Loss of RSPO3 as a potential mechanism of greater invasiveness in prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 333-333
Author(s):  
Aruz Mesci ◽  
Xiaoyong Huang ◽  
David Shin ◽  
Christianne Hoey ◽  
Jessica Ray ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Metastatic Disease ◽  
Radiation Resistance ◽  
Locally Advanced ◽  
Prostate Adenocarcinoma ◽  
Potential Mechanism ◽  
Normal Prostate ◽  
Potential Biomarker

333 Background: While prostate cancer can often manifest as an indolent disease, locally-advanced or metastatic disease can cause significant morbidity or mortality. Better understanding of molecular mechanisms leading to more aggressive presentations can lead to identification of prognostic or predictive biomarkers, as well as to possible therapeutic targets. Methods: We describe the generation of prostate cancer cell lines that have been selected through a course of hypofractionated radiotherapy. We show that R-spondin 3, a protein implicated previously as a marker of aggressive disease in colorectal and non-small cell lung cancer, is downregulated in these cell lines compared to parental cells. Then, we test the functional consequences of R-spondin 3 downregulation by siRNA-mediated interference using in vitro assays of radiation resistance, proliferation, and invasiveness . Experiments investigating any change in metastatic propensity following R-spondin 3 downregulation are forthcoming. We further investigate signaling pathways that may be implicated in the mechanism of R-spondin 3 action. Lastly, we use the Oncomine Platform to look for any changes in R-spondin 3 levels between normal prostate tissue and prostate adenocarcinoma. Results: Although siRNA-mediated loss of R-spondin 3 does not confer radiation resistance in vitro, it does result in increased invasiveness in Matrigel assays. Paradoxically, R-spondin 3 downregulation results in decreased proliferation. Interference with R-spondin 3 also results in decreased β-catenin, ERK, and Akt signaling, but increased JNK signaling. In support of our in vitro results, R-spondin 3 expression is lower in human prostate adenocarcinoma compared to normal prostate in several gene expression datasets. Conclusions: Our preliminary data suggest that R-spondin 3 loss may lead to increased disease aggression via altered cell signaling. R-spondin 3 downregulation may represent a potential biomarker to identify patients at greater risk of developing locally advanced or metastatic disease, or a potential mechanism to target in future therapeutic efforts.

scholarly journals O13 Acid ceramidase: a potential biomarker for locally advanced rectal cancer?

2021 ◽  
Vol 108 (Supplement_5) ◽  
Author(s):  
Rachael Elizabeth Clifford ◽  
Naren Govindarajah ◽  
David Bowden ◽  
Paul Sutton ◽  
Jason Parsons ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Cell Lines ◽  
Locally Advanced ◽  
Underlying Mechanism ◽  
Acid Ceramidase ◽  
Clinical Role ◽  
Clonogenic Assays ◽  
Potential Biomarker ◽  
Optimal Drug

Abstract Introduction We have previously utilized proteomic and immuno-histochemical data to validate that high levels of acid ceramidase (AC) expression confers poorer neoadjuvant response in rectal cancer. Biological (siRNA, plasmid and CRISPR) AC manipulation altered radiosensitivity in-vitro. We aimed to assess the radiosensitising effect of pharmacological AC inhibitions and elucidate the potential underlying mechanism. Methods Optimal drug dosing was achieved using ELISA activity assays in multiple colorectal cancer cell lines (HCT116, HT29, LIM1215). Carmofur and a novel small molecular inhibitor (LCL521) were used as pharmacological inhibitors. Standard clonogenic assays assessed cell survival following increasing irradiation (2 D), volume change in 3 D spheroids and cell viability in patient derived organoids. Annexin V/PI staining was used to determine apoptosis. Results Carmofur clonogenic assays demonstrated reduced colony formation efficiency (CFE) and improved radiosensitivity across cell lines. HCT116 showed 0.438(CFE) control v 0.183(CFE) carmofur at 1 Gy, 0.140(CFE) control v 0.076(CFE) at 2 Gy (P = 0.000563). LCL521 dosing improved radiosensitivity in spheroid models. HCT116 volume day-15 2.36x10-5mm v control 4.15x10-5mm. siRNA-AC demonstrated increased apoptosis across time points compared to NT control (P = 0.035), and increased poly-ADP ribose polymerase-1 (PARP-1) cleavage in a p53-dependent process. Conclusion Initial work demonstrates that pharmacological inhibition of AC produces comparative radiosensitizing effects in these cell lines and cancer models. siRNA-AC increases apoptosis, suggestive of a potential underlying mechanism. This work further solidifies AC as a potential biomarker, however further recapitulation in more complex models and ultimately in-vivo is required to establish a translatable clinical role.

scholarly journals Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xuehui Wang ◽  
Changle Ji ◽  
Jiashu Hu ◽  
Xiaochong Deng ◽  
Wenfang Zheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Potential Biomarker

Abstract Background Circular RNAs (circRNAs), a novel class of endogenous RNAs, have shown to participate in the development of breast cancer (BC). Hsa_circ_0005273 is a circRNA generated from several exons of PTK2. However, the potential functional role of hsa_circ_0005273 in BC remains largely unknown. Here we aim to evaluate the role of hsa_circ_0005273 in BC. Methods The expression level of hsa_circ_0005273 and miR-200a-3p were examined by RT-qPCR in BC tissues and cell lines. The effect of knocking down hsa_circ_0005273 in BC cell lines were evaluated by examinations of cell proliferation, migration and cell cycle. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0005273 in BC. RNA immunoprecipitation assay, RNA probe pull-down assay, luciferase reporter assay and fluorescence in situ hybridization were conducted to confirm the relationship between hsa_circ_0005273, miR-200a-3p and YAP1. Results Hsa_circ_0005273 is over-expressed in BC tissues and cell lines, whereas miR-200a-3p expression is repressed. Depletion of hsa_circ_0005273 inhibited the progression of BC cells in vitro and in vivo, while overexpression of hsa_circ_0005273 exhibited the opposite effect. Importantly, hsa_circ_0005273 upregulated YAP1 expression and inactivated Hippo pathway via sponging miR-200a-3p to promote BC progression. Conclusions Hsa_circ_0005273 regulates the miR-200a-3p/YAP1 axis and inactivates Hippo signaling pathway to promote BC progression, which may become a potential biomarker and therapeutic target.

scholarly journals HERV-K Gag RNA and Protein Levels Are Elevated in Malignant Regions of the Prostate in Males with Prostate Cancer

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 449
Author(s):  
Simin D. Rezaei ◽  
Joshua A. Hayward ◽  
Sam Norden ◽  
John Pedersen ◽  
John Mills ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Normal Prostate ◽  
Tissue Samples ◽  
Gag Protein ◽  
Protein Levels ◽  
Prostate Epithelial Cells ◽  
Prostate Cancers

Heightened expression of human endogenous retrovirus (HERV) sequences has been associated with a range of malignancies, including prostate cancer, suggesting that they may serve as useful diagnostic or prognostic cancer biomarkers. We analysed the expression of HERV-K (Gag and Env/Np9 regions), HERV-E 4.1 (Pol and Env regions), HERV-H (Pol) and HERV-W (Gag) sequences in prostate cancer cells lines and normal prostate epithelial cells using qRT-PCR. HERV expression was also analysed in matched malignant and benign prostate tissue samples from men with prostate cancer (n = 27, median age 65.2 years (range 47–70)) and compared to prostate cancer-free male controls (n = 11). Prostate cancer epithelial cell lines exhibited a signature of HERV RNA overexpression, with all HERVs analysed, except HERV-E Pol, showing heightened expression in at least two, but more commonly all, cell lines analysed. Analysis of primary prostate material indicated increased expression of HERV-E Pol but decreased expression of HERV-E Env in both malignant and benign regions of the prostate in men with prostate cancer as compared to those without. Expression of HERV-K Gag was significantly higher in malignant regions of the prostate in men with prostate cancer as compared to matched benign regions and prostate cancer-free men (p < 0.001 for both), with 85.2% of prostate cancers donors showing malignancy-associated upregulation of HERV-K Gag RNA. HERV-K Gag protein was detected in 12/18 (66.7%) malignant tissues using immunohistochemistry, but only 1/18 (5.6%) benign tissue sections. Heightened expression of HERV-K Gag RNA and protein appears to be a sensitive and specific biomarker of prostate malignancy in this cohort of men with prostate carcinoma, supporting its potential utility as a non-invasive, adjunct clinical biomarker.

scholarly journals ATM Kinase Inhibition Preferentially Sensitises PTEN-Deficient Prostate Tumour Cells to Ionising Radiation

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 79
Author(s):  
Conor Hanna ◽  
Victoria L. Dunne ◽  
Steven M. Walker ◽  
Karl T. Butterworth ◽  
Nuala McCabe ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cellular Response ◽  
Advanced Prostate Cancer ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Biochemical Failure ◽  
Ionising Radiation ◽  
Effective Treatment Option ◽  
Normal Prostate ◽  
Minimal Toxicity

Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8–18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations.

scholarly journals Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioiso-Mers for Antimalarial, Antiproliferative and Antimicrobial Activities

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3268
Author(s):  
Katja S. Håheim ◽  
Emil Lindbäck ◽  
Kah Ni Tan ◽  
Marte Albrigtsen ◽  
Ida T. Urdal Helgeland ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antimicrobial Activities ◽  
Ring System ◽  
Human Prostate ◽  
The Novel ◽  
Human Prostate Cancer ◽  
Biofilm Inhibition

A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).

scholarly journals Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Denisa Baci ◽  
Antonino Bruno ◽  
Caterina Cascini ◽  
Matteo Gallazzi ◽  
Lorenzo Mortara ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Dietary Supplements ◽  
Cell Lines ◽  
Angiogenic Factors ◽  
Migration And Invasion ◽  
Prostate Cancer Cells

Abstract Background Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible “repurposed agent’ for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.

scholarly journals NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1861
Author(s):  
Tyler Sheetz ◽  
Joseph Mills ◽  
Anna Tessari ◽  
Megan Pawlikowski ◽  
Ashley E. Braddom ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Therapeutic Option ◽  
The United States ◽  
Mrna Levels ◽  
Advanced Stage ◽  
Castration Resistant Prostate Cancer ◽  
Single Chain

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer (CRPC). The protein nucleolin (NCL) is overexpressed in several types of human tumors where it is also mislocalized to the cell surface. We previously reported the identification of a single-chain fragment variable (scFv) immuno-agent that is able to bind NCL on the surface of breast cancer cells and inhibit proliferation both in vitro and in vivo. In the present study, we evaluated whether NCL could be a valid therapeutic target for PCa, utilizing DU145, PC3 (CRPC), and LNCaP (androgen-sensitive) cell lines. First, we interrogated the publicly available databases and noted that higher NCL mRNA levels are associated with higher Gleason Scores as well as with recurrent and metastatic tumors. Then, using our anti-NCL scFv, we demonstrated that NCL is expressed on the surface of all three tested cell lines and that NCL inhibition results in reduced proliferation and migration. We also measured the inhibitory effect of NCL targeting on the biogenesis of oncogenic microRNAs such as miR-21, -221 and -222, which was cell context dependent. Taken together, our data provide evidence that NCL targeting inhibits the key hallmarks of malignancy in PCa cells and may provide a novel therapeutic option for patients with advanced-stage PCa.

scholarly journals EVALUATION OF [11C]MPC-6827 AS A MICROTUBULE TARGETING PET RADIOTRACER IN CANCER CELL LINES

2019 ◽  
pp. 43-47
Author(s):  
J. S. DILEEP KUMAR ◽  
JAYA PRABHAKARAN ◽  
NARESH DAMUKA ◽  
JUSTIN W. HINES ◽  
STEVEN J. KRIDEL ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Specific Binding ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Microtubule Targeting Agents ◽  
Pc3 Cells

Objective: The objective of this study was to evaluate the uptake and specificity of [11C]MPC-6827, a MT targeted PET ligand in prostate, glioblastoma and breast cancer cells. Methods: [11C]MPC-6827 was synthesized by reacting corresponding desmethyl precursors with [11C]CH3I in a GE-FX2MeI/FX2M radiochemistry module. In vitro binding of [11C]MPC-6827 was performed in breast cancer MDA-MB-231, glioblastoma (GBM) patient-derived tumor (GBM-PDX), GBM U251 and prostate cancer 3 (PC3) cell lines at 37 °C in quadruplicate at 5, 15, 30, 60, and 90 minute incubation time. The nonspecific bindings were determined by incubation with unlabeled microtubule targeting agents MPC-6827, HD-800, colchicine, paclitaxel and docetaxel (5.0 mM). Results: [11C]MPC-6827 provided the highest binding in the breast cancer cell, MDA-MB-231, among all the cells studied, with 90% specific binding. [11C]MPC-6827 binds to glioblastoma PDX and U251 cells with ~50% and 40% specific binding, whereas, prostate cancer cell line, PC3 cells showed 40% specific binding. [11C]MPC-6827 also exhibits binding to the taxane and colchicine binding sites of MTs, in MDA-MB-231 cells. Conclusion: These data indicate that [11C]MPC-6827 can be a promising PET radiotracer for preclinical imaging of the brain and peripheral cancers.

scholarly journals Some Wild Edible Mushroom Anticancer Activity Against Prostate Cell Lines

Proceedings ◽  
2019 ◽  
Vol 40 (1) ◽  
pp. 40
Author(s):  
Hatice Bekci ◽  
Mustafa Cam ◽  
Ahmet Cumaoglu
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Prostate Cancer Cell ◽  
Cancer Cell Lines ◽  
Anticancer Activities ◽  
Prostate Cancer Cell Lines ◽  
Prostate Cell

Prostate cancer is one of the cause of mortality and morbidity in men. High nutritional quality mushrooms have been consumed as food for a long time and Thanks to their bioactive components, they can be used in many fields such as pharmaceuticals, cosmetic products, dietary supplements and functional food production. The purpose of the research was to evaluate these derivatives against in vitro to obtain novel specific and effective anticancer agents against prostate cancer. In the study, Amanita caesarea, Sparassis crispa, Lepista nuda, Auricularia auricula, Tricholoma terreum and Lentinus tigrinus fungi were used. Anticancer activities of the compounds were evaluated in vitro by using MTT method against PC-3 and DU-143 (androgen-independent human prostate cancer cell lines) prostate cancer cell lines. Cisplatin was used as the positive sensitivity reference standard. The most effective among these fungus species biological activity against PC3 cancer cell line (IC50 = 327.34 µM), against DU-145 (IC50 = 459.19 µM).

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