Dryhurst D.,University of Victoria |
Dryhurst D.,Immno Precise Antibodies Ltd. |
McMullen B.,University of Victoria |
Fazli L.,The Vancouver Prostate Center |
And 3 more authors.
Cancer Letters | Year: 2012
The histone variant H2A.Z is present at many eukaryotic gene regulatory regions and can affect rates of transcription. Here we show that total H2A.Z and an acetylated form of H2A.Z is mainly present at the prostate specific antigen (PSA) enhancer and promoter in prostate cancer cell lines where the gene is expressed, but the levels decrease during rapid cycles of transcription. Treatment of prostate cancer cells with androgen results in increased H2A.Z levels due to upregulation of the H2A.Z-1, but not the H2A.Z-2 gene. This upregulation is likely the result of increased MYC transcription factor binding that occurs in response to androgen at the H2A.Z-1 promoter. Furthermore, we show that in a LNCaP xenograft model of prostate cancer progression, there is a significant increase of H2A.Z protein in castration resistant LNCaP tumors resulting from increased expression of the H2A.Z-1 gene. While a similar trend was observed in samples from prostate cancer patients, the results were not statistically significant. Nevertheless, there may be a subset of prostate cancers where elevated expression of H2A.Z-1 is indicative of prostate cancer progression to androgen independence. © 2011 Elsevier Ireland Ltd.
PubMed | University of British Columbia, The Vancouver Prostate Center, Kyoto University, Stanford University and Peking University
Type: Journal Article | Journal: Gene therapy | Year: 2016
Urothelial bladder cancer is the most common malignancy of the urinary tract. Although most cases are initially diagnosed as non-muscle-invasive, more than 80% of patients will develop recurrent or metastatic tumors. No effective therapy exists currently for late-stage metastatic tumors. By intravesical application, local administration of oncolytic Herpes Simplex virus (oHSV-1) can provide a promising new therapy for this disease. However, its inherent neurotoxicity has been a perceived limitation for such application. In this study, we present a novel microRNA-regulatory approach to reduce HSV-1-induced neurotoxicity by suppressing viral replication in neurons while maintaining oncolytic selectivity toward urothelial tumors. Specifically, we designed a recombinant virus that utilizes differentially expressed endogenous microR143 (non-cancerous, ubiquitous) and microR124 (neural-specific) to regulate expression of ICP-4, a gene essential for HSV-1 replication. We found that expression of ICP-4 must be controlled by a combination of both miR143 and miR124 to achieve the most effective attenuation in HSV-1-induced toxicity while retaining maximal oncolytic capacity. These results suggest that interaction between miR143 and miR124 may be required to successfully regulate HSV-1 replication. Our resent study is the first proof-in-principle that miRNA combination can be exploited to fine-tune the replication of HSV-1 to treat human cancers.
PubMed | University of Texas M. D. Anderson Cancer Center, The Vancouver Prostate Center and University of Oslo
Type: Journal Article | Journal: EMBO molecular medicine | Year: 2015
The six transmembrane protein of prostate 2 (STAMP2) is an androgen-regulated gene whose mRNA expression is increased in prostate cancer (PCa). Here, we show that STAMP2 protein expression is increased in human PCa compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP2 significantly increased reactive oxygen species (ROS) in PCa cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP2 expression in PCa cells inhibited proliferation, colony formation, and anchorage-independent growth, and significantly increased apoptosis. Furthermore, STAMP2 effects were, at least in part, mediated by activating transcription factor 4 (ATF4), whose expression is regulated by ROS. Consistent with in vitro findings, silencing STAMP2 significantly inhibited PCa xenograft growth in mice. Finally, therapeutic silencing of STAMP2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in two established preclinical PCa models in mice. These data suggest that STAMP2 is required for PCa progression and thus may serve as a novel therapeutic target.
Choi S.Y.C.,BC Cancer Agency |
Gout P.W.,BC Cancer Agency |
Collins C.C.,University of British Columbia |
Collins C.C.,The Vancouver Prostate Center |
And 3 more authors.
Differentiation | Year: 2012
The immune system plays a key role in eliminating cancer cells in the body. However, even in fully immune-competent bodies cancers can evade anti-tumor immune action. There is increasing evidence that epithelial cancers can . actively suppress anti-tumor immune responses by creating an immune-suppressive micro-environment. It has been reported that epithelial cancers can express immune genes/proteins not normally expressed by their parental tissues, including a variety of cytokines/receptors, immune transcription factors and Ig motifs in cell surface molecules. Recently we observed increased expression of immune genes, including immune-suppressive genes, by prostate epithelial cancers. In view of the above, we propose that immune-suppressive activity of epithelial cancers may stem from their acquisition of immune properties via a transdifferentiation process, we term "Epithelial Immune Cell-like Transition" (EIT), similar to neuroendocrine-like transdifferentiation of prostate adenocarcinoma cells. We propose that the acquired immune properties enable the cancer cells to "communicate" with immune cells, leading to suppression of anti-cancer immune activity in their micro-environment and facilitation of the expansion and malignant progression of the disease. Acquired immune properties of epithelial cancers, which might be quite common, could provide novel targets for reducing cancer-generated immune-suppressive activity and enhancing anti-tumor immune activity. This proposed paradigm shift could lead to novel therapeutic approaches with improved efficacy and broad application. © 2012 .
Levina E.,University of South Carolina |
Ji H.,University of South Carolina |
Chen M.,University of South Carolina |
Baig M.,Albany Research Center |
And 10 more authors.
Oncotarget | Year: 2015
Prostate cancer progression to castration refractory disease is associated with anomalous transcriptional activity of the androgen receptor (AR) in an androgendepleted milieu. To identify novel gene products whose downregulation transactivates AR in prostate cancer cells, we performed a screen of enzymatically-generated shRNA lenti-libraries selecting for transduced LNCaP cells with elevated expression of a fluorescent reporter gene under the control of an AR-responsive promoter. The shRNAs present in selected populations were analyzed using high-throughput sequencing to identify target genes. Highly enriched gene targets were then validated with siRNAs against selected genes, testing first for increased expression of luciferase from an AR-responsive promoter and then for altered expression of endogenous androgenregulated genes in LNCaP cells. We identified 20 human genes whose silencing affected the expression of exogenous and endogenous androgen-responsive genes in prostate cancer cells grown in androgen-depleted medium. Knockdown of four of these genes upregulated the expression of endogenous AR targets and siRNAs targeting two of these genes (IGSF8 and RTN1) enabled androgen-independent proliferation of androgen-dependent cells. The effects of IGSF8 appear to be mediated through its interaction with a tetraspanin protein, CD9, previously implicated in prostate cancer progression. Remarkably, homozygous deletions of IGSF8 are found almost exclusively in prostate cancers but not in other cancer types. Our study shows that androgen independence can be achieved through the inhibition of specific genes and reveals a novel set of genes that regulate AR signaling in prostate cancers.
Seim I.,Queensland University of Technology |
Lubik A.A.,Queensland University of Technology |
Lubik A.A.,The Vancouver Prostate Center |
Lehman M.L.,Queensland University of Technology |
And 7 more authors.
Journal of Molecular Endocrinology | Year: 2013
Ghrelin is a multifunctional hormone, with roles in stimulating appetite and regulating energy balance, insulin secretion and glucose homoeostasis. The ghrelin gene locus (GHRL) is highly complex and gives rise to a range of novel transcripts derived from alternative first exons and internally spliced exons. The wild-type transcript encodes a 117 amino acid preprohormone that is processed to yield the 28 amino acid peptide ghrelin. Here, we identified insulin-responsive transcription corresponding to cryptic exons in intron 2 of the human ghrelin gene. A transcript, termed in2c-ghrelin (intron 2-cryptic), was cloned from the testis and the LNCaP prostate cancer cell line. This transcript may encode an 83 amino acid preproghrelin isoform that codes for ghrelin, but not obestatin. It is expressed in a limited number of normal tissues and in tumours of the prostate, testis, breast and ovary. Finally, we confirmed that in2c-ghrelin transcript expression, as well as the recently described in1-ghrelin transcript, is significantly upregulated by insulin in cultured prostate cancer cells. Metabolic syndrome and hyperinsulinaemia have been associated with prostate cancer risk and progression. This may be particularly significant after androgen deprivation therapy for prostate cancer, which induces hyperinsulinaemia, and this could contribute to castrate-resistant prostate cancer growth. We have previously demonstrated that ghrelin stimulates prostate cancer cell line proliferation in vitro. This study is the first description of insulin regulation of a ghrelin transcript in cancer and should provide further impetus for studies into the expression, regulation and function of ghrelin gene products. © 2013 Society for Endocrinology Printed in Great Britain.
Nakamura H.,British Columbia Cancer Agency |
Nakamura H.,The Vancouver Prostate Center |
Wang Y.,British Columbia Cancer Agency |
Kurita T.,Northwestern University |
And 4 more authors.
PLoS ONE | Year: 2011
Genistein is an isoflavone found in soy, and its chemo-preventive and -therapeutic effects have been well established from in vitro studies. Recently, however, its therapeutic actions in vivo have been questioned due to contradictory reports from animal studies, which rely on rodent models or implantation of cell lines into animals. To clarify in vivo effects of genistein in advanced prostate cancer patients, we developed a patient-derived prostate cancer xenograft model, in which a clinical prostatectomy sample was grafted into immune deficient mice. Our results showed an increased lymph node (LN) and secondary organ metastases in genistein-treated mice compared to untreated controls. Interestingly, invasive malignant cells aggregated to form islands/micrometastasis only in the secondary organs of the genistein-treated groups, not in the untreated control group. To understand the underlying mechanism for metastatic progression, we examined cell proliferation and apoptosis on paraffin-sections. Immunohistological data show that tumors of genistein-treated groups have more proliferating and fewer apoptotic cancer cells than those of the untreated group. Our immunoblotting data suggest that increased proliferation and metastasis are linked to enhanced activities of tyrosine kinases, EGFR and its downstream Src, in genistein-treated groups. Despite the chemopreventive effects proposed by earlier in vitro studies, the cancer promoting effect of genistein observed here suggests the need for careful selection of patients and safer planning of clinical trials. © 2011 Nakamura et al.
Mugabe C.,University of British Columbia |
Raven P.A.,The Vancouver Prostate Center |
Fazli L.,The Vancouver Prostate Center |
Baker J.H.E.,British Columbia Cancer Research Center |
And 9 more authors.
Biomaterials | Year: 2012
Recently, we have reported that docetaxel (DTX) loaded, amine terminated hyperbranched polyglycerol (HPG-C8/10-MePEG-NH2) nanoparticles significantly increased drug uptake in mouse bladder tissues and was the most effective formulation to significantly inhibit tumor growth in an orthotopic model of bladder cancer. The objective of this study was to investigate the effects of HPG-C8/10-MePEG-NH2 nanoparticles on bladder urothelial morphology and integrity, DTX uptake and permeability in bladder tissue and the extent of bladder urothelial recovery following exposure to, and then washout of, HPG-C8/10-MePEG-NH2 nanoparticles. HPG-C8/10-MePEG-NH2 nanoparticles significantly increased the uptake of DTX in both isolated pig bladder as well as in live mouse bladder tissues. Furthermore, HPG-C8/10-MePEG-NH2 nanoparticles were demonstrated to increase the permeability of the urinary bladder wall by causing changes to the urothelial barrier function and morphology through opening of tight junctions and exfoliation of the superficial umbrella cells. These data suggest that exfoliation may be triggered by an apoptosis mechanism, which was followed by a rapid recovery of the urothelium within 24 h post-instillation of HPG-C8/10-MePEG-NH2 nanoparticles. HPG-C8/10-MePEG-NH2 nanoparticles cause significant but rapidly recoverable changes in the bladder urothelial morphology, which we believe may make them suitable for increasing drug permeability of bladder tissue and intravesical drug delivery. © 2011 Elsevier Ltd.
PubMed | Indiana University, The Vancouver Prostate Center, University of Wisconsin - Madison, Goethe University Frankfurt and Purdue University
Type: Journal Article | Journal: Molecular and cellular biology | Year: 2015
The Wnt/-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the -catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in several in vivo studies. Here, we show that Plk1 is a negative regulator of Wnt/-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear -catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/-catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the -catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of -catenin by enhancing binding between glycogen synthase kinase 3 (GSK3) and -catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC.
PubMed | The Vancouver Prostate Center and British Columbia Cancer Agency
Type: Journal Article | Journal: Nature reviews. Urology | Year: 2015
The survival of malignant cells is constantly threatened by a myriad of cellular insults. In the context of such proteotoxic stress, cancer cells activate cytoprotective adaptive pathways. Heat shock proteins (HSPs) are highly conserved molecular chaperones that are expressed at low levels under normal conditions, but upregulated by cellular stress. As molecular chaperones, HSPs control the stability and function of client proteins, preventing aggregation of misfolded proteins, facilitating intracellular protein trafficking, maintaining protein conformation to enable ligand binding, phosphorylating proteins in signalling complexes and degrading severely damaged proteins via the ubiquitin-proteasome pathway. A key client protein of several HSPs is the androgen receptor (AR). HSPs facilitate binding of dihydrotestosterone to the AR, and enhance AR-mediated transcriptional activity. The integral role of HSPs in AR function speaks to their potential utility as therapeutic targets in castration-resistant prostate cancer (CRPC), a disease state characterized by persistent activation of the androgen-AR axis. Inhibition of HSPs has the additional benefit of potentially modulating signalling and transcriptional networks that are associated with HSP client proteins in CRPC cells. As a consequence, HSPs represent highly attractive targets in the development of treatments for CRPC.