scholarly journals MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
En-Chi Hsu ◽  
Michelle Shen ◽  
Merve Aslan ◽  
Shiqin Liu ◽  
Manoj Kumar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
De Novo ◽  
Treatment Resistance ◽  
Dna Helicase ◽  
Tumor Xenograft ◽  
Primary Tumors ◽  
Neuroendocrine Prostate Cancer ◽  
And Migration

AbstractNeuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.

scholarly journals Circulating tumor cell heterogeneity in neuroendocrine prostate cancer by single cell copy number analysis

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Vincenza Conteduca ◽  
Sheng-Yu Ku ◽  
Luisa Fernandez ◽  
Angel Dago-Rodriquez ◽  
Jerry Lee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Cell ◽  
De Novo ◽  
Genomic Analysis ◽  
Treatment Resistance ◽  
Circulating Tumor Cell ◽  
Prostate Adenocarcinoma ◽  
Neuroendocrine Prostate Cancer ◽  
Patient Heterogeneity ◽  
Tumor Cell Heterogeneity

AbstractNeuroendocrine prostate cancer is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. The combined loss of tumor suppressors RB1, TP53, and PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with a phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer.

scholarly journals Conditionally Reprogrammed Cells from Patient-Derived Xenograft to Model Neuroendocrine Prostate Cancer Development

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1398 ◽  
Author(s):  
Xinpei Ci ◽  
Jun Hao ◽  
Xin Dong ◽  
Hui Xue ◽  
Rebecca Wu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ex Vivo ◽  
Cancer Cell Line ◽  
Marker Genes ◽  
Patient Derived Xenograft ◽  
Pdx Model ◽  
Neuroendocrine Prostate Cancer ◽  
Parental Tumor

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. It develops mainly via NE transdifferentiation of prostate adenocarcinoma in response to androgen receptor (AR)-inhibition therapy. The study of NEPC development has been hampered by a lack of clinically relevant models. We previously established a unique and first-in-field patient-derived xenograft (PDX) model of adenocarcinoma (LTL331)-to-NEPC (LTL331R) transdifferentiation. In this study, we applied conditional reprogramming (CR) culture to establish a LTL331 PDX-derived cancer cell line named LTL331_CR_Cell. These cells retain the same genomic mutations as the LTL331 parental tumor. They can be continuously propagated in vitro and can be genetically manipulated. Androgen deprivation treatment on LTL331_CR_Cells had no effect on cell proliferation. Transcriptomic analyses comparing the LTL331_CR_Cell to its parental tumor revealed a profound downregulation of the androgen response pathway and an upregulation of stem and basal cell marker genes. The transcriptome of LTL331_CR_Cells partially resembles that of post-castrated LTL331 xenografts in mice. Notably, when grafted under the renal capsules of male NOD/SCID mice, LTL331_CR_Cells spontaneously gave rise to NEPC tumors. This is evidenced by the histological expression of the NE marker CD56 and the loss of adenocarcinoma markers such as PSA. Transcriptomic analyses of the newly developed NEPC tumors further demonstrate marked enrichment of NEPC signature genes and loss of AR signaling genes. This study provides a novel research tool derived from a unique PDX model. It allows for the investigation of mechanisms underlying NEPC development by enabling gene manipulations ex vivo and subsequent functional evaluations in vivo.

scholarly journals YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiangfeng Li ◽  
Haiyun Xie ◽  
Yufan Ying ◽  
Hong Chen ◽  
Huaqing Yan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressors ◽  
Mrna Degradation ◽  
Akt Phosphorylation ◽  
Knock Down ◽  
Phosphorylated Akt ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background N6-methyladenosine (m6A) is the most abundant modification in mRNA of humans. Emerging evidence has supported the fact that m6A is comprehensively involved in various diseases especially cancers. As a crucial reader, YTHDF2 usually mediates the degradation of m6A-modified mRNAs in m6A-dependent way. However, the function and mechanisms of m6A especially YTHDF2 in prostate cancer (PCa) still remain elusive. Methods To investigate the functions and mechanisms of YTHDF2 in PCa, in vitro, in vivo biofunctional assays and epigenetics experiments were performed. Endogenous expression silencing of YTHDF2 and METTL3 was established with lentivirus-based shRNA technique. Colony formation, flow cytometry and trans-well assays were performed for cell function identifications. Subcutaneous xenografts and metastatic mice models were combined with in vivo imaging system to investigate the phenotypes when knocking down YTHDF2 and METTL3. m6A RNA immunoprecipitation (MeRIP) sequencing, mRNA sequencing, RIP-RT-qPCR and bioinformatics analysis were mainly used to screen and validate the direct common targets of YTHDF2 and METTL3. In addition, TCGA database was also used to analyze the expression pattern of YTHDF2, METTL3 and the common target LHPP in PCa, and their correlation with clinical prognosis. Results The upregulated YTHDF2 and METTL3 in PCa predicted a worse overall survival rate. Knocking down YTHDF2 or METTL3 markedly inhibited the proliferation and migration of PCa in vivo and in vitro. LHPP and NKX3–1 were identified as the direct targets of both YTHDF2 and METTL3. YTHDF2 directly bound to the m6A modification sites of LHPP and NKX3–1 to mediate the mRNA degradation. Knock-down of YTHDF2 or METTL3 significantly induced the expression of LHPP and NKX3–1 at both mRNA and protein level with inhibited phosphorylated AKT. Overexpression of LHPP and NKX3–1 presented the consistent phenotypes and AKT phosphorylation inhibition with knock-down of YTHDF2 or METTL3. Phosphorylated AKT was consequently confirmed as the downstream of METTL3/YTHDF2/LHPP/NKX3–1 to induce tumor proliferation and migration. Conclusion We propose a novel regulatory mechanism in which YTHDF2 mediates the mRNA degradation of the tumor suppressors LHPP and NKX3–1 in m6A-dependent way to regulate AKT phosphorylation-induced tumor progression in prostate cancer. We hope our findings may provide new concepts of PCa biology.

scholarly journals MTA1-Dependent Anticancer Activity of Gnetin C in Prostate Cancer

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2096 ◽  
Author(s):  
Avinash Kumar ◽  
Kshiti Dholakia ◽  
Gabriela Sikorska ◽  
Luis A. Martinez ◽  
Anait S. Levenson
Keyword(s):  
Prostate Cancer ◽  
Intraepithelial Neoplasia ◽  
Inhibitory Effect ◽  
Tumor Aggressiveness ◽  
Therapeutic Approaches ◽  
Anticancer Efficacy ◽  
Anticancer Effects ◽  
And Migration

The overexpression of metastasis-associated protein 1 (MTA1) in prostate cancer (PCa) contributes to tumor aggressiveness and metastasis. We have reported the inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of prostatic intraepithelial neoplasia and adenocarcinoma in mouse models by inhibiting MTA1 expression and signaling. In the current study, we investigated the MTA1 targeted anticancer effects of Gnetin C, a resveratrol dimer, in comparison with resveratrol and pterostilbene. Using DU145 and PC3M PCa cells, we found that Gnetin C downregulates MTA1 more potently than resveratrol and pterostilbene. Further, Gnetin C demonstrated significant MTA1-mediated inhibitory effect on cell viability, colony formation, and migration, while showing a more potent induction of cell death than resveratrol or pterostilbene. In addition, we identified Gnetin C-induced substantial ETS2 (erythroblastosis E26 transformation-specific 2) downregulation, which is not only MTA1-dependent, but is also independent of MTA1 as a possible mechanism for the superior anticancer efficacy of Gnetin C in PCa. Together, these findings underscore the importance of novel potent resveratrol dimer, Gnetin C, as a clinically promising agent for the future development of chemopreventive and possibly combinatorial therapeutic approaches in PCa.

scholarly journals TRIM59 is Suppressed by Androgen Receptor and Acts to Promote Lineage Plasticity and Neuroendocrine Differentiation in Prostate Cancer

2021 ◽  
Author(s):  
Liancheng Fan ◽  
Yiming Gong ◽  
Yuman He ◽  
Wei-Qiang Gao ◽  
Baijun Dong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Neuroendocrine Differentiation ◽  
Tumor Model ◽  
Strongly Correlated ◽  
Neuroendocrine Prostate Cancer ◽  
In Vitro Effects

Abstract Background: The incidence of treatment-induced neuroendocrine prostate cancer (t-NEPC) has been greatly increasing after the usage of second-generation androgen receptor (AR) pathway inhibitors (ARPIs). Neuroendocrine differentiation (NED) is closely associated with ARPI treatment failure and poor prognosis in prostate cancer (PCa) patients. However, the molecular mechanisms of NED are not fully understood. Methods: TRIM59 expression was evaluated in PCa samples from patients at first diagnosis or at relapse stage post ARPI treatment by immunohistochemistry; in vitro effects of TRIM59 were determined by cell proliferation, sphere formation and cell migration assays; while in vivo analysis was performed using subcutaneous tumor model. Western blot, qPCR assay, dual luciferase assessment, chromatin immunoprecipitation and RNA sequencing were applied for mechanistic exploration.Results: Here we report that upregulation of TRIM59, a TRIM family protein, is strongly correlated with ARPI treatment mediated NED and shorter patient survival in PCas. AR binds to TRIM59 promoter and represses its transcription. ARPI treatment leads to a reversal of repressive epigenetic modifications on TRIM59 gene and the transcriptional restraint on TRIM59 by AR. Upregulated TRIM59 then drives the NED of PCa by enhancing the degradation of RB1 and P53 and upregulating downstream lineage plasticity-promoting transcription factor SOX2. Conclusion: Altogether, TRIM59 is negatively regulated by AR and acts as a key driver for NED in PCas. Our study provides a novel prognostic marker for PCas and shed new light on the molecular pathogenesis of t-NEPC, a deadly variant of PCa.

scholarly journals LncRNA SNHG20 promotes migration and invasion of ovarian cancer via modulating the microRNA-148a/ROCK1 axis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Qi Yang ◽  
Yu-Jie Dong
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Noncoding Rna ◽  
Tumor Xenograft ◽  
Migration And Invasion ◽  
Epithelial Cell Line ◽  
Invasion And Migration ◽  
And Migration

Abstract Background Ovarian cancer (OC) is characterized by early metastasis and poor prognosis, which threatens the health of women worldwide. Small nucleolar RNA host gene 20 (SNHG20), a long noncoding RNA (lncRNA), has been verified to be significantly up-regulated in several tumors, including OC. MicroRNA-148a (miR-148a)/rho-kinase1 (ROCK1) axis plays an important role in the modulation of tumor development. However, whether SNHG20 can regulate OC progression through miR-148a/ROCK1 axis remains unclear. Normal human ovarian epithelial cell line and four OC cell lines were adopted for in vitro experiments. Real-time PCR was performed to assess the levels of SNHG20 and miR-148a. OC cell proliferation, apoptosis, invasion and migration were detected using clone formation, flow cytometry, transwell, and wound healing assays, respectively. Tumor xenograft assay was applied to evaluate the effect of SNHG20 on tumor growth in vivo. Results Significant higher expression of SNHG20 was observed in OC cell lines. SNHG20 markedly promoted the invasion, migration, proliferation and inhibited the apoptosis of OC cells. SNHG20 enhanced ROCK1 expression by sponging miR-148a, and the direct binding between SNHG20/ROCK1 and miR-148a was identified. Conclusion SNHG20 promoted invasion and migration of OC via targeting miR-148a/ROCK1 axis. The present research may provide a novel insight for the therapeutic strategies of OC.

scholarly journals Simultaneous Multi-Organ Metastases from Chemo-Resistant Triple-Negative Breast Cancer Are Prevented by Interfering with WNT-Signaling

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2039 ◽  
Author(s):  
Iram Fatima ◽  
Ikbale El-Ayachi ◽  
Hilaire C. Playa ◽  
Jackelyn A. Alva-Ornelas ◽  
Aysha B. Khalid ◽  
...  
Keyword(s):  
Cell Lines ◽  
Triple Negative ◽  
De Novo ◽  
Tumor Model ◽  
Model Systems ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Multiple Organs

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of multiple TNBC cell lines and TNBC patient-derived xenograft (PDX)-derived cell lines. In vitro, ICG-001 was effective in combination with the conventional cytotoxic chemotherapeutics, cisplatin and doxorubicin, to decrease the proliferation of MDA-MB-231 cells. In contrast, in TNBC PDX-derived cells doxorubicin plus ICG-001 was synergistic, while pairing with cisplatin was not as effective. Mechanistically, cytotoxicity induced by doxorubicin, but not cisplatin, with ICG-001 was associated with increased cleavage of PARP-1 in the PDX cells only. In vivo, MDA-MB-231 and TNBC PDX orthotopic primary tumors initiated de novo simultaneous multi-organ metastases, including bone metastases. WNT monotherapy blocked multi-organ metastases as measured by luciferase imaging and histology. The loss of expression of the WNT10B/β-catenin direct targets HMGA2, EZH2, AXIN2, MYC, PCNA, CCND1, transcriptionally active β-catenin, SNAIL and vimentin both in vitro and in vivo in the primary tumors mechanistically explains loss of multi-organ metastases. WNT monotherapy induced VEGFA expression in both tumor model systems, whereas increased CD31 was observed only in the MDA-MB-231 tumors. Moreover, WNT-inhibition sensitized the anticancer response of the TNBC PDX model to doxorubicin, preventing simultaneous metastases to the liver and ovaries, as well as to bone. Our data demonstrate that WNT-inhibition sensitizes TNBC to anthracyclines and treats multi-organ metastases of TNBC.

scholarly journals Double-Edged Lipid Nanoparticles Combining Liposome-Bound TRAIL and Encapsulated Doxorubicin Showing an Extraordinary Synergistic Pro-Apoptotic Potential

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1948 ◽  
Author(s):  
Diego De Miguel ◽  
Ana Gallego-Lleyda ◽  
Miguel Martinez-Ara ◽  
Javier Plou ◽  
Alberto Anel ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Molecular Mechanisms ◽  
Xenograft Model ◽  
Carcinoma Cells ◽  
Tumor Xenograft ◽  
Cytotoxic Potential ◽  
Primary Tumors ◽  
Soluble Trail

Although TRAIL (TNF-related apoptosis-inducing ligand, also known as Apo2L) was described as capable of inducing apoptosis in transformed cells while sparing normal cells, limited results obtained in clinical trials has limited its use as an anti-tumor agent. Consequently, novel TRAIL formulations with enhanced bioactivity are necessary for overcoming resistance to conventional soluble TRAIL (sTRAIL) exhibited by many primary tumors. Our group has generated artificial liposomes with sTRAIL anchored on their surface (large unilamellar vesicle (LUV)-TRAIL), which have shown a greater cytotoxic activity both in vitro and in vivo when compared to sTRAIL against distinct hematologic and epithelial carcinoma cells. In this study, we have improved LUV-TRAIL by loading doxorubicin (DOX) in its liposomal lumen (LUVDOX-TRAIL) in order to improve their cytotoxic potential. LUVDOX-TRAIL killed not only to a higher extent, but also with a much faster kinetic than LUV-TRAIL. In addition, the concerted action of the liposomal DOX and TRAIL was specific of the liposomal DOX and was not observed when with soluble DOX. The cytotoxicity induced by LUVDOX-TRAIL was proven to rely on two processes due to different molecular mechanisms: a dynamin-mediated internalization of the doxorubicin-loaded particle, and the strong activation of caspase-8 exerted by the liposomal TRAIL. Finally, greater cytotoxic activity of LUVDOX-TRAIL was also observed in vivo in a tumor xenograft model. Therefore, we developed a novel double-edged nanoparticle combining the cytotoxic potential of DOX and TRAIL, showing an exceptional and remarkable synergistic effect between both agents.

LncRNA MEG3 inhibits the progression of prostate cancer by facilitating H3K27 trimethylation of EN2 through binding to EZH2

2019 ◽  
Vol 167 (3) ◽  
pp. 295-301 ◽  
Author(s):  
Yaojun Zhou ◽  
Hongqiong Yang ◽  
Wei Xia ◽  
Li Cui ◽  
Renfang Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Colony Formation ◽  
H3k27 Trimethylation ◽  
Invasion And Migration ◽  
Over Expression ◽  
Pc3 Cells ◽  
Underlying Mechanisms ◽  
And Migration

Abstract This study aims to study the effects of intra-nuclear lncRNA MEG3 on the progression of prostate cancer and the underlying mechanisms. Expressions of relative molecules were detected by Quantitative real time PCR (qRT-PCR) and western blot. Chromatin immunoprecipitation and RNA immunoprecipitation (RIP) assays were used to evaluate the interaction between intra-nuclear MEG3, histone methyltransferase EZH2 and Engrailed-2 (EN2). The impacts of MEG3 on the viability, proliferation and invasion of prostate cancer cells (PC3) were evaluated by methyl thiazolyl tetrazolium, colony formation and transwell assays, respectively. PC3 cells were transfected with MEG3 and transplanted into nude mice to analyse the effect of MEG3 on tumourigenesis of PC3 cells in vivo. EN2 expression was inversely proportional to MEG3 in the prostate cancer tissues and PC3 cells. RIP results showed that intra-nuclear MEG3 could bind to EZH2. Knockdown of MEG3 and/or EZH2 up-regulated EN2 expression and reduced the recruitment of EZH2 and H3K27me3 to EN2, while over-expressed MEG3 caused opposite effects. MEG3 over-expression suppressed cell viability, colony formation, cell invasion and migration of PC3 cells in vitro and inhibited tumourigenesis of PC3 cells in vivo, while EN2 over-expression diminished the effects. These findings indicated that MEG3 facilitated H3K27 trimethylation of EN2 via binding to EZH2, thus suppressed the development of prostate cancer.

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