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  • American Association for Cancer Research (AACR)  (7)
  • 1
    Online Resource
    Online Resource
    Gonadotropin-Releasing Hormone Promotes Ovarian Cancer Cell Invasiveness through c-Jun NH2-Terminal Kinase–Mediated Activation of Matrix Metalloproteinase (MMP)-2 and MMP-9
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 22 ( 2006-11-15), p. 10902-10910
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 22 ( 2006-11-15), p. 10902-10910
    Abstract: Gonadotropin-releasing hormone (GnRH) receptor is present in 80% of ovarian cancer, and numerous studies have provided evidence for a role of GnRH in cell proliferation. In this study, the effect of GnRH on the invasion potential of ovarian cancer cells was investigated. In vitro migration and cell invasion assays with the ovarian cancer cell lines Caov-3 and OVCAR-3 revealed the biphasic nature of GnRH; low concentrations of GnRH agonist (GnRHa) increased the cell motility and invasiveness of these cells, but at increased concentrations, the stimulatory effect was insignificant. Reverse transcription-PCR, Western blot, and gelatin zymography showed that the expression of metastasis-related proteinases, matrix metalloproteinase (MMP)-2 and MMP-9, was up-regulated and activated by GnRHa. Moreover, we observed that GnRHa was able to transactivate the MMP-2 and MMP-9 promoters. The invasive/migratory phenotype activated by GnRHa can be blocked by specific inhibitors or neutralizing antibodies to MMP-2 and MMP-9. Knockdown of the GnRH receptor using small interfering RNA significantly inhibited the GnRH-induced MMP activation, invasion, and migration. In addition, we showed that the c-Jun NH2-terminal kinase, but not extracellular signal-regulated kinase 1/2 or p38 mitogen-activated protein kinase, signaling pathway was critical for GnRH-mediated up-regulation of MMP, cell invasion, and motility. These results indicate for the first time an expanded role for GnRH in other aspects of ovarian tumor progression, such as metastasis, via activation of MMP and the subsequent increase in cell migration and invasion. (Cancer Res 2006; 66(22): 10902-10)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-2217
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
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    detail.hit.zdb_id: 410466-3
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  • 2
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    Online Resource
    Abstract 4769: Growth hormone-releasing hormone (GHRH) antagonist attenuates cell motility of human endometrial cancer by down-regulating Twist and N-Cadherin expression.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4769-4769
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4769-4769
    Abstract: Introduction : More than 25% of patients diagnosed with endometrial carcinoma have an invasive primary cancer accompanied by metastases. GHRH is secreted by the hypothalamus and stimulates the synthesis and secretion of GH from the pituitary. The expression of GHRH and its receptors has been demonstrated in peripheral tissues. In recent years, many antagonistic analogs of GHRH were developed. GHRH antagonists have effects on tumor cells, but the underlying molecular mechanism is not well known. Although Twist and N-Cadherin play important roles in cancer cell motility, it is not established whether Twist and N-Cadherin are required for GHRH antagonists-attenuated cell motility on endometrial cancer cells. In the present study, we examined the action of GHRH antagonist-attenuated cell motility and the mechanisms of the action in endometrial cancer. Methods and Materials : Endometrial cancer cell line Ishikawa and ECC-1 were derived from an endometrial adenocarcinoma. GHRH antagonist MIA-602 was synthesized by solid phase methods. Cell motility was estimated by invasion and migration assay. Immunoblot analysis and RT-PCR were performed to investigate the expression of GHRH receptor, GHRH, and the effects of GHRH antagonist in Twist and N-Cadherin. Human GHRH receptor siRNA was used to knock down the expression of GHRH receptor for elucidating the mechanisms of GHRH antagonist action. Results : The GHRH receptor was expressed in human endometrial cancer cells. The GHRH antagonist attenuated cell motility in a dose-dependent manner. GHRH antagonist-attenuated cell motility was restored in cells pretreated with GHRH receptor siRNA. GHRH antagonist suppressed Twist and N-Cadherin signaling. Knockdown of GHRH receptor with siRNA recovered the expression of Twist and N-Cadherin signaling. Conclusions These results demonstrate that the GHRH antagonist suppressed the cell motility of human endometrial cancer through the GHRH receptor and the down-regulation of Twist and N-Cadherin. Our findings represent a new concept regarding the mechanisms of GHRH antagonist-suppressed cell motility in human endometrial cancer, suggesting the possibility of GHRH antagonist as a potential therapeutic intervention for the treatment of human endometrial cancer. Citation Format: Hsien-Ming Wu, Andrew V. Schally, Peter C.K. Leung. Growth hormone-releasing hormone (GHRH) antagonist attenuates cell motility of human endometrial cancer by down-regulating Twist and N-Cadherin expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4769. doi:10.1158/1538-7445.AM2013-4769 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-4769
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 3
    Online Resource
    Online Resource
    Gonadotropin-Releasing Hormone Type II Induces Apoptosis of Human Endometrial Cancer Cells by Activating GADD45α
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 10 ( 2009-05-15), p. 4202-4208
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 10 ( 2009-05-15), p. 4202-4208
    Abstract: Gonadotropin-releasing hormone type II (GnRH-II) has an antiproliferative effect on human endometrial cancer cells. Apoptosis in cancer cells may play a critical role in regulating cell proliferation. However, more studies are necessary to elucidate the underlying molecular mechanisms and develop potential applications of GnRH-II. Therefore, we explored the mechanisms of GnRH-II–induced apoptosis and the effects of GnRH-II on GADD45α activation in human endometrial cancer cell lines. GnRH-II decreased cell viability in a dose- and time-dependent manner. Apoptosis was induced with increased terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling apoptotic cells after GnRH-II treatment. Knockdown of the endogenous GnRH-I receptor with small interfering RNA (siRNA) rescued the cells from GnRH-II–mediated cell growth inhibition and abolished the induction of apoptosis. GnRH-II activated extracellular signal–regulated kinase (ERK)-1/2 and p38 mitogen-activated protein kinase (MAPK) in a time-dependent manner, and the activation was abolished by GnRH-I receptor siRNA and MAPK inhibitors. Cells pretreated with MAPK inhibitors were rescued from GnRH-II–mediated cell growth inhibition. Moreover, both inhibitors abolished GnRH-II–induced apoptosis. GnRH-II induced GADD45α expression, which was abolished by knockdown of endogenous GnRH-I receptors and MAPK inhibitors. GnRH-II–stimulated cell growth inhibition was rescued by knockdown of endogenous GADD45α with siRNA. Cells treated with GADD45α siRNA were refractory to GnRH-II–induced apoptosis. Thus, GnRH-II inhibits cell growth by inducing apoptosis through binding of the GnRH-I receptor, activation of the ERK1/2 and p38 MAPK pathways, and induction of GADD45α signaling. This finding may provide a new concept relating to the mechanism of GnRH-II–induced antiproliferation and apoptosis in endometrial cancer cells, indicating the possibility of GnRH-II as a promising therapeutic intervention for human endometrial cancer. [Cancer Res 2009;69(10):4202–8]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-4591
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 4
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    Online Resource
    Abstract 3018: Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the invasiveness of endometrial cancer cells through GnRH-I receptor and mitogen-activated protein kinases (MAPKs)-dependent activation of matrix metalloproteinase (MMP)-2
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3018-3018
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3018-3018
    Abstract: Introduction: More than 25% of patients diagnosed with endometrial carcinoma have an invasive primary cancer accompanied by metastases. The GnRH has an important role in reproduction. In mammals, GnRH-II is more widely identified than GnRH-I in peripheral tissues. GnRH-II may regulate tumor progression of endometrial cancer. MAPKs have been considered important components of GnRH-induced signaling pathways. MMPs are largely implicated in promoting angiogenesis and tumor metastasis. In the present study, we examined the action of GnRH-II agonist-promoted motility of endometrial cancer cells and the mechanisms of the action in endometrial cancer. Materials and methods: Endometrial cancer cell line Ishikawa and ECC-1 were derived from an endometrial adenocarcinoma. D-Arg6, AzaGly10-GnRH II was a synthetic decapeptide. Cell motility was estimated by invasion and migration assay. The activities of MMP-2 was assessed by gelatin zymography. Immunoblot analysis was done to study the expression of GnRH-I receptor and the effects of GnRH-II agonist in the activation of ERK1/2, JNK and MMP-2. ERK1/2 inhibitor (U0126), and JNK inhibitor (SP600125) were pretreated for 30 min to evaluate the effects of MAPKs. MMP-2 inhibitor (OA-Hy) was pretreated for 30 min to evaluate the effects of MMP-2 in cell motility. Human GnRH-I receptor siRNA was used to knock down the expression of GnRH-I receptor. Results: The GnRH-I receptor was expressed in endometrial cancer cells. The GnRH-II agonist promoted cell motility in a dose-dependent manner. GnRH-II agonist activated the phosphorylation of ERK1/2 and JNK signaling and the phosphorylation was abolished by 1μM U0126 and 1μM SP600125. GnRH-II agonist-promoted cell motility was suppressed in cells pretreated with U0126 and SP600125. Moreover, U0126 and SP600125 abolished GnRH-II agonist-induced activation of MMP-2. Inhibition of MMP-2 with 10μM OA-Hy suppressed cell motility in response to GnRH-II agonist. GnRH-II agonist-mediated cell motility was suppressed by knockdown of endogenous GnRH-I receptor with siRNA. Conclusion: Our results confirmed that GnRH-I receptor may be a common receptor that mediates the effects of both GnRH-I and GnRH-II in endometrial cancer cells. Our study shows that the GnRH-II agonist promoted the cell motility of endometrial cancer cells through the GnRH-I receptor, and the phosphorylation of ERK1/2 and JNK-dependent activation of MMP-2. Our findings represent a new concept regarding the mechanisms of GnRH-II-promoted cell motility in endometrial cancer cells, suggesting the possibility of GnRH-II as a potential therapeutic intervention for the treatment of human endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3018. doi:1538-7445.AM2012-3018
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-3018
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
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    Online Resource
    Gonadotropins Activate Proteolysis and Increase Invasion through Protein Kinase A and Phosphatidylinositol 3-Kinase Pathways in Human Epithelial Ovarian Cancer Cells
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 7 ( 2006-04-01), p. 3912-3920
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 7 ( 2006-04-01), p. 3912-3920
    Abstract: Despite evidence that gonadotropins may facilitate peritoneal metastasis of ovarian cancer by increasing cell adhesion, the action and molecular mechanism of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in ovarian cancer invasion is not well characterized. In the present study, we investigated the effects of FSH and LH on the invasive activity and the expression of metastasis-related proteinases in human epithelial ovarian cancer by Western blot, zymography, reverse transcription-PCR (RT-PCR), ELISA, and Boyden chamber assay. Treatment with FSH or LH (10, 100, or 1,000 ng/mL) significantly increased the invasion of ovarian cancer cell lines, including BG-1, CaOV-3, and SKOV-3 cells but not OVCAR-3 cells. In addition, treatment of SKOV-3 cells with FSH or LH (100 or 1,000 ng/mL) enhanced the expression and activation of matrix metalloproteinases (MMP-2 and MMP-9) as shown by RT-PCR, gelatin zymography, and ELISA. Pretreatment with [(2R)-2-(hydroxamido-carbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (10 μmol/L), a total MMP inhibitor, and 3-(4-phenoxyphenylsulfonyl)-propylthiirane (20 μmol/L), a specific gelatinase inhibitor, neutralized the proinvasive effect of gonadotropins in SKOV-3 cells. In addition, the secretion of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and plasminogen activator inhibitor-1 was significantly decreased by FSH and LH (100 or 1,000 ng/mL). We further showed that gonadotropins induced an increase in SKOV-3 invasiveness via the activation of protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. Taken together, these results suggest that gonadotropins may contribute to ovarian cancer metastasis via activation of proteolysis and increase in invasion through the PKA and PI3K pathways. (Cancer Res 2006; 66(7): 3912-20)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-1785
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
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  • 6
    Online Resource
    Online Resource
    Caspase-1α Is Down-regulated in Human Ovarian Cancer Cells and the Overexpression of Caspase-1α Induces Apoptosis
    American Association for Cancer Research (AACR) ; 2005
    In:  Cancer Research Vol. 65, No. 19 ( 2005-10-01), p. 8591-8596
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 19 ( 2005-10-01), p. 8591-8596
    Abstract: Caspase-1 plays a key role in the processing of cytokines and in the apoptosis of neurons and macrophages. Whether it also causes apoptosis of cancer cells has been unclear. In this study, we screened an array of apoptosis-related proteins in ovarian carcinoma cell lines and their tissue of origin, ovarian surface epithelium (OSE). Caspase-1α protein was abundant in OSE and in nontumorigenic OSE with extended but limited life spans (immortalized OSE), but was reduced in the cancer lines A2780 and OVCAR10. By Western blot and immunofluorescence, caspase-1α levels were greatly reduced in six of eight ovarian carcinoma lines compared with OSE. By real-time reverse transcription-PCR, steady-state transcripts of the CASP1 gene were proportional to protein levels. Caspase-1α overexpression caused significant apoptosis, but overexpression of a caspase-1α mutant without catalytic activity did not, confirming that the effect was caspase-1α–specific. Immunofluorescence of caspase-1α and terminal nucleotidyl transferase–mediated dUTP-X nick end labeling colocalization clearly established a link between apoptosis and caspase-1α expression. Caspase-9 and caspase-3 were activated in caspase-1α overexpressing A2780 cells, suggesting involvement of an intrinsic apoptotic pathway. Caspase-1α overexpression did not change the apoptotic effect of cisplatin in A2780 and OVCAR10 cells, suggesting that this agent activates a different pathway. Immunohistochemically, caspase-1 was lower in ovarian serous carcinomas than in OSE. Our study indicates, for the first time, that caspase-1α is proapoptotic in ovarian cancer cells, and raises the possibility that its down-regulation is one of the mechanisms which increase resistance to apoptosis in cancer cells.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-0239
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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  • 7
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    Cell Motility and Spreading Are Suppressed by HOXA4 in Ovarian Cancer Cells: Possible Involvement of β1 Integrin
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Research Vol. 7, No. 9 ( 2009-09-01), p. 1425-1437
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 7, No. 9 ( 2009-09-01), p. 1425-1437
    Abstract: HOX genes are transcription factors that control morphogenesis, organogenesis and differentiation. Increasing evidence suggests that HOX genes play a role in ovarian cancer progression; however few studies have defined functional roles and mechanisms of action. We showed previously that HOXA4 expression is increased in invasive, compared to noninvasive, epithelial ovarian tumors. However, HOXA4 suppressed cell migration suggesting that elevated HOXA4 expression in invasive tumors constitutes a homeostatic response. In the present study, we used siRNA and forced-expression in multiple cell lines to define the role of HOXA4 in the regulation of transwell migration/invasion and cellular/colony morphology. Knockdown of endogenous HOXA4 increased migration, but not Matrigel invasion, of OVCAR-8 and OVCAR-3 cells. HOXA4 knockdown also increased cell spreading on plastic or fibronectin, reduced cell-cell adhesion, and increased filopodia in two- and three-dimensional cultures. These changes were not associated with significant changes in αV or β3 integrin and E- or N-cadherin. However, down-regulation of HOXA4 significantly reduced β1 integrin protein levels within cell colonies and cell aggregates, but not of single, nonadherent cells. It had no effect on β1 integrin, α5 integrin, or fibronectin mRNA levels. Conversely, overexpression of HOXA4 in CaOV-3 cells suppressed transwell migration and increased β1 integrin protein levels. Our results confirm that HOXA4 inhibits cell motility, show that it suppresses cell spreading and filopodia formation while enhancing cell-cell adhesion, and suggest a role for β1 integrin in mediating these changes. These observations support the hypothesis that overexpression of HOXA4 in invasive ovarian tumors is a homeostatic, invasion-suppressive response. (Mol Cancer Res 2009;7(9):1425–37)
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-08-0466
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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