The role of mesenchymal stem cells in promoting the transformation of androgen-dependent human prostate cancer cells into androgen-independent manner.
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ABSTRACT:
SUBMITTER: Cheng J
PROVIDER: S-EPMC4726385 | biostudies-other | 2016 Jan
REPOSITORIES: biostudies-other
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Project description:BackgroundCastration-resistant prostate cancer (CRPC) is still considered incurable, even though the mechanisms of CRPC had been extensively researched. Studies have demonstrated that exosomes in the tumor microenvironment contribute to prostate cancer development and progression. However, the role of exosomes in the process of CRPC progression has not yet been determined.MethodsCo-culturing and exosome treatment assays combined with in vitro and in vivo assays were performed to determine the function of exosomes in the transformation of androgen-dependent prostate cancer (ADPC) cells into androgen-independent cells. Then, the mRNA expression profiles of ADPC cells and ADPC cells co-cultured with androgen-independent prostate cancer (AIPC) cell-derived exosomes were studied using microarrays. After silencing the expression of heme oxygenase-1 (HMOX1), Western blotting, quantitative real-time PCR, immunohistochemistry (IHC) studies, and MTS assay were used to confirm the mechanisms of exosome participation in CRPC progression.ResultsThe results showed that ADPC cells acquired tolerance for androgen deprivation due to the exosome-mediated communication between cells. AIPC cell-derived exosomes promoted the transformation of ADPC cells into androgen-independent cells in vivo and in vitro. Microarray analysis revealed that HMOX1 in ADPC cells was up-regulated after treatment with AIPC cell-derived exosomes. Further results showed that HMOX1 is overexpressed in human AIPC specimens and protects ADPC cells from androgen deprivation.ConclusionsOur findings revealed that exosomes contribute to CRPC progression via promoting the transition of prostate cancer cells into an androgen-independent growth stage by activating HMOX1.
| S-EPMC7811443 | biostudies-literature
Project description:The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. In AR-positive PCa cells, C-1311 was found to inhibit the transcriptional activity of AR, uncovering a novel mechanism that may be relevant for its anticancer effect. Mechanistically, C-1311 decreased the AR binding to the prostate-specific antigen (PSA) promoter, reduced the PSA protein level, and, as shown by transcriptome sequencing, downregulated numerous AR target genes. Importantly, AR-negative PCa cells were also sensitive to C-1311, suggesting a promising efficacy in the androgen-independent PCa sub-type. Irrespective of AR status, C-1311 induced DNA damage, arrested cell cycle progression, and induced apoptosis. RNA sequencing indicated significant differences in the transcriptional response to C-1311 between the PCa cells. Gene ontology analysis showed that in AR-dependent PCa cells, C-1311 mainly affected the DNA damage response pathways. In contrast, in AR-independent PCa cells, C-1311 targeted the cellular metabolism and inhibited the genes regulating glycolysis and gluconeogenesis. Together, these results indicate that C-1311 warrants further development for the treatment of PCa.
| S-EPMC7555468 | biostudies-literature
Project description:Mesenchymal stem cells (MSCs) are, due to their immunomodulatory characteristics, utilized in therapy of immune-mediated diseases. We used murine model of cisplatin nephrotoxicity to explore the effects of MSCs on immune cells involved in the pathogenesis of this disease. Intraperitoneal application of MSCs significantly attenuated cisplatin nephrotoxicity, decreased inflammatory cytokines TNF-α and IL-17, and increased anti-inflammatory IL-10, IL-6, nitric oxide (NO), and kynurenine in sera of cisplatin-treated mice. MSC treatment significantly attenuated influx of leukocytes, macrophages, dendritic cells (DCs), neutrophils, CD4+ T helper (Th), and CD8+ cytotoxic T lymphocytes (CTLs) in damaged kidneys and attenuated the capacity of renal-infiltrated DCs, CD4+ Th, and CD8+ CTLs to produce TNF-α and IL-17. Similar effects were observed after intraperitoneal injection of MSC-conditioned medium (MSC-CM) indicating that MSCs exert their beneficial effects in paracrine manner. Inhibition of inducible nitric oxide synthase (iNOS) in MSC-CM resulted with increased number of TNF-α-producing DCs and IL-17-producing CTLs, decreased number of IL-10-producing tolerogenic DCs and regulatory CD4+FoxP3+ T cells, and completely diminished renoprotective effects of MSC-CM. In conclusion, MSCs, in iNOS-dependent manner, attenuated inflammation in cisplatin nephrotoxicity by reducing the influx and capacity of immune cells, particularly DCs and T lymphocytes, to produce inflammatory cytokines.
| S-EPMC5554561 | biostudies-other
Project description:BACKGROUND: Prostate cancer is one of the leading causes of cancer death in men. Androgen ablation, the most commonly-used therapy for progressive prostate cancer, is ineffective once the cancer cells become androgen-independent. The regulatory mechanisms that cause this transition (from androgen-dependent to androgen-independent) remain unknown. In this study, based on the microarray data comparing global gene expression patterns in the prostate tissue between androgen-dependent and -independent prostate cancer patients, we identify a set of transcription factors and microRNAs that potentially cause such difference, using a model-based computational approach. RESULTS: From 335 position weight matrices in the TRANSFAC database and 564 microRNAs in the microRNA registry, our model identify 5 transcription factors and 7 microRNAs to be potentially responsible for the level of androgen dependency. Of these transcription factors and microRNAs, the estimated function of all the 5 transcription factors are predicted to be inhibiting transcription in androgen-independent samples comparing with the dependent ones. Six out of 7 microRNAs, however, demonstrated stimulatory effects. We also find that the expression levels of three predicted transcription factors, including AP-1, STAT3 (signal transducers and activators of transcription 3), and DBP (albumin D-box) are significantly different between androgen-dependent and -independent patients. In addition, microRNA microarray data from other studies confirm that several predicted microRNAs, including miR-21, miR-135a, and miR-135b, demonstrate differential expression in prostate cancer cells, comparing with normal tissues. CONCLUSION: We present a model-based computational approach to identify transcription factors and microRNAs influencing the progression of androgen-dependent prostate cancer to androgen-independent prostate cancer. This result suggests that the capability of transcription factors to initiate transcription and microRNAs to facilitate mRNA degradation are both decreased in androgen-independent prostate cancer. The proposed model-based approach indicates that considering combinatorial effects of transcription factors and microRNAs in a unified model provides additional transcriptional and post-transcriptional regulatory mechanisms on global gene expression in the prostate cancer with different hormone-dependency.
| S-EPMC2559887 | biostudies-literature
Project description:PurposeIncreased murine double minute 2 (MDM2) expression, independent of p53 status, is associated with increased cancer-specific mortality for men with prostate cancer treated with radiotherapy. We assessed MI-219, a small molecule inhibitor of MDM2 with improved pharmacokinetics over nutlin-3, for sensitization of prostate cancer cells to radiotherapy and androgen deprivation therapy, a standard treatment option for men with high-risk prostate cancer.Experimental designThe effect of MDM2 inhibition by MI-219 was assessed in vitro and in vivo with mouse xenograft models across multiple prostate cancer cell lines containing varying p53 functional status.ResultsMDM2 inhibition by MI-219 resulted in dose- and time-dependent p53 activation and decreased clonogenic cell survival after radiation in a p53-dependent manner. Mechanistically, radiosensitization following inhibition of MDM2 was largely the result of p53-dependent increases in apoptosis and DNA damage as evidenced by Annexin V flow cytometry and ?-H2AX foci immunofluorescence. Similarly, treatment with MI-219 enhanced response to antiandrogen therapy via a p53-dependent increase in apoptotic cell death. Lastly, triple therapy with radiation, androgen deprivation therapy, and MI-219 decreased xenograft tumor growth compared with any single- or double-agent treatment.ConclusionMDM2 inhibition with MI-219 results in p53-dependent sensitization of prostate cancer cells to radiation, antiandrogen therapy, and the combination. These findings support MDM2 small molecule inhibitor therapy as a therapy intensification strategy to improve clinical outcomes in high-risk localized prostate cancer.Translational relevanceThe combination of radiotherapy and androgen deprivation therapy is a standard treatment option for men with high-risk prostate cancer. Despite improvements in outcomes when androgen deprivation therapy is added to radiation, men with high-risk prostate cancer have significant risk for disease recurrence, progression, and even death within the first 10 years following treatment. We demonstrate that treatment with MI-219 (an inhibitor of MDM2) results in prostate cancer cell sensitization to radiation and androgen deprivation therapy in vitro and in vivo. Triple therapy with MI-219, radiation, and androgen deprivation therapy dramatically decreased tumor growth compared with any single- or double-agent therapy. These findings provide evidence that inhibition of MDM2 is a viable means by which to enhance the efficacy of both radiation and androgen deprivation therapy and thereby improve outcomes in the treatment of prostate cancer. As such, further investigation is warranted to translate these findings to the clinical setting.
| S-EPMC4840291 | biostudies-literature
Project description:BackgroundCastration-resistant prostate cancer (CRPC), one of the prostate cancers, is a medical conundrum around the world. Some studies have demonstrated that many long noncoding RNAs in exosomes are very important in many types of cancer, including prostate cancer. However, until now, the function of exosomes in the occurrence and development of CRPC has not been reported.MethodsIn vitro, cell coculture was used in LNCap cells and PC-3 cells, while the isolation and purification of exosomes and the subsequent treatment assays were used in functional studies. In vitro assays were performed to detect the transformation of ADPC cells (androgen-dependent prostate cancer) into AIPC cells (androgen-independent prostate cancer). Subsequently, a lncRNA-sequencing assay was performed to detect different lncRNA expression profiles in ADPC cells cocultured with or without AIPC exosomes. The role of LINC01213 was analysed by a TCGA database after silencing the expression of LINC01213. CCK-8, qRT-PCR, and Western blotting studies were performed to analyse the possible mechanism by which exosomes participate in prostate cancer progression.ResultsIn the coculture system, ADPC cells acquired androgen deprivation tolerance through exosome-mediated intercellular communication. Exosomes secreted by AIPC cells can promote the transformation of ADPC cells into androgen-independent cells in vitro and in vivo. lncRNA sequencing showed that LINC01213 was upregulated in exosomes derived from AIPC cell lines. The rescue experiments were preformed, and the results revealed that most of the functions of LINC01213 were performed by Wnt/β-catenin.ConclusionsAll the findings showed that exosomes play a key role in CRPC progression by upregulating LINC01213 and activating Wnt/β-catenin signalling.
| S-EPMC8930242 | biostudies-literature
Project description:Prostate cancer (PCa) is the most commonly diagnosed cancer among men in western countries. Androgen receptor (AR) signaling plays key roles in the development of PCa. Androgen deprivation therapy (ADT) remains the standard therapy for advanced PCa. In addition to its ligand androgen, accumulating evidence indicates that posttranscriptional modification is another important mechanism to regulate AR activities during the progression of PCa, especially in castration resistant prostate cancer (CRPC). To date, a number of posttranscriptional modifications of AR have been identified, including phosphorylation (e.g. by CDK1), acetylation (e.g. by p300 and recognized by BRD4), methylation (e.g. by EZH2), ubiquitination (e.g. by SPOP), and SUMOylation (e.g. by PIAS1). These modifications are essential for the maintenance of protein stability, nuclear localization and transcriptional activity of AR. This review summarizes posttranslational modifications that influence androgen-dependent and -independent activities of AR, PCa progression and therapy resistance. We further emphasize that in addition to androgen, posttranslational modification is another important way to regulate AR activity, suggesting that targeting AR posttranslational modifications, such as proteolysis targeting chimeras (PROTACs) of AR, represents a potential and promising alternate for effective treatment of CRPC. Potential areas to be investigated in the future in the field of AR posttranslational modifications are also discussed.
| S-EPMC7525085 | biostudies-literature
Project description:BackgroundCastration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells.ResultsTreatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates.ConclusionsCollectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.
| S-EPMC2873440 | biostudies-literature
Project description:BackgroundClooxygenase-2 (COX-2) expression is overexpressed in human prostate cancer, and aberrant methylation of the COX-2 promoter has also been elucidated. However, how the methylation of CpG islands at COX-2 regulates its expression in prostate cancer is still unclear. We will determine the methylated 5' CpG island of the COX-2 gene and its role in the expression of COX-2 in prostate androgen-dependent and androgen-independent cancer cells, LNCaP and DU145.MethodsWe used western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to confirm the COX-2 expression in prostate cancer cell lines, including LNCaP (androgen-dependent) and DU145 (androgen-independent) cells. To investigate whether the COX-2 expression was regulated by the methylation status of the 5' CpG island, we treated LNCaP and DU145 cells with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine, and determined COX-2 expression in the treated/untreated cells by western blotting and qRT-PCR. Subsequently, bisulfite sequencing was performed to study the methylation sites in the treated/untreated cells. The effects of 5-aza-2'-deoxycytidine to cell proliferation, cell migration and cell cycle process in DU145 and LNCaP cells were determined using Cell Counting Kit-8 (CCK-8) assay, transwell assay and flow cytometry, respectively.ResultsThe results revealed that the expression of COX-2 in androgen-dependent LNCaP cells was 5.44-fold (in protein level) and 2.46-fold (in mRNA level) higher than that in androgen-independent DU145 cells. After 5-aza-2'-deoxycytidine treatment, COX-2 expression in DU145 cells was elevated significantly, but no change was found in LNCaP cells. The A and C regions of the COX-2 CpG island exhibited reduced methylation along with that an increased expression of COX-2 was noted in DU145 cell after 5-aza-2'-deoxycytidine treatment. Also, the treatment with 5-aza-2'-deoxycytidine inhibited cell proliferation, cell migration and influenced the cell cycle progression in both DU145 and LNCaP cells.ConclusionsOur results reveal that androgen receptor (AR)-dependent/independent prostate cancer cell lines exhibit different regulation of methylation in COX-2 that regulate its expression. Additionally, 5-aza-2'-deoxycytidine treatment of DU145 and LNCaP cells inhibits their ability of tumor progression.
| S-EPMC9239499 | biostudies-literature
Project description:Previously, we have developed a unique in vitro LNCaP cell model, which includes androgen-dependent (LNCaP-C33), androgen-independent (LNCaP-C81) and an intermediate phenotype (LNCaP-C51) cell lines resembling the stages of prostate cancer progression to hormone independence. This model is advantageous in overcoming the heterogeneity associated with the prostate cancer up to a certain extent. We characterized and compared the gene expression profiles in LNCaP-C33 (androgen-dependent) and LNCaP-C81 (androgen-independent) cells using Affymetrix GeneChip array analyses. Multiple genes were identified exhibiting differential expression during androgen-independent progression. Among the important genes upregulated in androgen-independent cells were PCDH7, TPTE, TSPY, EPHA3, HGF, MET, EGF, TEM8, etc., whereas many candidate tumor suppressor genes (HTATIP2, CDKN2A, CDKN2B, CDKN1C, TP53, TP73, ICAM1, SOCS1/2, SPRY2, PPP2CA, PPP3CA, etc.) were decreased. Pathway prediction analysis identified important gene networks associated with growth-promoting and apoptotic signaling that were perturbed during androgen-independent progression. Further investigation of one of the genes, PPP2CA, which encodes the catalytic subunit of a serine phosphatase PP2A, a potent tumor suppressor, revealed that its expression was decreased in prostate cancer compared to adjacent normal/benign tissue. Furthermore, the downregulated expression of PPP2CA was significantly correlated with tumor stage and Gleason grade. Future studies on the identified differentially expressed genes and signaling pathways may be helpful in understanding the biology of prostate cancer progression and prove useful in developing novel prognostic biomarkers and therapy for androgen-refractory prostate cancer.
| S-EPMC2784916 | biostudies-literature