Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1

Hayward, Simon W.; Dahiya, Rajvir; Cunha, Gerald R.; Bartek, J.; Deshpande, N.; Narayan, Perinchery

doi:10.1007/bf02631333

Cited by 300 publications

(271 citation statements)

References 53 publications

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“…BPH-1 cells have been activated with SV40 T antigen, which results in genetic and epigenetic instability and significant clonal variation [20,39]. However, the ''initiation events'' were the basis for their selection as the epithelial source for these studies, since this instability facilitates induction of malignancy in response to CAFs and/or hormonal carcinogenesis; normal epithelial cells from primary specimens are not susceptible to carcinogenesis using these assays [13,38].…”

Section: Discussionmentioning

confidence: 99%

“…In order to confirm that benign basal cells can be malignantly transformed, we used cells from the initiated but nontumorigenic BPH-1 epithelial cell line [20] that form tumors in recombination with tumor stroma (CAFs) [13]. Different to Goldstein et al [3], we used an alternate selection protocol to enrich for basal cells based on rapid adhesion to collagen.…”

Section: Selection Of Epithelial Stem Cellsmentioning

confidence: 99%

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Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

et al. 2012

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Normal prostatic epithelium is composed of basal and luminal cells. Prostate cancer can be initiated in both benign basal and luminal stem cells, but because basal cell markers are not expressed in patient tumors, the former result was unexpected. Since the cells of origin of prostate cancer are important therapeutic targets, we sought to provide further proof that basal stem cells have tumorigenic potential. Prostatic basal cells were enriched based on a2b1integrin hi expression and further enriched for stem cells using CD133 in nontumorigenic BPH-1 cells. Human embryonic stem cells (hESCs) were also used as a source of normal stem cells. To test their tumorigenicity, we used two alternate stromal-based approaches; (a) recombination with human cancer-associated fibroblasts (CAFs) or (b) recombination with embryonic stroma (urogenital mesenchyme) and treated host mice with testosterone and 17b-estradiol. Enriched a2b1integrin hi basal cells from BPH-1 cells resulted in malignant tumor formation using both assays of tumorigenicity. Surprisingly, the tumorigenic potential did not reside in the CD133 1 stem cells but was consistently observed in the CD133 2 population. CAFs also failed to induce prostatic tumors from hESCs. These data confirmed that benign human basal cells include cells of origin of prostate cancer and reinforced their importance as therapeutic targets. In addition, our data suggested that the more proliferative CD133 2 basal cells are more susceptible to tumorigenesis compared to the CD133 1 -enriched stem cells. These findings challenge the current dogma that normal stem cells and cells of origin of cancer are the same cell type(s).

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Section: Discussionmentioning

confidence: 99%

Section: Selection Of Epithelial Stem Cellsmentioning

confidence: 99%

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

et al. 2012

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“…In the experiments where LNCaP cells were treated with the synthetic androgen R1881 and/or the anti-androgen bicalutamide, these chemicals were refreshed every 48 h. The immortalized prostatic epithelial cell line BPH-1 was kindly provided by Dr. S. W. Hayward (43) and cultured in RPMI 1640 medium (Invitrogen) containing 5% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

Androgens Negatively Regulate Forkhead Transcription Factor FKHR (FOXO1) through a Proteolytic Mechanism in Prostate Cancer Cells

Huang

Muddiman

Tindall

2004

Journal of Biological Chemistry

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The ability of androgens to inhibit apoptosis in both normal and malignant prostatic cells has been well documented. However, the underlying mechanisms are understood poorly. Here we demonstrated that forkhead transcription factor FKHR (FOXO1)-induced death of LNCaP cells was blocked by a synthetic androgen R1881. Androgen treatment also resulted in a reduction in transcriptional activity of FKHR in these cells. Moreover, treatment of LNCaP cells with R1881 led to a decrease in the intact FKHR protein (70 kDa) and an increase in a faster migrating protein band (60 kDa). Androgen-enhanced appearance of the 60-kDa protein was diminished specifically by lysosomal acidic cysteine protease inhibitors. Mass spectrometry analyses of the purified FLAG-tagged 70-and 60-kDa proteins demonstrated that the 60-kDa species is a FKHR protein product that lacks about 120 amino acid residues of the C-terminal end. Mutagenesis of the basic amino acid Arg 537 in the protease cleavage region, as suggested by mass spectrometry, abrogated both the androgen-induced accumulation of the 60-kDa product and decrease in cell death induced by FKHR, suggesting that the residue Arg 537 is a potential protease cleavage site. Finally, ectopic expression of the first 537 amino acids of FKHR produced an inhibitory effect on transcriptional activity of the intact protein. Together, these results suggest that androgens induce increased activity of an acidic cysteine protease, which in turn cleaves FKHR. This provides a mechanism by which androgens protect prostate cancer cells from the killing effect of FKHR.Androgens are critical for proliferation and apoptosis in both normal and malignant prostatic epithelial cell (1). Orchitectomy results in extensive apoptosis and involution of the rat ventral prostate and human prostate cancer xenografts (2-4). Regression of prostatic tumors in patients following androgen ablation therapy is associated with apoptotic death in malignant prostatic epithelium (5, 6). These findings suggest that androgens function as antiapoptotic factors in both normal and malignant prostatic cells.The tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome ten; also known as MMAC1/ TEP1) is mutated frequently in a variety of tumors including prostate, brain, and endometrium (7-9). Although the overall prevalence of PTEN mutations in primary prostate cancer is low relative to other tumors (10), the gene product is lost frequently in advanced prostate tumors (11, 12). Inactivation of PTEN through different mechanisms such as deletion, methylation, or protein degradation has been implicated in progression of a number of tumors (7,8,(13)(14)(15)(16)(17). Heterozygous disruption results in hyperplasia of the prostate, skin, and colon. Prostate-specific homozygous deletion of PTEN alleles in mice results in metastatic prostate cancer (18). PTEN acts as a tumor suppressor protein primarily via its phosphatidylinositol phosphatase activity, which antagonizes the phosphatidylinositol 3-kinase/Akt pathway (19,20)....

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“…BPH-1 cell line was generously provided by Dr. Simon Hayward (Vanderbilt University Medical Center, Nashville, TN; ref. 38). Cells were maintained in Dulbecco's modified Eagle medium (high glucose) culture medium (Invitrogen Life Technologies) supplemented with 10% (v/v) FBS and antibiotics (Invitrogen).…”

Section: Cell Lines Culture Conditions and Treatmentsmentioning

confidence: 99%

AIM2, an IFN-Inducible Cytosolic DNA Sensor, in the Development of Benign Prostate Hyperplasia and Prostate Cancer

Ponomareva

Liu

Duan

et al. 2013

Molecular Cancer Research

102

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Close links have been noted between chronic inflammation of the prostate and the development of human prostatic diseases such as benign prostate hyperplasia (BPH) and prostate cancer. However, the molecular mechanisms that contribute to prostatic inflammation remain largely unexplored. Recent studies have indicated that the IFN-inducible AIM2 protein is a cytosolic DNA sensor in macrophages and keratinocytes. Upon sensing DNA, AIM2 recruits the adaptor ASC and pro-CASP1 to assemble the AIM2 inflammasome. Activation of the AIM2 inflammasome cleaves pro-interleukin (IL)-1b and pro-IL-18 and promotes the secretion of IL-1b and IL-18 proinflammatory cytokines. Given that human prostatic infections are associated with chronic inflammation, the development of BPH is associated with an accumulation of senescent cells with a proinflammatory phenotype, and the development of prostate cancer is associated with the loss of IFN signaling, the role of AIM2 in mediating the formation of prostatic diseases was investigated. It was determined that IFNs (a, b, or g) induced AIM2 expression in human prostate epithelial cells and cytosolic DNA activated the AIM2 inflammasome. Steady-state levels of the AIM2 mRNA were higher in BPH than in normal prostate tissue. However, the levels of AIM2 mRNA were significantly lower in clinical tumor specimens. Accordingly, constitutive levels of AIM2 mRNA and protein were lower in a subset of prostate cancer cells as compared with BPH cells. Further, the cytosolic DNA activated the AIM2 inflammasome in the androgen receptor-negative PC3 prostate cancer cell line, suggesting that AIM2-mediated events are independent of androgen receptor status.

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Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1

Cited by 300 publications

References 53 publications

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

Androgens Negatively Regulate Forkhead Transcription Factor FKHR (FOXO1) through a Proteolytic Mechanism in Prostate Cancer Cells

AIM2, an IFN-Inducible Cytosolic DNA Sensor, in the Development of Benign Prostate Hyperplasia and Prostate Cancer

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