Altered Gene Expression in Human Astrocytoma Cells Selected for Migration

McDonough, Wendy S.; Tran, Nhan L.; Giese, Alf; Norman, Sylvia A.; Berens, Michael E.

doi:10.1097/00005072-199805000-00008

Cited by 54 publications

(42 citation statements)

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“…TXSA, an enzyme operating downstream of the COX, has recently been identified as an antiapoptotic and invasion-associated factor in several human cancers (McDonough et al, 1998;Daniel et al, 1999;Giese et al, 1999;Rodrigues et al, 2001;Kurzel et al, 2002;Yoshizato et al, 2002). In this study, we demonstrate for the first time that p53 and ets-1 regulate transcription of the TXSA gene in an antagonistic manner.…”

Section: Discussionsupporting

confidence: 56%

“…Furthermore, experimental overexpression of TXSA promotes tumor growth in vivo, which has been demonstrated in an adenocarcinoma mouse model (Pradono et al, 2002). Although the cancerpromoting effects of TXSA remain poorly understood, it appears that high levels of TXSA enhance angiogenesis and increase the invasive potential of neoplastic cells (McDonough et al, 1998;Giese et al, 1999;Rodrigues et al, 2001;Kurzel et al, 2002;Yoshizato et al, 2002). TXSA may also play a certain role in rendering tumor cells resistant to apoptosis, and we have recently reported that specific inhibitors of TXSA block motility and sensitize migration-arrested glioma cells to apoptosis (Yoshizato et al, 2002).…”

Section: Introductionmentioning

confidence: 97%

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Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

et al. 2003

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Cancer formation and progression is a complex process determined by several mechanisms that promote cell growth, invasiveness, neo-angiogenesis, and render neoplastic cells resistant to apoptosis. The tumor suppressor p53 and the proto-oncogenic factor ets-1 are important regulators of such mechanisms. While it is well established that p53 and ets-1 influence various aspects of cell behavior by regulating the transcription of specific genes, little is known about the functional relationship between these transcription factors. We found that the gene encoding thromboxane synthase (TXSA), which we recently identified as a factor promoting invasion and resistance to apoptosis in gliomas, is a novel target gene for both p53 and ets-1. We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and interrelated manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. Negative interference with ets-1 transcription requires functional p53 and is lost in mutant p53 proteins. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53. An important implication of our findings is that the loss of p53-mediated negative control over ets-1-dependent transcription may lead to the acquisition of an invasive phenotype in tumor cells.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 97%

Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

et al. 2003

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“…Now an important role of TXSA as a tumor promoting factor emerges. Experimental overexpression of TXSA promotes tumor growth in vivo [4], and it appears that high levels of TXSA enhance angiogenesis and increase the invasive potential of neoplastic cells [2,3,[5][6][7]. In human gliomas TXSA renders tumor cells resistant to apoptosis and we have demonstrated that specific inhibitors of TXSA block motility and sensitize migration arrested glioma cells to apoptotic cell death [7].…”

Section: Introductionmentioning

confidence: 94%

“…We have previously shown that furegrelate, a pharmacological inhibitor of TXSA which impedes the metabolic conversion of cyclic endoperoxide into TXA-2, induces apoptosis in glioma cell lines in vitro [2,3,[5][6][7]. In this study, we examined the effects of furegrelate on the radio response in glioma cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of invasion-associated thromboxane synthase sensitizes experimental gliomas to γ-radiation

et al. 2008

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The invasion-and apoptosis-associated thromboxane synthase gene encoding an enzyme of the arachidonic acid pathway has been implicated in glioma progression. Furegrelate, a specific inhibitor of thromboxane synthase, blocks cell motility, induces apoptosis and increases sensitivity to drug induced apoptosis in human glioma cells in vitro. The impact of furegrelate on the sensitivity of human glioma cells to c-irradiation was analyzed using colony formation assay in vitro and an orthotopic mouse model in vivo. Pre-treatment of glioma cells with furegrelate increases radiation sensitivity of cultured glioma cells. Treatment of experimental gliomas with suboptimal doses of radiation and furegrelate results in a significant decrease in tumor volumes compared to untreated controls. Thus, the specific thromboxane synthase inhibitor furegrelate increases death response induced by c-radiation in glioma cells in vitro and sensitizes experimental gliomas to radiation treatment in vivo.

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“…In prostate cancer, the expression of thromboxane synthase was increased in tumor specimens of advanced stage and grade and particularly in the areas of perineural invasion (15,16). Thromboxane synthase expressed in prostate cancer cells was enzymatically active and may play a contributory role in tumor progression, especially tumor cell motility (15,17,18).…”

Section: Introductionmentioning

confidence: 99%

Thromboxane A2 Receptors in Prostate Carcinoma: Expression and Its Role in Regulating Cell Motility via Small GTPase Rho

et al. 2008

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Thromboxane A 2 (TxA 2 ) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product prostaglandin H 2 as the substrate. Previously, increased expression of thromboxane synthase was found in prostate tumors, and tumor cell motility was attenuated by inhibitors of thromboxane synthase. This study was undertaken to elucidate how tumor motility is regulated by TxA 2 . Here, we report that human prostate cancer cells express functional receptors for TxA 2 (TP). Ligand binding assay found that PC-3 cells binded to SQ29548, a high-affinity TP antagonist, in a saturable manner with K d of 3.64 nmol/L and B max of 120.4 fmol per million cells. Treatment of PC-3 cells by U46619, a TP agonist, induced PC-3 cell contraction, which was blocked by pretreatment with the TP antagonist SQ29548 or pinane TxA 2 . The migration of prostate cancer cells was significantly inhibited either by sustained activation of TP or by blockade of TP activation, suggesting that TP activation must be tightly controlled during cell migration. Further studies found that small GTPase RhoA was activated by TP activation, and pretreatment of PC-3 cells with Y27632, a Rho kinase (ROCK) inhibitor, blocked U46619-induced cell contraction. A dominant-negative mutant of RhoA also blocked U46619-induced cell contraction. Taken together, the data suggest that TPs are expressed in prostate cancer and activation of TPs regulates prostate cancer cell motility and cytoskeleton reorganization through activation of Rho. [Cancer Res 2008;68(1):115-21]

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Altered Gene Expression in Human Astrocytoma Cells Selected for Migration

Cited by 54 publications

References 0 publications

Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

Inhibition of invasion-associated thromboxane synthase sensitizes experimental gliomas to γ-radiation

Thromboxane A2 Receptors in Prostate Carcinoma: Expression and Its Role in Regulating Cell Motility via Small GTPase Rho

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