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Article ; Online: Arsenic Alters Exosome Quantity and Cargo to Mediate Stem Cell Recruitment Into a Cancer Stem Cell-Like Phenotype.

Ngalame, Ntube N O / Luz, Anthony L / Makia, Ngome / Tokar, Erik J

Toxicological sciences : an official journal of the Society of Toxicology

2018 Volume 165, Issue 1, Page(s) 40–49

Abstract: Inorganic arsenic is a human carcinogen that can target the prostate. Accumulating evidence suggests arsenic can disrupt stem cell (SC) dynamics during the carcinogenic process. Previous work demonstrated arsenic-transformed prostate epithelial (CAsE-PE) ...

Abstract	Inorganic arsenic is a human carcinogen that can target the prostate. Accumulating evidence suggests arsenic can disrupt stem cell (SC) dynamics during the carcinogenic process. Previous work demonstrated arsenic-transformed prostate epithelial (CAsE-PE) cells can recruit prostate SCs into rapidly acquiring a cancer SC (CSC) phenotype via the secretion of soluble factors. Exosomes are small, membrane-derived vesicles that contain lipids, RNA, and proteins, and actively contribute to cancer initiation and progression when taken up by target cells. Here we hypothesized that CAsE-PE cells are recruiting SCs to a CSC-like phenotype via exosomal signaling. CAsE-PE cells secreted 700% more exosomes than parental RWPE-1 cells. CAsE-PE exosomes were enriched with oncogenic factors, including oncogenes (KRAS, NRAS, VEFGA, MYB, and EGFR), inflammation-related (cyclooxygenase-2, interleukin 1B (IL1B), IL6, transforming growth factor-β, and tumor necrosis factor-A), and apoptosis-related (CASP7, CASP9, and BCL2) transcripts, and oncogenesis-associated microRNAs. When compared with SCs cultured in exosome-depleted conditioned medium (CM), SCs cultured in CM containing CAsE-PE-derived exosomes showed increased (198%) matrix metalloproteinase activity and underwent an epithelial-to-mesenchymal transition in morphology, suggesting an exosome-mediated transformation. KRAS plays an important role in arsenic carcinogenesis. Although KRAS transcript (>24 000%) and protein (866%) levels were elevated in CAsE-PE exosomes, knock-down of KRAS in these cells only partially mitigated the CSC-like phenotype in cocultured SCs. Collectively, these results suggest arsenic impacts both exosomal quantity and cargo. Exosomal KRAS is only minimally involved in this recruitment, and additional factors (eg, cancer-associated miRNAs) likely also play a role. This work furthers our mechanistic understanding of how arsenic disrupts SC dynamics and influences the tumor microenvironment during carcinogenesis.
MeSH term(s)	Arsenic/toxicity ; Cell Line, Tumor ; Cell Transformation, Neoplastic/drug effects ; Environmental Pollutants/toxicity ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Exosomes/drug effects ; Exosomes/genetics ; Exosomes/metabolism ; Gene Expression/drug effects ; Humans ; Male ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/pathology ; Prostate/drug effects ; Prostate/metabolism ; Prostate/pathology ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction
Chemical Substances	Environmental Pollutants ; KRAS protein, human ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Arsenic (N712M78A8G)
Language	English
Publishing date	2018-08-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfy176
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Article ; Online: Silencing KRAS Overexpression in Cadmium-Transformed Prostate Epithelial Cells Mitigates Malignant Phenotype.

Ngalame, Ntube N O / Waalkes, Michael P / Tokar, Erik J

Chemical research in toxicology

2016 Volume 29, Issue 9, Page(s) 1458–1467

Abstract: Cadmium (Cd) is a potential human prostate carcinogen. Chronic Cd exposure malignantly transforms RWPE-1 human prostate epithelial cells into CTPE cells by an unclear mechanism. Previous studies show that RWPE-1 can also be malignantly transformed by ... ...

Abstract	Cadmium (Cd) is a potential human prostate carcinogen. Chronic Cd exposure malignantly transforms RWPE-1 human prostate epithelial cells into CTPE cells by an unclear mechanism. Previous studies show that RWPE-1 can also be malignantly transformed by arsenic, and KRAS activation is key to causation and maintenance of this phenotype. Although Cd and arsenic can both transform prostate epithelial cells, it is uncertain whether their mechanisms are similar. Thus, here we determined whether KRAS activation is critical in causing and maintaining Cd-induced malignant transformation in CTPE cells. Expression of KRAS, miRNAs, and other genes of interest was analyzed by Western blot and RT-PCR. Following stable KRAS knockdown (KD) by RNA interference using shRNAmir, the malignant phenotype was assessed by various physical and genetic parameters. CTPE cells greatly overexpressed KRAS by 20-fold, indicating a likely role in Cd transformation. Thus, we attempted to reverse the malignant phenotype via KRAS KD. Two weeks after shRNAmir transduction, KRAS protein was undetectable in CTPE KD cells, confirming stable KD. KRAS KD reduced stimulated RAS/ERK and PI3K/AKT signaling pathways and markedly mitigated multiple physical and molecular malignant cell characteristics including: hypersecretion of MMP-2, colony formation, cell survival, and expression of cancer-relevant genes (reduced proliferation and cell cycle-related genes; activated tumor suppressor PTEN). However, KRAS KD did not reverse miRNA expression originally down-regulated by Cd transformation. These data strongly suggest KRAS is a key gene in development and maintenance of the Cd-induced malignant phenotype, at least in the prostate. It is not, however, the only genetic factor sustaining this phenotype.
MeSH term(s)	Cadmium/chemistry ; Cadmium/toxicity ; Cell Line ; Cell Proliferation/genetics ; Cell Transformation, Neoplastic/drug effects ; Cell Transformation, Neoplastic/genetics ; Epithelial Cells/pathology ; Epithelial Cells/physiology ; Gene Expression/genetics ; Gene Knockdown Techniques ; Gene Silencing ; Humans ; Male ; Prostate/physiopathology ; Prostatic Neoplasms/physiopathology ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction/genetics
Chemical Substances	KRAS protein, human ; Cadmium (00BH33GNGH) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2016-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.6b00137
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Zs.A 2320: Show issues

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Article ; Online: Investigating the Role of Mitochondrial Respiratory Dysfunction during Hexavalent Chromium-Induced Lung Carcinogenesis.

Wise, James T F / Wang, Lei / Alstott, Michael C / Ngalame, Ntube N O / Wang, Yuting / Zhang, Zhuo / Shi, Xianglin

Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer

2019 Volume 37, Issue 4, Page(s) 317–329

Abstract: Hexavalent chromium [Cr(VI)] is a lung carcinogen and its complete mechanism of action remains to be investigated. Metabolic reprogramming of key energy metabolism pathways (e.g., increased anaerobic glycolysis in the presence of oxygen or "Warburg ... ...

Abstract	Hexavalent chromium [Cr(VI)] is a lung carcinogen and its complete mechanism of action remains to be investigated. Metabolic reprogramming of key energy metabolism pathways (e.g., increased anaerobic glycolysis in the presence of oxygen or "Warburg effect", dysregulated mitochondrial function, and lipogenesis) are important to cancer cell and tumor survival and growth. In our current understanding of Cr(VI)-induced carcinogenesis, the role for metabolic reprogramming remains unclear. In this study, we treated human lung epithelial cells (BEAS-2B) with Cr(VI) for 6 months and obtained malignantly transformed cells from an isolated colony grown in soft agar. We also used Cr(VI)-transformed cells from two other human lung cell lines (BEP2D and WTHBF-6 cells). Overall, we found that all the Cr(VI)-transformed cells had no changes in their mitochondrial respiratory functions (measured by the Seahorse Analyzer) compared with passaged-matched control cells. Using a xenograft tumor growth model, we generated tumors from these transformed cells in Nude mice. Using cells obtained from the xenograft tumor tissues, we observed that these cells had decreased maximal mitochondrial respiration, spare respiratory capacity, and coupling efficiency. These results provide evidence that, although mitochondrial dysfunction does not occur during Cr(VI)-induced transformation of lung cells, it does occur during tumor development.
MeSH term(s)	Animals ; Carcinogens/toxicity ; Cell Respiration/drug effects ; Cells, Cultured ; Chromium/toxicity ; Epithelial Cells/drug effects ; Epithelial Cells/physiology ; Humans ; Lung Neoplasms/chemically induced ; Lung Neoplasms/physiopathology ; Mice ; Mice, Nude ; Mitochondria/drug effects ; Mitochondria/physiology ; Neoplasm Transplantation
Chemical Substances	Carcinogens ; Chromium (0R0008Q3JB) ; chromium hexavalent ion (18540-29-9)
Language	English
Publishing date	2019-02-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	441790-2
ISSN	2162-6537 ; 0731-8898 ; 0146-4779
ISSN (online)	2162-6537
ISSN	0731-8898 ; 0146-4779
DOI	10.1615/JEnvironPatholToxicolOncol.2018028689
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Zs.A 1472: Show issues

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Article ; Online: Mitigation of arsenic-induced acquired cancer phenotype in prostate cancer stem cells by miR-143 restoration.

Ngalame, Ntube N O / Makia, Ngome L / Waalkes, Michael P / Tokar, Erik J

Toxicology and applied pharmacology

2015 Volume 312, Page(s) 11–18

Abstract: Inorganic arsenic, an environmental contaminant and a human carcinogen is associated with prostate cancer. Emerging evidence suggests that cancer stem cells (CSCs) are the driving force of carcinogenesis. Chronic arsenic exposure malignantly transforms ... ...

Abstract	Inorganic arsenic, an environmental contaminant and a human carcinogen is associated with prostate cancer. Emerging evidence suggests that cancer stem cells (CSCs) are the driving force of carcinogenesis. Chronic arsenic exposure malignantly transforms the human normal prostate stem/progenitor cell (SC) line, WPE-stem to arsenic-cancer SCs (As-CSCs), through unknown mechanisms. MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. In prior work, miR-143 was markedly downregulated in As-CSCs, suggesting a role in arsenic-induced malignant transformation. In the present study, we investigated whether loss of miR-143 expression is important in arsenic-induced transformation of prostate SCs. Restoration of miR-143 in As-CSCs was achieved by lentivirus-mediated miR-143 overexpression. Cells were assessed bi-weekly for up to 30weeks to examine mitigation of cancer phenotype. Secreted matrix metalloproteinase (MMP) activity was increased by arsenic-induced malignant transformation, but miR-143 restoration decreased secreted MMP-2 and MMP-9 enzyme activities compared with scramble controls. Increased cell proliferation and apoptotic resistance, two hallmarks of cancer, were decreased upon miR-143 restoration. Increased apoptosis was associated with decreased BCL2 and BCL-XL expression. miR-143 restoration dysregulated the expression of SC/CSC self-renewal genes including NOTCH-1, BMI-1, OCT4 and ABCG2. The anticancer effects of miR-143 overexpression appeared to be mediated by targeting and inhibiting LIMK1 protein, and the phosphorylation of cofilin, a LIMK1 substrate. These findings clearly show that miR-143 restoration mitigated multiple cancer characteristics in the As-CSCs, suggesting a potential role in arsenic-induced transformation of prostate SCs. Thus, miR-143 is a potential biomarker and therapeutic target for arsenic-induced prostate cancer.
MeSH term(s)	Arsenic/toxicity ; Carcinogens/toxicity ; Cell Line, Tumor ; Humans ; Lim Kinases/metabolism ; Male ; Matrix Metalloproteinases/metabolism ; MicroRNAs/genetics ; Neoplastic Stem Cells/pathology ; Prostatic Neoplasms/chemically induced ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology
Chemical Substances	Carcinogens ; MIRN143 microRNA, human ; MicroRNAs ; LIMK1 protein, human (EC 2.7.11.1) ; Lim Kinases (EC 2.7.11.1) ; Matrix Metalloproteinases (EC 3.4.24.-) ; Arsenic (N712M78A8G)
Language	English
Publishing date	2015-12-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2015.12.013
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Zs.B 14: Show issues

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Article ; Online: Aberrant microRNA expression likely controls RAS oncogene activation during malignant transformation of human prostate epithelial and stem cells by arsenic.

Ngalame, Ntube N O / Tokar, Erik J / Person, Rachel J / Xu, Yuanyuan / Waalkes, Michael P

Toxicological sciences : an official journal of the Society of Toxicology

2014 Volume 138, Issue 2, Page(s) 268–277

Abstract: Inorganic arsenic (iAs), a human carcinogen, potentially targets the prostate. iAs malignantly transforms the RWPE-1 human prostate epithelial line to CAsE-PE cells, and a derivative normal stem cell (SC) line, WPE-stem, to As-Cancer SC (As-CSC) line. ... ...

Abstract	Inorganic arsenic (iAs), a human carcinogen, potentially targets the prostate. iAs malignantly transforms the RWPE-1 human prostate epithelial line to CAsE-PE cells, and a derivative normal stem cell (SC) line, WPE-stem, to As-Cancer SC (As-CSC) line. MicroRNAs (miRNA) are noncoding but exert negative control on expression by degradation or translational repression of target mRNAs. Aberrant miRNA expression is important in carcinogenesis. A miRNA array of CAsE-PE and As-CSC revealed common altered expression in both for pathways concerning oncogenesis, miRNA biogenesis, cell signaling, proliferation, and tumor metastasis and invasion. The KRAS oncogene is overexpressed in CAsE-PE cells but not by mutation or promoter hypomethylation, and is intensely overexpressed in As-CSC cells. In both transformants, decreased miRNAs targeting KRAS and RAS superfamily members occurred. Reduced miR-134, miR-373, miR-155, miR-138, miR-205, miR-181d, miR-181c, and let-7 in CAsE-PE cells correlated with increased target RAS oncogenes, RAN, RAB27A, RAB22A mRNAs, and KRAS protein. Reduced miR-143, miR-34c-5p, and miR-205 in As-CSC correlated with increased target RAN mRNA, and KRAS, NRAS, and RRAS proteins. The RAS/ERK and PI3K/PTEN/AKT pathways control cell survival, differentiation, and proliferation, and when dysregulated promote a cancer phenotype. iAs transformation increased expression of activated ERK kinase in both transformants and altered components of the PI3K/PTEN/AKT pathway including decreased PTEN and increases in BCL2, BCL-XL, and VEGF in the absence of AKT activation. Thus, dysregulated miRNA expression may be linked to RAS activation in both transformants.
MeSH term(s)	Arsenites/toxicity ; Blotting, Western ; Carcinogens, Environmental/toxicity ; Cell Line ; Cell Transformation, Neoplastic/chemically induced ; Cell Transformation, Neoplastic/genetics ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Gene Expression/drug effects ; Genes, ras/drug effects ; Genes, ras/genetics ; Humans ; Male ; MicroRNAs/genetics ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Prostate/drug effects ; Prostate/metabolism ; Prostate/pathology ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins p21(ras) ; Real-Time Polymerase Chain Reaction ; Sodium Compounds/toxicity ; ras Proteins/genetics
Chemical Substances	Arsenites ; Carcinogens, Environmental ; KRAS protein, human ; MicroRNAs ; Proto-Oncogene Proteins ; Sodium Compounds ; sodium arsenite (48OVY2OC72) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2014-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfu002
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Zs.A 1709: Show issues

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Article ; Online: Silencing KRAS overexpression in arsenic-transformed prostate epithelial and stem cells partially mitigates malignant phenotype.

Ngalame, Ntube N O / Tokar, Erik J / Person, Rachel J / Waalkes, Michael P

Toxicological sciences : an official journal of the Society of Toxicology

2014 Volume 142, Issue 2, Page(s) 489–496

Abstract: Inorganic arsenic is a human carcinogen that likely targets the prostate. Chronic arsenic exposure malignantly transforms the RWPE-1 human prostate epithelial line to chronic arsenic exposed-prostate epithelial (CAsE-PE) cells, and a derivative normal ... ...

Abstract	Inorganic arsenic is a human carcinogen that likely targets the prostate. Chronic arsenic exposure malignantly transforms the RWPE-1 human prostate epithelial line to chronic arsenic exposed-prostate epithelial (CAsE-PE) cells, and a derivative normal prostate stem cell (SC) line, WPE-stem to arsenic-cancer SCs (As-CSCs). The KRAS oncogene is highly overexpressed in CAsE-PE cells and activation precedes transformation, inferring mechanistic significance. As-CSCs also highly overexpress KRAS. Thus, we hypothesize KRAS activation is key in causing and maintaining an arsenic-induced malignant phenotype, and hence, KRAS knockdown (KD) may reverse this malignant phenotype. RNA interference using shRNAmirs to obtain KRAS KD was used in CAsE-PE and As-CSC cells. Cells analyzed 2 weeks post transduction showed KRAS protein decreased to 5% of control after KD, confirming stable KD. KRAS KD decreased phosphorylated ERK, indicating inhibition of RAS/ERK signaling, a proliferation/survival pathway activated with arsenic transformation. Secreted metalloproteinase (MMP) activity was increased by arsenic-induced malignant transformation, but KRAS KD from 4 weeks on decreased secreted MMP-9 activity by 50% in As-CSCs. Colony formation, a characteristic of cancer cells, was decreased in both KRAS KD transformants. KRAS KD also decreased the invasive capacity of both cell types. KRAS KD decreased proliferation in As-CSCs, consistent with loss of rapid tumor growth. Genes predicted to impact cell proliferation (eg, Cyclin D1, p16, and p21) changed accordingly in both KD cell types. Thus, KRAS silencing impacts aspects of arsenic-induced malignant phenotype, inducing loss of many typical cancer characteristics particularly in As-CSCs.
MeSH term(s)	Animals ; Arsenites/toxicity ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Movement/genetics ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Cell Transformation, Neoplastic/drug effects ; Cell Transformation, Neoplastic/genetics ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Male ; Mice, Nude ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Prostate/metabolism ; Prostate/pathology ; Prostatic Neoplasms/chemically induced ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins p21(ras) ; RNA Interference ; RNA, Small Interfering/genetics ; Sodium Compounds/toxicity ; Xenograft Model Antitumor Assays ; ras Proteins/genetics
Chemical Substances	Arsenites ; KRAS protein, human ; Proto-Oncogene Proteins ; RNA, Small Interfering ; Sodium Compounds ; sodium arsenite (48OVY2OC72) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2014-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfu201
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Zs.A 1709: Show issues

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Article ; Online: Delayed temporal increase of hepatic Hsp70 in ApoE knockout mice after prenatal arsenic exposure.

Ngalame, Ntube N O / Micciche, Andrew F / Feil, Marilyn E / States, J Christopher

Toxicological sciences : an official journal of the Society of Toxicology

2012 Volume 131, Issue 1, Page(s) 225–233

Abstract: Prenatal arsenic exposure accelerates atherosclerosis in ApoE(-/-) mice by unknown mechanism. Arsenic is a hepatotoxicant, and liver disease increases atherosclerosis risk. Prenatal arsenic exposure may predispose to liver disease by priming for ... ...

Abstract	Prenatal arsenic exposure accelerates atherosclerosis in ApoE(-/-) mice by unknown mechanism. Arsenic is a hepatotoxicant, and liver disease increases atherosclerosis risk. Prenatal arsenic exposure may predispose to liver disease by priming for susceptibility to other environmental insults. Earlier microarray analyses showed prenatal arsenic exposure increased Hsc70 (HspA8) and Hsp70 (HspA1a) mRNAs in livers of 10-week-old mice. We determined effects of prenatal arsenic exposure on hepatic Hsp70 and Hsc70 expression by Western blot and on DNA methylation by methyl acceptance assay during prenatal and postnatal development. Pregnant ApoE(-/-) mice were given drinking water containing 85 mg/l NaAsO(2) (49 ppm arsenic) from gestation day (GD) 8 to 18. Hsp70 and Hsc70 expression and DNA methylation were determined in GD18 fetuses and 3-, 10-, and 24-week-old mice. Hsc70 expression was unchanged at all ages. Hsp70 induction was observed at 3 and 10 weeks, but was unchanged in GD18 fetuses and 24-week livers of mice. Global DNA methylation increased with age; arsenic had no effects. Bisulfite sequencing of DNA from livers of 10-week-old mice showed Hsp70 promoter region methylation was unchanged, but methylation was increased within the transcribed region. Hsf1 and Nrf2 nuclear translocation were investigated as potential mechanisms of Hsp70 induction and found unaltered. Putative binding sites were identified in HSP70 for in utero arsenic exposure-suppressed microRNAs suggesting a possible mechanism. Thus, prenatal arsenic exposure causes delayed temporal hepatic Hsp70 induction, suggesting a transient state of stress in livers which can predispose the mice to developing liver disease.
MeSH term(s)	Animals ; Apolipoproteins E/genetics ; Apolipoproteins E/physiology ; Arsenites/toxicity ; Atherosclerosis/chemically induced ; Atherosclerosis/genetics ; Blotting, Western ; CpG Islands/genetics ; DNA Methylation/drug effects ; DNA-Binding Proteins/metabolism ; Epigenesis, Genetic/drug effects ; Female ; HSP70 Heat-Shock Proteins/genetics ; HSP70 Heat-Shock Proteins/metabolism ; Heat Shock Transcription Factors ; Liver/drug effects ; Liver/embryology ; Liver/growth & development ; Liver/metabolism ; Mice ; Mice, Knockout ; NF-E2-Related Factor 2/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced ; Prenatal Exposure Delayed Effects/metabolism ; Promoter Regions, Genetic ; Protein Transport ; Sodium Compounds/toxicity ; Transcription Factors/metabolism ; Water Pollutants, Chemical/toxicity
Chemical Substances	Apolipoproteins E ; Arsenites ; DNA-Binding Proteins ; HSP70 Heat-Shock Proteins ; Heat Shock Transcription Factors ; Hsf1 protein, mouse ; NF-E2-Related Factor 2 ; Nfe2l2 protein, mouse ; Sodium Compounds ; Transcription Factors ; Water Pollutants, Chemical ; sodium arsenite (48OVY2OC72)
Language	English
Publishing date	2012-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfs264
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Article ; Online: Recruitment of normal stem cells to an oncogenic phenotype by noncontiguous carcinogen-transformed epithelia depends on the transforming carcinogen.

Xu, Yuanyuan / Tokar, Erik J / Person, Rachel J / Orihuela, Ruben G / Ngalame, Ntube N O / Waalkes, Michael P

Environmental health perspectives

2013 Volume 121, Issue 8, Page(s) 944–950

Abstract: Background: Cancer stem cells (CSCs) drive tumor initiation, progression, and metastasis. The microenvironment is critical to the fate of CSCs. We have found that a normal stem cell (NSC) line from human prostate (WPE-stem) is recruited into CSC-like ... ...

Abstract	Background: Cancer stem cells (CSCs) drive tumor initiation, progression, and metastasis. The microenvironment is critical to the fate of CSCs. We have found that a normal stem cell (NSC) line from human prostate (WPE-stem) is recruited into CSC-like cells by nearby, but noncontiguous, arsenic-transformed isogenic malignant epithelial cells (MECs). Objective: It is unknown whether this recruitment of NSCs into CSCs by noncontact co-culture is specific to arsenic-transformed MECs. Thus, we used co-culture to examine the effects of neighboring noncontiguous cadmium-transformed MECs (Cd-MECs) and N-methyl-N-nitrosourea-transformed MECs (MNU-MECs) on NSCs. Results: After 2 weeks of noncontact Cd-MEC co-culture, NSCs showed elevated metalloproteinase-9 (MMP-9) and MMP-2 secretion, increased invasiveness, increased colony formation, decreased PTEN expression, and formation of aggressive, highly branched duct-like structures from single cells in Matrigel, all characteristics typical of cancer cells. These oncogenic characteristics did not occur in NSCs co-cultured with MNU-MECs. The NSCs co-cultured with Cd-MECs retained self-renewal capacity, as evidenced by multiple passages (> 3) of structures formed in Matrigel. Cd-MEC-co-cultured NSCs also showed molecular (increased VIM, SNAIL1, and TWIST1 expression; decreased E-CAD expression) and morphologic evidence of epithelial-to-mesenchymal transition typical for conversion to CSCs. Dysregulated expression of SC-renewal genes, including ABCG2, OCT-4, and WNT-3, also occurred in NSCs during oncogenic transformation induced by noncontact co-culture with Cd-MECs. Conclusions: These data indicate that Cd-MECs can recruit nearby NSCs into a CSC-like phenotype, but MNU-MECs do not. Thus, the recruitment of NSCs into CSCs by nearby MECs is dependent on the carcinogen originally used to malignantly transform the MECs.
MeSH term(s)	Animals ; Blotting, Western ; Cadmium/toxicity ; Carcinogens/toxicity ; Carcinoma/metabolism ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Environmental Pollutants/toxicity ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Fluorescent Antibody Technique ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Matrix Metalloproteinases/genetics ; Matrix Metalloproteinases/metabolism ; Methylnitrosourea/toxicity ; Mice ; Mice, Nude ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Polymerase Chain Reaction ; Prostatic Neoplasms/metabolism ; Transforming Growth Factor alpha/genetics ; Transforming Growth Factor alpha/metabolism
Chemical Substances	Carcinogens ; Environmental Pollutants ; Transforming Growth Factor alpha ; Cadmium (00BH33GNGH) ; Methylnitrosourea (684-93-5) ; Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2013-05-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	195189-0
ISSN	1552-9924 ; 0091-6765 ; 1078-0475
ISSN (online)	1552-9924
ISSN	0091-6765 ; 1078-0475
DOI	10.1289/ehp.1306714
Database	MEDical Literature Analysis and Retrieval System OnLINE

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