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Article ; Online: Circulating tumor cells exhibit a biologically aggressive cancer phenotype accompanied by selective resistance to chemotherapy.

Pavese, Janet M / Bergan, Raymond C

2014 Volume 352, Issue 2, Page(s) 179–186

Abstract: With prostate cancer (PCa), circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) portend a poor clinical prognosis. Their unknown biology precludes rational therapeutic design. We demonstrate that CTC and DTC cell lines, established from ... ...

Abstract	With prostate cancer (PCa), circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) portend a poor clinical prognosis. Their unknown biology precludes rational therapeutic design. We demonstrate that CTC and DTC cell lines, established from mice bearing human PCa orthotopic implants, exhibit increased cellular invasion in vitro, increased metastasis in mice, and express increased epithelial to mesenchymal transition biomarkers. Further, they are selectively resistant to growth inhibition by mitoxantrone-like agents. These findings demonstrate that CTC formation is accompanied by phenotypic progression without obligate reversion. Their increased metastatic potential, selective therapeutic resistance, and differential expression of potential therapeutic targets provide a rational basis to test further interventions.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; Epithelial-Mesenchymal Transition/drug effects ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitoxantrone/pharmacology ; Neoplasm Invasiveness ; Neoplastic Cells, Circulating/drug effects ; Neoplastic Cells, Circulating/metabolism ; Neoplastic Cells, Circulating/pathology ; Phenotype ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; Mitoxantrone (BZ114NVM5P)
Language	English
Publishing date	2014-07-10
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2014.06.012
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Article ; Online: Clinical Pharmacology of the Antibody-Drug Conjugate Enfortumab Vedotin in Advanced Urothelial Carcinoma and Other Malignant Solid Tumors.

Tang, Mei / Garg, Amit / Bonate, Peter L / Rosenberg, Jonathan E / Matsangou, Maria / Kadokura, Takeshi / Yamada, Akihiro / Choules, Mary / Pavese, Janet / Nagata, Masanori / Tenmizu, Daisuke / Koibuchi, Akira / Heo, Nakyo / Wang, Lu / Wojtkowski, Tomasz / Hanley, William D / Poondru, Srinivasu

Clinical pharmacokinetics

2024 Volume 63, Issue 4, Page(s) 423–438

Abstract: Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of ...

Abstract	Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n = 748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.
MeSH term(s)	Humans ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Immunoconjugates/pharmacokinetics ; Immunoconjugates/administration & dosage ; Immunoconjugates/pharmacology ; Immunoconjugates/adverse effects ; Immunoconjugates/therapeutic use ; Oligopeptides/pharmacokinetics ; Oligopeptides/administration & dosage ; Oligopeptides/therapeutic use ; Oligopeptides/pharmacology ; Oligopeptides/adverse effects ; Urologic Neoplasms/drug therapy ; Urologic Neoplasms/pathology ; Dose-Response Relationship, Drug ; Carcinoma, Transitional Cell/drug therapy ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents/pharmacology ; Nectins
Chemical Substances	enfortumab vedotin (DLE8519RWM) ; Antibodies, Monoclonal ; Immunoconjugates ; monomethyl auristatin E (V7I58RC5EJ) ; Oligopeptides ; Antineoplastic Agents ; NECTIN4 protein, human ; Nectins
Language	English
Publishing date	2024-04-12
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-024-01369-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Genistein inhibits human prostate cancer cell detachment, invasion, and metastasis.

Pavese, Janet M / Krishna, Sankar N / Bergan, Raymond C

The American journal of clinical nutrition

2014 Volume 100 Suppl 1, Page(s) 431S–6S

Abstract: Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the United States and the second leading cause of cancer death. Death is not caused by the primary tumor but rather by the formation of distinct metastatic tumors. Therefore, ... ...

Abstract	Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the United States and the second leading cause of cancer death. Death is not caused by the primary tumor but rather by the formation of distinct metastatic tumors. Therefore, prevention of metastasis is of utmost importance. The natural product genistein, found in high amounts in soy products, has been implicated in preventing PCa formation and metastasis in men who consume high amounts of soy. In vitro studies and in vivo rodent models that used human PCa cells, as well as prospective human clinical trials, provide a mechanistic explanation directly supporting genistein as an antimetastatic agent. Specifically, our group showed that genistein inhibits cell detachment, protease production, cell invasion, and human PCa metastasis at concentrations achieved in humans with dietary intake. Finally, phase I and phase II clinical trials conducted by us and others showed that concentrations of genistein associated with antimetastatic efficacy in preclinical models are achievable in humans, and treatment with genistein inhibits pathways that regulate metastatic transformation in human prostate tissue.
MeSH term(s)	Animals ; Anticarcinogenic Agents/pharmacology ; Anticarcinogenic Agents/therapeutic use ; Antineoplastic Agents, Phytogenic/pharmacology ; Antineoplastic Agents, Phytogenic/therapeutic use ; Genistein/pharmacology ; Genistein/therapeutic use ; Humans ; Male ; Neoplasm Invasiveness/prevention & control ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/prevention & control ; Glycine max/chemistry
Chemical Substances	Anticarcinogenic Agents ; Antineoplastic Agents, Phytogenic ; Genistein (DH2M523P0H)
Language	English
Publishing date	2014-05-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.3945/ajcn.113.071290
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Article ; Online: An orthotopic murine model of human prostate cancer metastasis.

Pavese, Janet / Ogden, Irene M / Bergan, Raymond C

Journal of visualized experiments : JoVE

2013 , Issue 79, Page(s) e50873

Abstract: Our laboratory has developed a novel orthotopic implantation model of human prostate cancer (PCa). As PCa death is not due to the primary tumor, but rather the formation of distinct metastasis, the ability to effectively model this progression pre- ... ...

Abstract	Our laboratory has developed a novel orthotopic implantation model of human prostate cancer (PCa). As PCa death is not due to the primary tumor, but rather the formation of distinct metastasis, the ability to effectively model this progression pre-clinically is of high value. In this model, cells are directly implanted into the ventral lobe of the prostate in Balb/c athymic mice, and allowed to progress for 4-6 weeks. At experiment termination, several distinct endpoints can be measured, such as size and molecular characterization of the primary tumor, the presence and quantification of circulating tumor cells in the blood and bone marrow, and formation of metastasis to the lung. In addition to a variety of endpoints, this model provides a picture of a cells ability to invade and escape the primary organ, enter and survive in the circulatory system, and implant and grow in a secondary site. This model has been used effectively to measure metastatic response to both changes in protein expression as well as to response to small molecule therapeutics, in a short turnaround time.
MeSH term(s)	Animals ; Cell Line, Tumor ; Disease Models, Animal ; Humans ; Lung Neoplasms/blood ; Lung Neoplasms/secondary ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Metastasis ; Neoplasm Transplantation/methods ; Neoplastic Cells, Circulating/pathology ; Prostatic Neoplasms/blood ; Prostatic Neoplasms/pathology ; Transplantation, Heterologous/methods
Language	English
Publishing date	2013-09-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/50873
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: An orthotopic murine model of human prostate cancer metastasis

Pavese, Janet / Ogden, Irene M / Bergan, Raymond C

Journal of visualized experiments. 2013 Sept. 18, , no. 79

2013

Abstract	Our laboratory has developed a novel orthotopic implantation model of human prostate cancer (PCa). As PCa death is not due to the primary tumor, but rather the formation of distinct metastasis, the ability to effectively model this progression pre-clinically is of high value. In this model, cells are directly implanted into the ventral lobe of the prostate in Balb/c athymic mice, and allowed to progress for 4-6 weeks. At experiment termination, several distinct endpoints can be measured, such as size and molecular characterization of the primary tumor, the presence and quantification of circulating tumor cells in the blood and bone marrow, and formation of metastasis to the lung. In addition to a variety of endpoints, this model provides a picture of a cells ability to invade and escape the primary organ, enter and survive in the circulatory system, and implant and grow in a secondary site. This model has been used effectively to measure metastatic response to both changes in protein expression as well as to response to small molecule therapeutics, in a short turnaround time.
Keywords	animal models ; blood ; bone marrow ; death ; humans ; lungs ; metastasis ; mice ; neoplasm cells ; prostatic neoplasms ; protein synthesis ; therapeutics
Language	English
Dates of publication	2013-0918
Size	p. e50873.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/50873
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Inhibition of cancer cell invasion and metastasis by genistein.

Pavese, Janet M / Farmer, Rebecca L / Bergan, Raymond C

Cancer metastasis reviews

2010 Volume 29, Issue 3, Page(s) 465–482

Abstract: Genistein is a small, biologically active flavonoid that is found in high amounts in soy. This important compound possesses a wide variety of biological activities, but it is best known for its ability to inhibit cancer progression. In particular, ... ...

Abstract	Genistein is a small, biologically active flavonoid that is found in high amounts in soy. This important compound possesses a wide variety of biological activities, but it is best known for its ability to inhibit cancer progression. In particular, genistein has emerged as an important inhibitor of cancer metastasis. Consumption of genistein in the diet has been linked to decreased rates of metastatic cancer in a number of population-based studies. Extensive investigations have been performed to determine the molecular mechanisms underlying genistein's antimetastatic activity, with results indicating that this small molecule has significant inhibitory activity at nearly every step of the metastatic cascade. Reports have demonstrated that, at high concentrations, genistein can inhibit several proteins involved with primary tumor growth and apoptosis, including the cyclin class of cell cycle regulators and the Akt family of proteins. At lower concentrations that are similar to those achieved through dietary consumption, genistein can inhibit the prometastatic processes of cancer cell detachment, migration, and invasion through a variety of mechanisms, including the transforming growth factor (TGF)-beta signaling pathway. Several in vitro findings have been corroborated in both in vivo animal studies and in early-phase human clinical trials, demonstrating that genistein can both inhibit human cancer metastasis and also modulate markers of metastatic potential in humans, respectively. Herein, we discuss the variety of mechanisms by which genistein regulates individual steps of the metastatic cascade and highlight the potential of this natural product as a promising therapeutic inhibitor of metastasis.
MeSH term(s)	Animals ; Anticarcinogenic Agents/therapeutic use ; Genistein/therapeutic use ; Humans ; Neoplasm Invasiveness ; Neoplasm Metastasis/prevention & control ; Neoplasms/drug therapy ; Neoplasms/pathology
Chemical Substances	Anticarcinogenic Agents ; Genistein (DH2M523P0H)
Language	English
Publishing date	2010-08-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	604857-2
ISSN	1573-7233 ; 0167-7659
ISSN (online)	1573-7233
ISSN	0167-7659
DOI	10.1007/s10555-010-9238-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 1812: Show issues

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Article: Genistein inhibits human prostate cancer cell detachment, invasion, and metastasis

Pavese, Janet M / Krishna, Sankar N / Bergan, Raymond C

American journal of clinical nutrition. 2014 July, v. 100, no. Supplement 1

2014

Abstract	Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the United States and the second leading cause of cancer death. Death is not caused by the primary tumor but rather by the formation of distinct metastatic tumors. Therefore, prevention of metastasis is of utmost importance. The natural product genistein, found in high amounts in soy products, has been implicated in preventing PCa formation and metastasis in men who consume high amounts of soy. In vitro studies and in vivo rodent models that used human PCa cells, as well as prospective human clinical trials, provide a mechanistic explanation directly supporting genistein as an antimetastatic agent. Specifically, our group showed that genistein inhibits cell detachment, protease production, cell invasion, and human PCa metastasis at concentrations achieved in humans with dietary intake. Finally, phase I and phase II clinical trials conducted by us and others showed that concentrations of genistein associated with antimetastatic efficacy in preclinical models are achievable in humans, and treatment with genistein inhibits pathways that regulate metastatic transformation in human prostate tissue.
Keywords	in vivo studies ; food intake ; men ; humans ; soybean products ; proteinases ; metastasis ; genistein ; animal models ; clinical nutrition ; prostatic neoplasms ; in vitro studies ; death ; clinical trials ; United States
Language	English
Dates of publication	2014-07
Size	p. 431S-436S.
Publishing place	American Society for Clinical Nutrition
Document type	Article
Note	2019-12-04
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.3945/ajcn.113.071290
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Mitogen-activated protein kinase kinase 4 (MAP2K4) promotes human prostate cancer metastasis.

Pavese, Janet M / Ogden, Irene M / Voll, Eric A / Huang, Xiaoke / Xu, Li / Jovanovic, Borko / Bergan, Raymond C

PloS one

2014 Volume 9, Issue 7, Page(s) e102289

Abstract: Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by ... ...

Abstract	Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by small molecule therapeutics that demonstrate favorable activity in phase II studies. However, MAP2K4's role in regulating metastatic behavior is controversial and unknown. To investigate, we engineered human PCa cell lines which overexpress either wild type or constitutive active MAP2K4. Orthotopic implantation into mice demonstrated MAP2K4 increases formation of distant metastasis. Constitutive active MAP2K4, though not wild type, increases tumor size and circulating tumor cells in the blood and bone marrow. Complementary in vitro studies establish stable MAP2K4 overexpression promotes cell invasion, but does not affect cell growth or migration. MAP2K4 overexpression increases the expression of heat shock protein 27 (HSP27) protein and protease production, with the largest effect upon matrix metalloproteinase 2 (MMP-2), both in vitro and in mouse tumor samples. Further, MAP2K4-mediated increases in cell invasion are dependent upon heat shock protein 27 (HSP27) and MMP-2, but not upon MAP2K4's immediate downstream targets, p38 MAPK or JNK. We demonstrate that MAP2K4 increases human PCa metastasis, and prolonged over expression induces long term changes in cell signaling pathways leading to independence from p38 MAPK and JNK. These findings provide a mechanistic explanation for human studies linking increases in HSP27 and MMP-2 to progression to metastatic disease. MAP2K4 is validated as an important therapeutic target for inhibiting human PCa metastasis.
MeSH term(s)	Animals ; Blotting, Western ; Cell Movement/physiology ; Gene Expression Regulation, Neoplastic/genetics ; HSP27 Heat-Shock Proteins/metabolism ; Humans ; MAP Kinase Kinase 4/metabolism ; Male ; Matrix Metalloproteinase 2/metabolism ; Mice ; Mice, Transgenic ; Neoplasm Metastasis/physiopathology ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/physiopathology ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	HSP27 Heat-Shock Proteins ; MAP Kinase Kinase 4 (EC 2.7.12.2) ; MAP2K4 protein, human (EC 2.7.12.2) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Mmp2 protein, mouse (EC 3.4.24.24)
Language	English
Publishing date	2014-07-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0102289
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Heat shock protein 27 regulates human prostate cancer cell motility and metastatic progression.

Voll, Eric A / Ogden, Irene M / Pavese, Janet M / Huang, XiaoKe / Xu, Li / Jovanovic, Borko D / Bergan, Raymond C

Oncotarget

2014 Volume 5, Issue 9, Page(s) 2648–2663

Abstract: Prostate cancer (PCa) is the most common form of cancer in American men. Mortality from PCa is caused by the movement of cancer cells from the primary organ to form metastatic tumors at distant sites. Heat shock protein 27 (HSP27) is known to increase ... ...

Abstract	Prostate cancer (PCa) is the most common form of cancer in American men. Mortality from PCa is caused by the movement of cancer cells from the primary organ to form metastatic tumors at distant sites. Heat shock protein 27 (HSP27) is known to increase human PCa cell invasion and its overexpression is associated with metastatic disease. The role of HSP27 in driving PCa cell movement from the prostate to distant metastatic sites is unknown. Increased HSP27 expression increased metastasis as well as primary tumor mass. In vitro studies further examined the mechanism of HSP27-induced metastatic behavior. HSP27 did not affect cell detachment, adhesion, or migration, but did increase cell invasion. Cell invasion was dependent upon matrix metalloproteinase 2 (MMP-2), whose expression was increased by HSP27. In vivo, HSP27 induced commensurate changes in MMP-2 expression in tumors. These findings demonstrate that HSP27 drives metastatic spread of cancer cells from the prostate to distant sites, does so across a continuum of expression levels, and identifies HSP27-driven increases in MMP-2 expression as functionally relevant. These findings add to prior studies demonstrating that HSP27 increases PCa cell motility, growth and survival. Together, they demonstrate that HSP27 plays an important role in PCa progression.
MeSH term(s)	Animals ; Apoptosis ; Blotting, Western ; Cell Adhesion ; Cell Movement ; Cell Proliferation ; HSP27 Heat-Shock Proteins/antagonists & inhibitors ; HSP27 Heat-Shock Proteins/genetics ; HSP27 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins ; Humans ; Male ; Matrix Metalloproteinase 2/genetics ; Matrix Metalloproteinase 2/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Chaperones ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	HSP27 Heat-Shock Proteins ; HSPB1 protein, human ; Heat-Shock Proteins ; Molecular Chaperones ; RNA, Messenger ; RNA, Small Interfering ; MMP2 protein, human (EC 3.4.24.24) ; Matrix Metalloproteinase 2 (EC 3.4.24.24)
Language	English
Publishing date	2014-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.1917
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mitogen-activated protein kinase kinase 4 (MAP2K4) promotes human prostate cancer metastasis.

Janet M Pavese / Irene M Ogden / Eric A Voll / Xiaoke Huang / Li Xu / Borko Jovanovic / Raymond C Bergan

PLoS ONE, Vol 9, Iss 7, p e

2014 Volume 102289

Abstract	Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by small molecule therapeutics that demonstrate favorable activity in phase II studies. However, MAP2K4's role in regulating metastatic behavior is controversial and unknown. To investigate, we engineered human PCa cell lines which overexpress either wild type or constitutive active MAP2K4. Orthotopic implantation into mice demonstrated MAP2K4 increases formation of distant metastasis. Constitutive active MAP2K4, though not wild type, increases tumor size and circulating tumor cells in the blood and bone marrow. Complementary in vitro studies establish stable MAP2K4 overexpression promotes cell invasion, but does not affect cell growth or migration. MAP2K4 overexpression increases the expression of heat shock protein 27 (HSP27) protein and protease production, with the largest effect upon matrix metalloproteinase 2 (MMP-2), both in vitro and in mouse tumor samples. Further, MAP2K4-mediated increases in cell invasion are dependent upon heat shock protein 27 (HSP27) and MMP-2, but not upon MAP2K4's immediate downstream targets, p38 MAPK or JNK. We demonstrate that MAP2K4 increases human PCa metastasis, and prolonged over expression induces long term changes in cell signaling pathways leading to independence from p38 MAPK and JNK. These findings provide a mechanistic explanation for human studies linking increases in HSP27 and MMP-2 to progression to metastatic disease. MAP2K4 is validated as an important therapeutic target for inhibiting human PCa metastasis.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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