Human cell lines as an in vitro/in vivo model for prostate carcinogenesis and progression

Webber, Mukta M.; Quader, Salmaan T.A.; Kleinman, Hynda K.; Deocampo, Daniel M.; Storto, Patrick D.; Bice, Gillian; DeMendonca‐Calaca, Wanderley; Williams, Daniel E.

doi:10.1002/pros.1041

Cited by 81 publications

(53 citation statements)

References 29 publications

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“…Thus, although all three transformed cell lines produce xenograft carcinomas in mice, the mechanism by which they acquire a malignant phenotype appears quite distinct. This is consistent with prior work showing little evidence of ODD during Cd- or iAs-induced transformation of these prostate epithelial cells or other cell types (Qu et al , 2005; Kojima et al , 2009; Person et al , 2013) Given the large differences in exposure time needed to achieve transformation by MNU, Cd, or iAS (four hours, eight weeks, or 29 weeks, respectively) it is not surprising that the mechanism driving transformation with each agent is unique (Achanzar et al , 2001; Webber et al , 2001; Achanzar et al , 2002)). In the case of all five genes interrogated, exposure to Cd or iAs altered the gene expression in such a way that would favor carcinogenesis.…”

Section: Discussionsupporting

confidence: 89%

“…Transformed cells showed multiple molecular and cellular markers of acquired cancer cell phenotype and have the ability to form carcinoma upon inoculation into nude mice (Achanzar et al , 2001; Achanzar et al , 2002). For comparison, control RWPE-1 cells were transformed with the mutagenic organic carcinogen, MNU resulting in the WPE1-NB26 cell line (herein referred to as B26 cells), which also produces carcinoma after injection in nude mice (Webber et al , 2001). …”

Section: Methodsmentioning

confidence: 99%

“…The non-tumorigenic immortalized human prostate epithelial cell line RWPE-1 is a well-characterized model for exploring the mechanism of malignant transformation by carcinogenic inorganics (Bello et al , 1997; Achanzar et al , 2001; Webber et al , 2001; Achanzar et al , 2002). Long-term exposure of RWPE-1 cells to environmentally relevant levels of Cd or iAs induces the acquisition of a malignant phenotype with both physical (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

Pelch

Tokar

Merrick

et al. 2015

Toxicology and Applied Pharmacology

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Previous work shows altered methylation patterns in inorganic arsenic (iAs)-or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10 μM Cd for 11 weeks (CTPE) or 5 μM iAs for 29 weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1) were chosen for in depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (>25-fold) and S100P (>40-fold) in transformants was correlated with hypomethylation near the transcription start site. Decreased expression of NES (>15-fold) and NTM (>1000-fold) in transformants was correlated with hypermethylation near the transcription start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status.

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

Pelch

Tokar

Merrick

et al. 2015

Toxicology and Applied Pharmacology

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“…The development of the human nontumorigenic parental RWPE-1 cell line, used as the control in this work, and the derivation of the cadmium-transformed prostate epithelial cell line are described in detail elsewhere (Achanzar et al 2001; Bello et al 1997; Webber et al 2001). Although immortalized, RWPE-1 cells have retained properties exhibited by normal prostate epithelium in vivo .…”

Section: Methodsmentioning

confidence: 99%

Acquisition of Apoptotic Resistance in Cadmium-Transformed Human Prostate Epithelial Cells: Bcl-2 Overexpression Blocks the Activation of JNK Signal Transduction Pathway

et al. 2007

Environ Health Perspect

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BackgroundWe have recently shown that cadmium can induce malignant transformation of the human prostate epithelial cell line (RWPE-1) and that these cadmium-transformed prostate epithelial (CTPE) cells acquire apoptotic resistance concurrently with malignant phenotype.ObjectiveThe present study was designed to define the mechanism of acquired apoptotic resistance in CTPE cells.MethodsVarious molecular events associated with apoptosis were assessed in control and CTPE cells that were obtained after 8 weeks of continuous cadmium exposure.ResultsCompared with control, CTPE cells showed a generalized resistance to apoptosis induced by cadmium, cisplatin, or etoposide. Signal-regulated mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2, c-Jun N-terminal kinases (JNK1 and JNK2), and p38 were phosphorylated in a cadmium concentration-dependent fashion in CTPE and control cells. However, phosphorylated JNK1/2 levels and JNK kinase activity were much lower in CTPE cells. The pro-apoptotic gene Bax showed lower transcript and protein levels, whereas the anti-apoptotic gene Bcl-2 showed higher levels in CTPE cells. The ratio of Bcl-2/Bax, a key determinant in apoptotic commitment, increased more than 4-fold in CTPE cells. In Bcl-2–transfected PT-67 cells, phosphorylated JNK1/2 levels were much lower after apoptogenic stimulus, and apoptosis induced by cadmium or etoposide was reduced compared with control. Mutation of tyrosine to serine at the 21st amino acid of the Bcl-2 protein BH4 domain resulted in a loss both of suppression of JNK1/2 phosphorylation and its anti-apoptotic function.ConclusionsCTPE cells become resistant to apoptosis during malignant transformation, and disruption of the JNK pathway and Bcl-2 overexpression play important roles in this resistance. Bcl-2 BH4 domain is required for modulating JNK phosphorylation and anti-apoptotic function.

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“…Therefore, we hypothesised that ENL could restrict the proliferation of more than just the later stages of prostate disease. To investigate our hypothesis we used an in vitro model system of six prostate cell lines representing the early (RWPE-1 and WPE1-NA22), mid (WPE1-NB14 and WPE1-NB11) and later (WPE1-NB26 and LNCaP) stages of prostate tumourigenesis [36,37]. The LNCaP cell line is a model of the switch between androgen sensitivity and insensitivity during prostate disease that occurs in the later stages of carcinogenesis [37].…”

Section: Introductionmentioning

confidence: 99%

The Anti-Proliferative Effects of Enterolactone in Prostate Cancer Cells: Evidence for the Role of DNA Licencing Genes, mi-R106b Cluster Expression, and PTEN Dosage

2014

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The mammalian lignan, enterolactone, has been shown to reduce the proliferation of the earlier stages of prostate cancer at physiological concentrations in vitro. However, efficacy in the later stages of the disease occurs at concentrations difficult to achieve through dietary modification. We have therefore investigated what concentration(s) of enterolactone can restrict proliferation in multiple stages of prostate cancer using an in vitro model system of prostate disease. We determined that enterolactone at 20 μM significantly restricted the proliferation of mid and late stage models of prostate disease. These effects were strongly associated with changes in the expression of the DNA licencing genes (GMNN, CDT1, MCM2 and 7), in reduced expression of the miR-106b cluster (miR-106b, miR-93, and miR-25), and in increased expression of the PTEN tumour suppressor gene. We have shown anti-proliferative effects of enterolactone in earlier stages of prostate disease than previously reported and that these effects are mediated, in part, by microRNA-mediated regulation.

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Human cell lines as an in vitro/in vivo model for prostate carcinogenesis and progression

Abstract: This family of cell lines with a common lineage represents a unique and relevant model which mimics stages in prostatic intra-epithelial neoplasia (PIN) and progression to invasive cancer, and can be used to study carcinogenesis, progression, intervention, and chemoprevention.

Cited by 81 publications

References 29 publications

Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

Acquisition of Apoptotic Resistance in Cadmium-Transformed Human Prostate Epithelial Cells: Bcl-2 Overexpression Blocks the Activation of JNK Signal Transduction Pathway

The Anti-Proliferative Effects of Enterolactone in Prostate Cancer Cells: Evidence for the Role of DNA Licencing Genes, mi-R106b Cluster Expression, and PTEN Dosage

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