophagy, showing that AURKA inhibition induced autophagy, which may represent a novel mechanism of drug resistance in apoptosis-aimed therapy for breast cancer.
-
Inhibition of mitotic kinase Aurora suppresses Akt-1 activation and induces apoptotic cell death in all-trans retinoid acid-resistant acute promyelocytic leukemia cells
Journal of translational medicine, 2011Co-Authors: Shan Huang, Zhengzhi Zou, Zijie Long, Jia-jie Chen, Dong Jun Lin, Quentin LiuAbstract:Background Aurora kinase ensures accurate chromosome segregation during cell cycle, maintaining genetic integrity in cell division. VX-680, a small-molecule Aurora kinase inhibitor, interferes with mitotic entry and formation of bipolar spindles. Here, we evaluated VX-680 as a potential agent for treatment of all-trans retinoid acid (ATRA)-resistant acute promyelocytic leukemia (APL) in vitro.
-
Inhibition of Aurora-A results in increased cell death in 3-dimensional culture microenvironment, reduced migration and is associated with enhanced radiosensitivity in human nasopharyngeal carcinoma.
Cancer biology & therapy, 2009Co-Authors: Xiang Bo Wan, Zijie Long, Xin Juan Fan, Ming Yuan Chen, Yi Jun Hua, Ming Huang Hong, Yi Xin ZengAbstract:Mitosis related Aurora-A kinase is amplified in a variety of carcinomas. Overexpression of Aurora-A contributes to tumorigenesis and disease progression, and has emerged as an attractive molecular target for the design of anticancer drugs. In this study, we investigated the function of Aurora-A selectively small molecule inhibitor VX-680 in nasopharyngeal carcinoma (NPC) CNE-2 cells. We found that VX-680 suppressed proliferation and induced apoptosis of 2-dimensional (2-D) cultured NPC CNE-2 cells. Moreover, CNE-2 cells formed a tumor-like cell mass in 3-dimensional (3-D) matrix culture microenvironment, and the tumor mass formation could be impaired when pretreated with VX-680 for indicated time. Similarly, when adding VX-680 to preformed 3-D CNE-2 tumor mass, the tight spatial tumor mass experienced apparent apoptotic cell death and consequently dissociated into individual dead cells, as detected by cleaved Caspase-3 immunofluorescence assay. The migration assay showed that VX-680 decreased NPC CNE-2 ce...
-
Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells.
Carcinogenesis, 2008Co-Authors: Xiang Bo Wan, Zijie Long, Min Yan, Xue Fei Huang, Xian Ren Wang, Liang Ping Xia, Yan Zhao, Xiao Feng ZhuAbstract:Mitotic serine/threonine kinase Aurora-A (Aur-A) plays a critical role in regulating centrosome segregation and spindle assemble. Aur-A overexpression causes excessive centrosome duplication and abnormal spindle structure, leading to tumor malignant progression. Here, we investigated Aur-A expression in nasopharyngeal carcinoma (NPC) and the association between Aur-A and NPC invasiveness. We showed that overexpression of Aur-A in tumor tissues was correlated with cranial bone invasion and clinical stage in NPC patients. Suppression of Aur-A by either selective Aurora inhibitory VX-680 or small-interfering RNA caused G(2)/M arrest and apoptotic cell death in NPC CNE-2 cells. Significantly, inhibition of Aur-A suppressed CNE-2 cell invasion and restored membrane expression of epithelial markers, E-cadherin and beta-catenin, suggesting a reversed epithelial-mesenchymal transition process in cancer cells. In addition, we found that Aur-A-regulated epithelial-mesenchymal transition and invasion were mediated by mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, suppression of MAP kinase by small-interfering RNA or its upstream MEK1/2-selective inhibitor U0126 abrogated cell invasion enhanced by Aur-A overexpression. On the other hand, forced overexpression of constitutively active form of MEK1/2, MEK2DD, in CNE-2 cancer cells rescued cell invasive ability suppressed by VX-680-imposed Aur-A inhibition. Our results indicated that Aur-A acted through a downstream MAP kinase pathway to promote epithelial-mesenchymal transition and invasiveness in nasopharyngeal tumorigenesis. Small chemical inhibitor VX-680 may offer as a promising molecular targeting agent in human NPC.
-
aurora kinase small molecule inhibitor destroys mitotic spindle suppresses cell growth and induces apoptosis in oral squamous cancer cells
Oral Oncology, 2008Co-Authors: Caobing Pan, Zijie Long, Min Yan, Jine Yao, Hongzhang Huang, Quentin LiuAbstract:Mitotic Aurora kinases are required for accurate chromosome segregation during cell division. Ectopic expression of Aurora-A (Aur-A) kinase results in centrosome amplification, aberrant spindles, and consequent aneuploidy. In the present study, we showed that Aurora kinase inhibitory small molecule VX-680 inhibited histone H3 phosphorylation at Ser10, a known in vivo substrate residue of Aurora kinase, in oral squamous cell carcinoma (OSCC) KB cells. In addition, monopolar spindle structures, typical abnormalities induced by inhibition of Aur-A, were generated in VX-680-treated cells. Inhibition of Aurora kinase led to reduced KB cell growth, as assessed by MTT assay. Western blot analysis revealed that VX-680 caused cleavage of two critical apoptotic associated proteins, PARP and caspase-3. In contrast, expression of cell survival factor Bcl-2 was reduced by VX-680 treatment in a dose-dependent manner. Subsequently, nuclear characteristic of DNA fragmentation, indicative of apoptotic cell death, was clearly observed in these OSCC cells with Aurora kinase inhibitory VX-680. Taken together, we showed that Aurora kinase inhibitory VX-680 led to apoptotic cell death in OSCC cells, suggesting a novel therapeutic target in oral cancer.
Xue Fei Huang - One of the best experts on this subject based on the ideXlab platform.
-
apoptosis in Aurora-A-high acute myeloid leukemia Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces
2013Co-Authors: Xiang Bo Wan, Quentin Liu, Yi Xin Zeng, Xue Fei Huang, Shao Kai Luo, Fei Meng Zheng, Li Hui WangAbstract:Abstract Previously we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression of Aur-A was markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680-induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML ( P< .0001) or normal BMMCs ( P< .0001), suggesting the possible pharmacologic window in targeting Aurora kinase among Aur-A-high VX-680-sensitive leukemia patients. VX-680-induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G 2 /M phase arrest, decreased phosphorylated(p)-Akt-1 and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase (PARP). Notably, VX-680 increased Bax/Bcl-2 expression ratio, a favorable pro-apoptotic predictor for drug-response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and Aur-A-high expression may serve as a differential marker for selective treatment. From bloodjournal.hematologylibrary.org by guest on June 3, 2013. For personal use only.
-
Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells.
Carcinogenesis, 2008Co-Authors: Xiang Bo Wan, Zijie Long, Min Yan, Xue Fei Huang, Xian Ren Wang, Liang Ping Xia, Yan Zhao, Xiao Feng ZhuAbstract:Mitotic serine/threonine kinase Aurora-A (Aur-A) plays a critical role in regulating centrosome segregation and spindle assemble. Aur-A overexpression causes excessive centrosome duplication and abnormal spindle structure, leading to tumor malignant progression. Here, we investigated Aur-A expression in nasopharyngeal carcinoma (NPC) and the association between Aur-A and NPC invasiveness. We showed that overexpression of Aur-A in tumor tissues was correlated with cranial bone invasion and clinical stage in NPC patients. Suppression of Aur-A by either selective Aurora inhibitory VX-680 or small-interfering RNA caused G(2)/M arrest and apoptotic cell death in NPC CNE-2 cells. Significantly, inhibition of Aur-A suppressed CNE-2 cell invasion and restored membrane expression of epithelial markers, E-cadherin and beta-catenin, suggesting a reversed epithelial-mesenchymal transition process in cancer cells. In addition, we found that Aur-A-regulated epithelial-mesenchymal transition and invasion were mediated by mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, suppression of MAP kinase by small-interfering RNA or its upstream MEK1/2-selective inhibitor U0126 abrogated cell invasion enhanced by Aur-A overexpression. On the other hand, forced overexpression of constitutively active form of MEK1/2, MEK2DD, in CNE-2 cancer cells rescued cell invasive ability suppressed by VX-680-imposed Aur-A inhibition. Our results indicated that Aur-A acted through a downstream MAP kinase pathway to promote epithelial-mesenchymal transition and invasiveness in nasopharyngeal tumorigenesis. Small chemical inhibitor VX-680 may offer as a promising molecular targeting agent in human NPC.
-
aurora kinase inhibitory vx 680 increases bax bcl 2 ratio and induces apoptosis in aurora a high acute myeloid leukemia
Blood, 2008Co-Authors: Xue Fei Huang, Min Yan, Xiang Bo Wan, Yi Xin Zeng, Shao Kai Luo, Li Hui Wang, Xian Ren Wang, Fei Meng Zheng, Quentin LiuAbstract:Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression ofAur-Awas markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680‐induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase amongAur-A-high VX-680‐ sensitive leukemia patients. VX-680‐ induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/ Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment. (Blood. 2008;111: 2854-2865)
-
Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia.
Blood, 2007Co-Authors: Xue Fei Huang, Min Yan, Xiang Bo Wan, Shao Kai Luo, Li Hui Wang, Xian Ren Wang, Fei Meng ZhengAbstract:Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression ofAur-Awas markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680‐induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase amongAur-A-high VX-680‐ sensitive leukemia patients. VX-680‐ induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/ Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment. (Blood. 2008;111: 2854-2865)
-
aurora a a negative prognostic marker increases migration and decreases radiosensitivity in cancer cells
Cancer Research, 2007Co-Authors: Zhong Guan, Zijie Long, Yi Xin Zeng, Xue Fei Huang, Li Hui Wang, Xian Ren Wang, Jie Xu, Gong Kan Feng, Wenlin Huang, Fu Jin ChenAbstract:Centrosomal Aurora-A (Aur-A) kinase ensures proper spindle assembly and accurate chromosome segregation in mitosis. Overexpression of Aur-A leads to centrosome amplification, aberrant spindle, and consequent genetic instability. In the present study, Aur-A was found to be overexpressed in laryngeal squamous cell carcinoma (LSCC). Moreover, Aur-A expression was adversely correlated with median survival, and further identified as a potential independent factor for disease prognosis. Suppression of Aurora kinase activity chemically or genetically led to LSCC Hep2 cell cycle arrest and apoptotic cell death. Importantly, we found that Aur-A increases cell migration and this novel function was correlated with Akt1 activation. The enhanced cell migration induced by Aur-A overexpression could be abrogated by either small-molecule Akt1 inhibitor or short interfering RNA. VX-680, a selective Aurora kinase inhibitor, decreased Akt1 phosphorylation at Ser473 and inhibited cell migration, but failed to do so in constitutive active Akt1 (myr- Akt1 )–overexpressed cells. Moreover, our data suggested that overexpression of Aur-A kinase might also contribute to radioresistance of LSCC. Inhibiting Aur-A by VX-680 induced expression of p53 and potently sensitized cells to radiotherapy, leading to significant cell death. Ectopic overexpression of Aur-A, however, reduced p53 level and rendered cells more resistant to irradiation. Taken together, we showed that Aur-A kinase, a negative prognostic marker, promotes migration and reduces radiosensitivity in laryngeal cancer cells. [Cancer Res 2007;67(21):10436–44]
Xian Ren Wang - One of the best experts on this subject based on the ideXlab platform.
-
Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells.
Carcinogenesis, 2008Co-Authors: Xiang Bo Wan, Zijie Long, Min Yan, Xue Fei Huang, Xian Ren Wang, Liang Ping Xia, Yan Zhao, Xiao Feng ZhuAbstract:Mitotic serine/threonine kinase Aurora-A (Aur-A) plays a critical role in regulating centrosome segregation and spindle assemble. Aur-A overexpression causes excessive centrosome duplication and abnormal spindle structure, leading to tumor malignant progression. Here, we investigated Aur-A expression in nasopharyngeal carcinoma (NPC) and the association between Aur-A and NPC invasiveness. We showed that overexpression of Aur-A in tumor tissues was correlated with cranial bone invasion and clinical stage in NPC patients. Suppression of Aur-A by either selective Aurora inhibitory VX-680 or small-interfering RNA caused G(2)/M arrest and apoptotic cell death in NPC CNE-2 cells. Significantly, inhibition of Aur-A suppressed CNE-2 cell invasion and restored membrane expression of epithelial markers, E-cadherin and beta-catenin, suggesting a reversed epithelial-mesenchymal transition process in cancer cells. In addition, we found that Aur-A-regulated epithelial-mesenchymal transition and invasion were mediated by mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, suppression of MAP kinase by small-interfering RNA or its upstream MEK1/2-selective inhibitor U0126 abrogated cell invasion enhanced by Aur-A overexpression. On the other hand, forced overexpression of constitutively active form of MEK1/2, MEK2DD, in CNE-2 cancer cells rescued cell invasive ability suppressed by VX-680-imposed Aur-A inhibition. Our results indicated that Aur-A acted through a downstream MAP kinase pathway to promote epithelial-mesenchymal transition and invasiveness in nasopharyngeal tumorigenesis. Small chemical inhibitor VX-680 may offer as a promising molecular targeting agent in human NPC.
-
aurora kinase inhibitory vx 680 increases bax bcl 2 ratio and induces apoptosis in aurora a high acute myeloid leukemia
Blood, 2008Co-Authors: Xue Fei Huang, Min Yan, Xiang Bo Wan, Yi Xin Zeng, Shao Kai Luo, Li Hui Wang, Xian Ren Wang, Fei Meng Zheng, Quentin LiuAbstract:Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression ofAur-Awas markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680‐induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase amongAur-A-high VX-680‐ sensitive leukemia patients. VX-680‐ induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/ Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment. (Blood. 2008;111: 2854-2865)
-
Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia.
Blood, 2007Co-Authors: Xue Fei Huang, Min Yan, Xiang Bo Wan, Shao Kai Luo, Li Hui Wang, Xian Ren Wang, Fei Meng ZhengAbstract:Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression ofAur-Awas markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680‐induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase amongAur-A-high VX-680‐ sensitive leukemia patients. VX-680‐ induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/ Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment. (Blood. 2008;111: 2854-2865)
-
aurora a a negative prognostic marker increases migration and decreases radiosensitivity in cancer cells
Cancer Research, 2007Co-Authors: Zhong Guan, Zijie Long, Yi Xin Zeng, Xue Fei Huang, Li Hui Wang, Xian Ren Wang, Jie Xu, Gong Kan Feng, Wenlin Huang, Fu Jin ChenAbstract:Centrosomal Aurora-A (Aur-A) kinase ensures proper spindle assembly and accurate chromosome segregation in mitosis. Overexpression of Aur-A leads to centrosome amplification, aberrant spindle, and consequent genetic instability. In the present study, Aur-A was found to be overexpressed in laryngeal squamous cell carcinoma (LSCC). Moreover, Aur-A expression was adversely correlated with median survival, and further identified as a potential independent factor for disease prognosis. Suppression of Aurora kinase activity chemically or genetically led to LSCC Hep2 cell cycle arrest and apoptotic cell death. Importantly, we found that Aur-A increases cell migration and this novel function was correlated with Akt1 activation. The enhanced cell migration induced by Aur-A overexpression could be abrogated by either small-molecule Akt1 inhibitor or short interfering RNA. VX-680, a selective Aurora kinase inhibitor, decreased Akt1 phosphorylation at Ser473 and inhibited cell migration, but failed to do so in constitutive active Akt1 (myr- Akt1 )–overexpressed cells. Moreover, our data suggested that overexpression of Aur-A kinase might also contribute to radioresistance of LSCC. Inhibiting Aur-A by VX-680 induced expression of p53 and potently sensitized cells to radiotherapy, leading to significant cell death. Ectopic overexpression of Aur-A, however, reduced p53 level and rendered cells more resistant to irradiation. Taken together, we showed that Aur-A kinase, a negative prognostic marker, promotes migration and reduces radiosensitivity in laryngeal cancer cells. [Cancer Res 2007;67(21):10436–44]
-
Aurora-A, a negative prognostic marker, increases migration and decreases radiosensitivity in cancer cells.
Cancer research, 2007Co-Authors: Zhong Guan, Zijie Long, Xiang Bo Wan, Xue Fei Huang, Li Hui Wang, Xian Ren Wang, Xiao Feng Zhu, Jian Nan Liu, Gong Kan FengAbstract:Centrosomal Aurora-A (Aur-A) kinase ensures proper spindle assembly and accurate chromosome segregation in mitosis. Overexpression of Aur-A leads to centrosome amplification, aberrant spindle, and consequent genetic instability. In the present study, Aur-A was found to be overexpressed in laryngeal squamous cell carcinoma (LSCC). Moreover, Aur-A expression was adversely correlated with median survival, and further identified as a potential independent factor for disease prognosis. Suppression of Aurora kinase activity chemically or genetically led to LSCC Hep2 cell cycle arrest and apoptotic cell death. Importantly, we found that Aur-A increases cell migration and this novel function was correlated with Akt1 activation. The enhanced cell migration induced by Aur-A overexpression could be abrogated by either small-molecule Akt1 inhibitor or short interfering RNA. VX-680, a selective Aurora kinase inhibitor, decreased Akt1 phosphorylation at Ser(473) and inhibited cell migration, but failed to do so in constitutive active Akt1 (myr-Akt1)-overexpressed cells. Moreover, our data suggested that overexpression of Aur-A kinase might also contribute to radioresistance of LSCC. Inhibiting Aur-A by VX-680 induced expression of p53 and potently sensitized cells to radiotherapy, leading to significant cell death. Ectopic overexpression of Aur-A, however, reduced p53 level and rendered cells more resistant to irradiation. Taken together, we showed that Aur-A kinase, a negative prognostic marker, promotes migration and reduces radiosensitivity in laryngeal cancer cells.
