Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells
© Zhao et al; licensee BioMed Central Ltd. 2009
Received: 25 July 2008
Accepted: 20 August 2009
Published: 20 August 2009
Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA).
We systematically assessed gene expression changes induced by clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction.
The expression of 156 genes was significantly increased by clorgyline at all time points over the time course of 6 – 96 hr identified by Significance Analysis of Microarrays (SAM). The list is enriched with genes repressed in 7 of 12 oncogenic pathway signatures compiled from the literature. In addition, genes downregulated ≥ 2-fold by clorgyline were significantly enriched with those upregulated by key oncogenes including beta-catenin and ERBB2, indicating an anti-oncogenic effect of clorgyline. Another striking effect of clorgyline was the induction of androgen receptor (AR) and classic AR target genes such as prostate-specific antigen together with other secretory epithelial cell-specific genes, suggesting that clorgyline promotes differentiation of cancer cells. Moreover, clorgyline downregulated EZH2, a critical component of the Polycomb Group (PcG) complex that represses the expression of differentiation-related genes. Indeed, many genes in the PcG repression signature that predicts PCa outcome were upregulated by clorgyline, suggesting that the differentiation-promoting effect of clorgyline may be mediated by its downregulation of EZH2.
Our results suggest that inhibitors of MAO-A, already in clinical use to treat depression, may have potential application as therapeutic PCa drugs by inhibiting oncogenic pathway activity and promoting differentiation.
Adenocarcinomas of the prostate are categorized according to the Gleason grading system, which consists of five histological patterns based on microscopic tumor architecture . Numerous studies have shown a correlation between Gleason grade and disease outcome . In particular, the percentage of the largest (index) cancer that is Gleason grade 4 and/or 5 (poorly differentiated) has strong predictive value [2, 3]. Specifically, cancers composed entirely of Gleason grade 3 (well-differentiated) have a > 95% chance of being cured by surgery. In contrast, each increase of 10% in the percent of the tumor classified as grade 4/5 at the time of surgery leads to a 10% increase in the failure rate as measured by detectable and rising serum prostate specific antigen (PSA), a biomarker of prostate cancer (PCa). Therefore, understanding the molecular basis of the aggressive behavior of grade 4/5 cancer is of considerable clinical relevance. Despite the accumulating knowledge about the biology of PCa, the molecular machineries that differ between grade 3 and 4/5 cancers and mark a critical change from curable to lethal are largely unknown.
Monoamine oxidase A (MAO-A) is a mitochondrial enzyme that degrades monoamine neurotransmitters including 5-hydroxytryptamine (5-HT, or serotonin) and norepinephrine . It is one of the most highly over-expressed genes in Gleason grade 4/5 PCa compared to grade 3 cancer , raising the possibility that activity of this enzyme is a key factor in the increased lethality of high grade PCa [2, 3]. MAO-A is also highly expressed in basal cells of the normal prostatic epithelium. Using primary cultures of normal human prostatic epithelial cells as a model of basal cells, we showed that MAO-A prevents their differentiation into secretory epithelial cells , consistent with an anti-differentiation role of MAO-A in neural stem cells . Specifically, under differentiation-promoting culture conditions, clorgyline, an irreversible MAO-A inhibitor , induced expression of androgen receptor (AR), a hallmark of secretory epithelial cells, and repressed expression of cytokeratin 14, a basal cell marker . It also induced secretory epithelial cell-like morphology . Our results suggest that increased expression of MAO-A in high grade PCa may be an important contributor to its poorly differentiated and aggressive phenotype. In our recent study using a cohort of high grade cancers, increased expression of MAO-A correlated with an increased percentage of Gleason grade 4 and 5 cancer in the largest (index) tumor and with pre-operative serum PSA levels , two powerful prognostic factors for recurrence of PCa after radical prostatectomy [3, 10].
The above findings suggest that inhibition of MAO-A might restore differentiation and reverse the aggressive behavior of high grade PCa. The functions of MAO-A in the nervous system have been extensively studied  and its inhibitors are currently used to treat several neurological diseases such as depression , therefore, insights into the effects of MAO-A inhibitors on PCa could rapidly lead to clinical trials to test therapeutic activity of such inhibitors. In this study, we examined the gene expression changes in primary cultures of cancer cells derived from high grade surgical specimens (E-CA cells) in response to clorgyline treatment, and identified two major effects of clorgyline on PCa cells.
Isolation, culture, and treatment of prostatic cancer cells
Primary cultures of human prostatic cancer cells, E-CA-88 and -90, were established from histologically confirmed cancer tissues in radical prostatectomy specimens as previously described . All human subject studies were done in compliance with the Helsinki Declaration and reviewed by Institutional Review Board at Stanford University. E-CA-88 was derived from cancer composed of 80% Gleason grade 4 and 20% Gleason grade 3, and E-CA-90 from cancer of 100% Gleason grade 4. The patients did not have prior chemical, hormonal, or radiation therapy. Primary cultures were passaged three times, then cells were grown in Complete MCDB 105 (Sigma-Aldrich, St. Louis, MO) until 50% confluent as previously described . At time zero, control cells were fed Complete PFMR-4A  without epidermal growth factor (EGF) and with 10 nM 1,25-dihydroxyvitamin D3, 1 μM all-trans retinoic acid, 1 ng/ml transforming growth factor (TGF)-β1, and 1 nM R1881 (designated as "VRTR"). This "differentiation-promoting" medium was previously shown to be essential for the differentiation of normal prostatic cells in response to clorgyline . Experimental cells were fed the same medium as control cells except that 1 μM clorgyline was added. Total RNA was isolated from control and clorgyline-treated cells at 6, 24, and 96 hr after treatment as previously described .
1,25-dihydroxyvitamin D3 (Biomol International, Plymouth Meeting, PA) was prepared at 10 mM in DMSO. TGF-β1 (Preprotech, Inc., Rocky Hill, NJ) was prepared in 10 mM citric acid (pH 3.0) at 100 μg/ml. All-trans retinoic acid (Sigma-Aldrich) was prepared in DMSO at 1 mM. Clorgyline (Sigma) was prepared at 100 mM in water. The synthetic androgen R1881 (Perkin Elmer, Waltham, MA) was prepared in ethanol at 10 μM.
Oligonucleotide microarray hybridizations
Fluorescently-labeled cDNA probes were prepared from 50 to 70 μg total RNA by reverse transcription using an Oligo dT primer 50-TTTTTTTTTTTTTTTT-30 (Qiagen, Valencia, CA) and indirect amino-allyl labeling as described previously . Cy5-labeled probes from control or clorgyline-treated cells for each time point were mixed with Cy3-labeled probe from Universal Human Reference RNA (Stratagene, La Jolla, CA) and hybridized overnight at 65°C to spotted oligonucleotide microarrays with 44,544 70 mer elements (Stanford Functional Genomics Facility). Microarray slides were then washed to remove unbound probe and scanned with a GenePix 4000B scanner (Axon Instruments, Inc., Union City, CA).
Data processing and analysis
The acquired fluorescence intensities for each fluoroprobe were analyzed with GenePix Pro 5.0 software (Axon Instruments, Inc.). Spots of poor quality were removed from further analysis by visual inspection. Data files containing fluorescence ratios were entered into the Stanford Microarray Database (SMD) where biological data were associated with fluorescence ratios and genes were selected for further analysis . Data were retrieved only from spots with a signal intensity >150% above background in either Cy5- or Cy3-channels from SMD. Genes with potentially significant changes in expression in response to clorgyline were identified using the significance analysis of microarrays (SAM) procedure . Common genes among different data sets were identified using Microsoft Excel. The genes and arrays in the resulting data tables were ordered by their patterns of gene expression and visualized using Treeview software http://rana.lbl.gov/EisenSoftware.htm. The Chi-square test was used to determine gene enrichment. All data have been deposited into Gene Expression Omnibus (GEO) with accession number GSE17167.
Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR)
Total RNA from control and treated cells was reverse transcribed as described above. cDNA product was then mixed with SYBR® GreenER™ qPCR SuperMix (Invitrogen, Carlsbad, CA) and primers of choice in the subsequent PCR reaction using an MxPro3000 real-time PCR Detection System (Stratagene) according to the manufacture's instructions. Each reaction was done in triplicate to minimize the experimental variations (standard deviation was calculated for each reaction). Transcript levels of GAPDH were assayed simultaneously with each of the twenty selected genes as an internal control to normalize transcript levels in control and treated cells. The primer sequences used were listed in Additional file 1.
Cells were grown in Complete PFMR-4A without EGF and supplemented with VRTR plus 1 μm clorgyline for 6, 24, or 96 hr. Control cells were grown in Complete PFMR-4A in parallel. Cells were then detached using TrypLE Express (Invitrogen) and seeded in Complete MCDB 105 medium at a density of 500 cells/60-mm collagen-coated dish. After 10 days, cells were fixed with 10% formalin and stained with 0.1% crystal violet. The number of cells on each plate was counted under a microscope. Triplicate plates were set up for each condition to minimize experimental variations. The statistical significance of the differences in cell numbers was assessed by t-test.
Significance analysis of microarrays (SAM) identifies genes upregulated by clorgyline
A primary culture of epithelial cells (E-CA-88) derived from a high grade adenocarcinoma of the prostate was treated with diluent or 1 μM of clorgyline, an irreversible inhibitor of MAO-A. The concentration of 1 μM was chosen because previous studies have shown that it is an effective dose to elicit a variety of effects in cultured animal cells [16–18]. Our earlier study using normal primary prostatic basal epithelial cells also showed that 1 μM clorgyline induced secretory differentiation . In normal cells, secretory differentiation occurred by 96 hr after clorgyline treatment. Therefore, the three time points chosen for profiling are sufficient to capture the gene expression changes elicited by clorgyline at early and late stages. Total RNA was isolated at 6, 24 and 96 hr. Gene expression profiling was carried out on high-density oligonucleotide microarrays.
Clorgyline induces genes suppressed by oncogenic pathways
Comparison of genes identified by SAM with oncogenic pathway signatures*
Number of unique genes down
Number of genes overlap with SAM
Expected number of genes overlap with SAM
The oncogenic pathways regulated by beta-catenin, Src, ERBB2, and Ras overlap and have common target genes. For example, 1110 of the 1839 (60%) named genes downregulated by beta-catenin as complied by Creighton  are also downregulated by Src. Similarly, 595 (32%) and 308 (17%) of genes downregulated by beta-catenin are also downregulated by Ras and ERBB2, respectively . In our dataset, these genes downregulated in oncogenic pathways are the most enriched in the SAM list of clorgyline-induced genes and the enriched genes downregulated by beta-catenin, Src, Ras, and ERBB2 also overlap considerably. Specifically, 21, 19, and 12 out of the 36 genes (58%, 53%, and 33%) that overlap between beta-catenin downregulated genes and the SAM list of clorgyline upregulated genes were also downregulated by Src, Ras, and ERBB2, respectively.
Clorgyline induces APC and FAS expression and counteracts beta-catenin and ERBB2 pathways
To gain a comprehensive understanding of the effects of clorgyline on the beta-catenin pathway, we compared genes whose expression changed at least 2-fold in response to clorgyline with beta-catenin pathway signatures. Of the 1839 genes downregulated by beta-catenin, 564, 624, and 474 were up-regulated by clorgyline at 6, 24, and 96 hr, respectively, which is significantly enriched (higher than expected by chance) as determined by Chi-square test (Figure 3B and 3D). In addition, of the 934 genes upregulated by beta-catenin, 119, 191, and 56 were downregulated by clorgyline at 6, 24, and 96 hr, respectively, which is also significantly enriched (Figure 3B and 3D). Moreover, genes upregulated by beta-catenin are significantly anti-enriched (fewer than expected by chance) in the lists of genes upregulated by clogyline at all three time points (Figure 3D). Finally, although genes downregulated by beta-catenin showed enrichment at 6 and 24 hr in the lists of genes downregulated by clorgyline, the number is fewer than expected at 96 hr (Figure 3D). These results suggest that, in large part, clorgyline induced a transcriptional program that is inversely correlated with beta-catenin pathway signatures. In other words, clorgyline seems to reverse the oncogenic pathway of beta-catenin, perhaps through upregulation of APC.
Since APC is downregulated when ERBB2 is overexpressed in breast cancer cells , we performed a similar analysis to that described above to determine the effects of clorgyline treatment on ERBB2 pathway signatures. Of 1350 genes downregulated by ERBB2, 476, 604, and 328 were upregulated in clorgyline-treated E-CA-88 cells at 6, 24, and 96 hr, respectively, which is significantly enriched as determined by Chi-square test (Figure 3C and 3E). In addition, of the 1302 genes upregulated by ERBB2, 475, 222, and 55 were downregulated by clorgyline at 6, 24, and 96 hr, respectively, which is also significantly enriched (Figure 3C and 3E). Moreover, genes upregulated by ERBB2 are significantly anti-enriched (fewer than expected by chance) in the lists of genes upregulated by clogyline at all three time points (Figure 3E). Finally, genes downregulated by ERBB2 showed significant anti-enrichment at 96 hr in the list of genes downregulated by clorgyline (Figure 3E). These results demonstrate that clorgyline induced genes that are suppressed by ERBB2 and repressed genes that are activated by ERBB2. Therefore, similar to its effects on beta-catenin pathways, clorgyline reverses the transcriptional program induced by ERBB2.
Clorgyline upregulates AR and modulates expression of androgen-regulated genes
Clorgyline induces differentiation-related genes possibly through downregulation of EZH2
Expression change of cell type specific cell surface antigens in response to clorglyine
Cell surface antigen
Cell type expression
To systematically examine the effect of clorgyline on EZH2 targets, we compared genes whose expression changed by 2-fold or more in response to clorgyline with a Polycomb repression signature consisting of 87 PcG-occupied genes that has been shown to predict patient survival in PCa . Of these 87 genes, 23, 29, and 10 were upregulated by clorgyline at 6, 24, and 96 hr, respectively (Figure 6B). The enrichment of this Polycomb repression signature in genes upregulated by clorgyline is statistically significant at 6 and 24 hr. In addition, 13 of these PcG-repressed genes were upregulated at both 6 and 24 hr, demonstrating a consistent upregulation of a subset of the Polycomb repression signature by clorgyline.
We attempted to validate four Polycomb signature genes that have been implicated in the differentiation of various cell types, namely MYO6, SATB2, SOCS2, and RGC32, by qRT-PCR [29–32]. As shown in Figure 6A, expression of three of the four genes was significantly upregulated in treated E-CA-88 cells compared to control, suggesting that clorgyline induced genes suppressed by the Polycomb complex. Taken together, these results suggest that downregulation of EZH2 and reversal of repression of its target genes may play a role in clorgyline-induced differentiation.
Validation of the effects of clorgyline using E-CA-90 cells
We systematically assessed gene expression changes induced by the MAO-A – specific inhibitor, clorgyline, in primary cultures of prostatic epithelial cells from high grade cancer. SAM identified 156 unique named genes whose expression was significantly upregulated by clorgyline across all three time points (6 – 96 hrs) tested in this study. Strikingly, more than half of these genes are reportedly suppressed by at least one known oncogene (beta-catenin, Src, ERBB2, Ras, E2F3, MEK and Myc) , suggesting an anti-oncogenic effect of clorgyline. For example, SAMD9, the gene most significantly upregulated by clorgyline, is repressed in a variety of neoplasms associated with beta-catenin stabilization . Knockdown of SAMD9 increased the proliferation and invasiveness of cancer cells, whereas SAMD9 overexpression reduced cell proliferation and motility . In addition, SAMD9 expression was dramatically increased in an aggressive fibromatosis tumor with inactivation of the APC gene after transfection of wild type APC . In our data set, APC is the 24th most significantly upregulated gene by clorgyline, indicating a possible regulation of SAMD9 by APC in E-CA cells.
When considering genes up- and -downregulated by at least 2-fold at individual time points, it is clear that clorgyline elicits an extensive anti-oncogenic effect in E-CA cells. Specifically, clorgyline repressed oncogene-activated gene expression and induced oncogene-suppressed gene expression in E-CA cells, which was observed consistently across all time points. Moreover, this attenuation is effective on multiple oncogenic pathways. Such a broad spectrum counteracting role of a single agent on multiple oncogenic pathway activities has not been reported. It is well known that the development and progression of PCa involves the activation of oncogenic pathways. For example, mutations and alterations in expression pattern of beta-catenin have been detected in PCa samples and in some studies were correlated with Gleason grade [34, 35]. Another oncogene, ERBB2, was found overexpressed in PCa with an increasing incidence from localized to metastatic disease . ERBB2 may also play a role in the progression of PCa from androgen-dependent to -independent . Given the importance of these oncogenic pathways in PCa development and progression, an anti-oncogenic agent that counteracts multiple pathways may be an effective therapeutic drug against PCa.
Clorgyline also has a major effect on androgen signaling in E-CA cells by upregulating AR as well as classic AR target genes such as PSA and PSMA. The overall pattern of androgen-related gene expression changes in E-CA cells possibly reflects cell-specific activity. For example, clorgyline treatment of E-CA cells upregulated a set of androgen-induced genes at all three time points that were also upregulated by androgen in LNCaP cells in the study by DiPrimo et al. . Meanwhile, other sets of androgen-regulated genes were increased in LNCaP cells by androgen and decreased in E-CA cells by clorgyline, or vice versa. Similarly, comparison with another published list of genes regulated by androgen in LNCaP cells engineered to overexpress wild type AR (LNCaP-AR) revealed similarities and differences to responses of the parental LNCaP cells themselves as well as to E-CA cells . Cell-specific responses to hormones are well-documented and are due to a number of factors, including the repertoire of co-regulators available in each type of cell [38, 39].
Whether increased expression of AR and androgen signaling in a high grade primary adenocarcinoma would be clinically beneficial or detrimental is a subject of debate. On the one hand, androgen can promote prostatic differentiation . Classic androgen withdrawal and repletion experiments in rodents have suggested that androgen functions primarily to maintain the homeostasis of differentiated luminal epithelial cells [41, 42]. Recent molecular studies have shown that, in addition to the well-characterized androgen-regulated genes such as PSA, many additional androgen-regulated genes are predicted to be secreted proteins, or play a role in prostate secretory function . From this point of view, upregulation of androgen signaling may be anti-oncogenic by promoting differentiation of PCa cells. This idea is supported by the work of Berger et al. using immortalized and tumorigenic human prostatic epithelial cells, in which introduction of AR induced differentiation of these cells to a secretory phenotype reminiscent of organ-confined PCa . However, caution needs to be taken when drawing conclusions from these cell lines because the genetic makeup of these cells has been altered during establishment and long-term propagation, and AR was introduced exogenously. In contrast, our primary cultured cells are not genetically manipulated and will provide new insights into androgen-regulated differentiation in PCa.
On the other hand, AR-mediated androgen signaling may be oncogenic. For example, elevated AR expression is thought to contribute to the progression of PCa from androgen-sensitive to androgen-insensitive. Most so-called "androgen-insensitive" prostate cancers in fact retain high levels of AR expression  and PSA continues to be expressed . In PCa xenografts, an increase in AR mRNA and protein was both necessary and sufficient to convert growth from a hormone-sensitive to a hormone-refractory stage , while knocking down AR reduced cell growth in both androgen-sensitive and -insensitive cancer cells . Therefore, counteracting AR-mediated androgen signaling in PCa may prevent progression of the disease. Because clorgyline induced a subset of androgen-regulated genes while repressing others, it is possible that clorgyline counteracts androgen-mediated tumor proliferation while promoting tumor-repressing, androgen-mediated differentiation.
In conjunction with induction of AR, the quintessential marker of differentiated prostatic secretory epithelial cells, clorgyline induced other genes associated with secretory differentiation and repressed genes associated with a basal cell phenotype. Although preliminary, some evidence from this study suggests that induction of differentiation upon clorgyline treatment might be mediated through downregulation of EZH2. At 24 hr, EZH2 was significantly downregulated by clorgyline while genes known to be repressed by EZH2, such as ADRB2, were upregulated as determined by qRT-PCR. Moreover, a significant enrichment of genes repressed by the Polycomb protein complex (consisting of EZH2 and two other partners) in clorgyline-upregulated genes supports this possibility. Expression of this Polycomb repression signature is associated with poor prognosis in multiple PCa datasets , suggesting that clorgyline may improve patient outcome through upregulation of Polycomb protein complex repressed genes.
We identified two major effects of clorgyline in high grade PCa cells, namely anti-oncogenesis and pro-differentiation. Our results suggest novel therapeutic applications against PCa of antidepressant drugs that target MAO-A. Additional studies are needed to determine whether induction of differentiation and inhibition of oncogenic signaling pathways in high grade primary adenocarcinomas of the prostate would prevent progression to metastatic disease and death, and to investigate the expression and function of MAO-A in metastatic and/or androgen-refractory PCa.
human prostatic cancer cells
epidermal growth factor
monoamine oxidase A
prostate specific antigen
prostate specific membrane antigen
quantitative Real-Time Reverse Transcription Polymerase Chain Reaction
significance analysis of microarrays
Stanford Microarray Database
transforming growth factor
10 nM 1,25-dihydroxyvitamin D3, 1 μM all-trans retinoic acid, 1 ng/ml transforming growth factor (TGF)-β1, and 1 nM R1881
Dr. Zhao is supported by NCI 1 K01 CA123532, Dr. Flamand by Association Francaise d'Urologie (French Urology Association) Fellowship, and Dr. Peehl by NIH 1 R01 CA121460.
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