Target For Prostate Cancer Therapy Research Articles

FGFR1 governs iron homeostasis via regulating intracellular protein degradation pathways of IRP2 in prostate cancer cells

The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression, notably in conferring tumor growth advantage and facilitating metastasis. However, how FGFR1 contributes to PCa progression is not fully revealed. Here we report that ectopic FGFR1 in PCa cells promotes transferrin receptor 1 (TFR1) expression and expands the labile iron pool (LIP), and vice versa. We further demonstrate that FGFR1 stabilizes iron regulatory proteins 2 (IRP2) and therefore, upregulates TFR1 via promoting IRP2 binding to the IRE of TFR1. Deletion of FGFR1 in DU145 cells decreases the LIP, which potentiates the anticancer efficacy of iron chelator. Intriguingly, forced expression of IRP2 in FGFR1 depleted cells reinstates TFR1 expression and LIP, subsequently restoring the tumorigenicity of the cells. Together, our results here unravel a new mechanism by which FGFR1 drives PCa progression and suggest a potential novel target for PCa therapy.

Pentagalloyl Glucose (PGG) Exhibits Anti-Cancer Activity against Aggressive Prostate Cancer by Modulating the ROR1 Mediated AKT-GSK3β Pathway.

Androgen-receptor-negative, androgen-independent (ARneg-AI) prostate cancer aggressively proliferates and metastasizes, which makes treatment difficult. Hence, it is necessary to continue exploring cancer-associated markers, such as oncofetal Receptor Tyrosine Kinase like Orphan Receptor 1 (ROR1), which may serve as a form of targeted prostate cancer therapy. In this study, we identify that Penta-O-galloyl-β-D-glucose (PGG), a plant-derived gallotannin small molecule inhibitor, modulates ROR1-mediated oncogenic signaling and mitigates prostate cancer phenotypes. Results indicate that ROR1 protein levels were elevated in the highly aggressive ARneg-AI PC3 cancer cell line. PGG was selectively cytotoxic to PC3 cells and induced apoptosis of PC3 (IC50 of 31.64 µM) in comparison to normal prostate epithelial RWPE-1 cells (IC50 of 74.55 µM). PGG was found to suppress ROR1 and downstream oncogenic pathways in PC3 cells. These molecular phenomena were corroborated by reduced migration, invasion, and cell cycle progression of PC3 cells. PGG minimally and moderately affected RWPE-1 and ARneg-AI DU145, respectively, which may be due to these cells having lower levels of ROR1 expression in comparison to PC3 cells. Additionally, PGG acted synergistically with the standard chemotherapeutic agent docetaxel to lower the IC50 of both compounds about five-fold (combination index = 0.402) in PC3 cells. These results suggest that ROR1 is a key oncogenic driver and a promising target in aggressive prostate cancers that lack a targetable androgen receptor. Furthermore, PGG may be a selective and potent anti-cancer agent capable of treating ROR1-expressing prostate cancers.

Abstract 5899: Evaluation of Up284 as a selective proteasome inhibitor for prostate cancer therapy

Abstract Recent research into prostate cancer treatment has unveiled a promising contender known as Up284. In laboratory experiments, this compound has exhibited a remarkable preference for targeting prostate cancer cells as opposed to normal cells. Specifically, in vitro cell viability assays using MTT have shown that prostate cancer cells display high sensitivity to Up284 at low nanomolar IC50 values, while primary human prostate epithelial cells and mouse keratinocytes exhibit minimal sensitivity. This establishes a notable therapeutic window between cancerous and non-cancerous cells, with Up284 significantly inhibiting colony formation in PC3 cells. Additional functional assays have confirmed Up284's potential, including the 4UbFL Reporter Gene assay, which has revealed robust, dose-dependent proteasome inhibition. This effect is supported by the accumulation of polyubiquitinated proteins in various prostate cancer cell lines following Up284 treatment, suggesting a distinct mechanism of toxicity compared to bortezomib. Furthermore, Up284 has been found to induce apoptosis in PC3 cells, surpassing the efficacy of bortezomib. Competitive binding assays have shown that Up284 exhibits a stronger binding affinity to the proteasomal receptor RPN13 than the prototype inhibitor RA190B. This is further supported by a Cellular Thermo Stabilization Assay (CETSA), which indicates that Up284 stabilizes RPN13 in cells. A preliminary in vivo study utilizing the bone metastatic prostate cancer genetically engineered mouse model(BMPC GEMM) model for metastatic prostate adenocarcinoma has demonstrated that Up284 leads to significant tumor regression and increased levels of poly-ubiquitinated proteins in residual tumor tissues. Moreover, when Up284 is conjugated with an E3 ligase ligand, it successfully degrades RPN13, resulting in the death of PC3 cells. Up284 has also shown favorable pharmacokinetics/pharmacodynamics (PK/PD) profiles and safety in animal models. It is well-tolerated in mice and holds promise for oral administration, demonstrating a proteasome-dependent reporter protein stabilization effect superior to ixazomib. Importantly, Up284 has induced tumor regression and improved survival rates in various cancer models, including ovarian and breast cancers. In conclusion, Up284 emerges as a lead candidate for targeted prostate cancer therapy due to its high specificity, substantial therapeutic index, and potent anti-cancer activity both in vitro and in vivo. Further development and clinical investigation of Up284 are warranted to fully explore its therapeutic potential. Citation Format: Balasubramanyam Karanam, Ravi Anchoori, Yung Chang. Evaluation of Up284 as a selective proteasome inhibitor for prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5899.

B7-H3 specific CAR-T cells exhibit potent activity against prostate cancer

B7-H3 is an attractive target for immunotherapy because of its high expression across multiple solid tumors, including prostate cancer, and restricted expression in normal tissues. Among various types of tumor immunotherapy, chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematological tumors. However, the potency of CAR-T cell therapy in solid tumors is still limited. Here, we examined the expression of B7-H3 in prostate cancer tissues and cells and developed a second-generation CAR that specifically targets B7-H3 and CD28 as costimulatory receptor to explore its tumoricidal potential against prostate cancer in vitro and in vivo. The high expression of B7-H3 was detected on both the surface of PC3, DU145 and LNCaP cells and prostate cancer tissues. B7-H3 CAR-T cells efficiently controlled the growth of prostate cancer in an antigen-dependent manner in vitro and in vivo. Moreover, tumor cells could induce the proliferation of CAR-T cells and the release of high levels of cytokines of IFN-γ and TNF-α in vitro. Results demonstrated that B7-H3 is a potential target for prostate cancer therapy that supports the clinical development of B7-H3 specific CAR-T cells for prostate cancer.

Histone methyltransferase KMT2D promotes prostate cancer progression through paracrine IL-6 signaling.

Histone methyltransferase KMT2D plays a critical role as a human oncogene in prostate cancer (PCa). Dysregulated inflammatory responses and cytokine signaling are implicated in cancer progression. Furthermore, interleukin 6 (IL-6) is a pleiotropic cytokine that contributes to PCa progression; however, the association between KMT2D and IL-6 in PCa remains unclear. PCa cell proliferative potential, migratory potential, and apoptosis invitro were determined using cell counting kit-8 (CCK-8), EdU incorporation, wound healing, and apoptosis assays. Proliferation and migratory potential were impaired and apoptosis was induced in PCa cells cultured with the conditioned medium from KMT2D-depleted cells. Cytokine array analysis showed that IL-6 was the most affected cytokine in the conditioned media. KMT2D knockdown significantly downregulated the expression of IL-6 in PCa cells. What's more, proliferation and migration were also impaired and apoptosis was also induced by silencing IL-6R expression. Immunohistochemistry (IHC) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were performed to validate the positive correlation between KMT2D and IL-6 in PCa tissue samples. Chromatin immunoprecipitation (ChIP)-PCR demonstrated that KMT2D and H3K4me1 occupied IL-6 enhancer regions and therefore, directly regulated IL-6 expression. The present study revealed that the KMT2D knockdown suppressed prostate cancer progression through the downregulation of paracrine IL-6 signaling. These results suggest that KMT2D could be regarded as a potential new target for PCa therapy.

Ribosomal protein L22-like1 promotes prostate cancer progression by activating PI3K/Akt/mTOR signalling pathway.

Prostate cancer (PCa) is one of the most common malignancies in men. Ribosomal protein L22-like1 (RPL22L1), a component of the ribosomal 60 S subunit, is associated with cancer progression, but the role and potential mechanism of RPL22L1 in PCa remain unclear. The aim of this study was to investigate the role of RPL22L1 in PCa progression and the mechanisms involved. Bioinformatics and immunohistochemistry analysis showed that the expression of RPL22L1 was significantly higher in PCa tissues than in normal prostate tissues. The cell function analysis revealed that RPL22L1 significantly promoted the proliferation, migration and invasion of PCa cells. The data of xenograft tumour assay suggested that the low expression of RPL22L1 inhibited the growth and invasion of PCa cells in vivo. Mechanistically, the results of Western blot proved that RPL22L1 activated PI3K/Akt/mTOR pathway in PCa cells. Additionally, LY294002, an inhibitor of PI3K/Akt pathway, was used to block this pathway. The results showed that LY294002 remarkably abrogated the oncogenic effect of RPL22L1 on PCa cell proliferation and invasion. Taken together, our study demonstrated that RPL22L1 is a key gene in PCa progression and promotes PCa cell proliferation and invasion via PI3K/Akt/mTOR pathway, thus potentially providing a new target for PCa therapy.

Intercomparison of S-Factor values calculated in Zubal voxelized phantom for eleven radionuclides commonly used in targeted prostate cancer therapy.

In this study we aimed at comparing various radionuclides ordinarily used in targeted prostate cancer therapy, thereby evaluating S-Factor parameter in the prostate organs as well as in its surrounding healthy tissues, namely the urinary bladder and rectum. InterDosi code version 1.1 was used to estimate S-Factor values in Zubal voxelized phantom for 11 radionuclides, namely 225Ac, 21At, 67Cu, 125I, 131I, 212Pb, 177Lu, 223Ra, 161Tb, 227Th and 90Y. The prostate organ was considered the source of different ionizing radiation emitted by the radionuclides cited above. The results showed that among all studied alpha-emitting radionuclides, 225 Ac, 223 Ra and 227 Th provide equidistantly the highest self-irradiation S-Factors whereas, 211At provides the lowest cross-irradiation S-Factors. On the other hand, considering only beta-emitting radionuclides, it is shown that 177Lu and 90Y induce respectively lowest and highest cross-absorption S-Factors on the surrounding healthy organs. We conclude that 177Lu and 211At are more adequate for prostate radionuclide therapy because they can relatively prevent surrounding organs from radiation toxicity and at the same time provide sufficient dose to treat the prostate tumor.

Stem Cells as Target for Prostate cancer Therapy: Opportunities and Challenges.

Cancer stem cells (CSCs) and cells in a cancer stem cell-like (CSCL) state have proven to be responsible for tumor initiation, growth, and relapse in Prostate Cancer (PCa) and other cancers; therefore, new strategies are being developed to target such cellular populations. TLR3 activation-based immunotherapy using Polyinosinic:Polycytidylic acid (PIC) has been proposed to be used as a concomitant strategy to first-line treatment. This strategy is based on the induction of apoptosis and an inflammatory response in tumor cells. In combination with retinoids like 9cRA, this treatment can induce CSCs differentiation and apoptosis. A limitation in the use of this combination is the common decreased expression of TLR3 and its main positive regulator p53. observed in many patients suffering of different cancer types such as PCa. Importantly, human exposure to certain toxicants, such as iAs, not only has proven to enrich CSCs population in an in vitro model of human epithelial prostate cells, but additionally, it can also lead to a decreased p53, TLR3 and RA receptor (RARβ), expression/activation and thus hinder this treatment efficacy. Therefore, here we point out the relevance of evaluating the TLR3 and P53 status in PCa patients before starting an immunotherapy based on the use of PIC +9cRA to determine whether they will be responsive to treatment. Additionally, the use of strategies to overcome the lower TLR3, RARβ or p53 expression in PCa patients, like the inclusion of drugs that increase p53 expression, is encouraged, to potentiate the use of PIC+RA based immunotherapy in these patients.

Methylation status of TK1 correlated with immune infiltrates in prostate cancer.

TK1 is overexpressed in numerous cancers and is associated with to a poor prognosis. However, the relationship between methylation status of TK1 and Immune Infiltrates in Prostate Cancer (PCa) is unknown. The goal of this study was to use comprehensive bioinformatic analyses to elucidate the involvement relationship between methylation status of TK1 and Immune Infiltrates in PCa. TK1 mRNA expression and methylation data in PCa were investigated via GEPIA, TIMER, and UALCAN coupled with MEXPRESS data resources. We employed the LinkedOmics data resource to determine the signaling cascades linked to TK1 expression. Single-cell analysis was performed using the CancerSEA data resource. GeneMANIA and CancerSEA were used to analyze the correlation between TK1 and TK1 coexpressed genes. In addition, TIMER and TISIDB were adopted to assess tumor-invading immune cells and immunomodulators. CTD was utilized to detect the drugs acting on TK1. This study found that TK1 was overexpressed in PCa, and its contents were linked to tumor stage and prognosis. Genes co-expressed with TK1 were enriched in cascades involved in the ribosome, cell cycle, oxidative phosphorylation, DNA replication, oocyte meiosis, and the proteasome. The expression of TK1 along with its methylation status was found to be linked to tumor-invading immune cells, as well as PCa immunomodulators. We also examined the prospect of employing TK1 as a possible target for PCa therapy. This work provides the clinical value of TK1 hypermethylation in PCa and highlights new insights into its novel immunomodulatory functions.

Sirtuin 4 Inhibits Prostate Cancer Progression and Metastasis by Modulating p21 Nuclear Translocation and Glutamate Dehydrogenase 1 ADP-Ribosylation.

Protein posttranslational modification regulates several biological mechanisms, including tumor progression. In this study, we show that the mitochondrial Sirtuin 4 (SIRT4), which has ADP-ribosylation activity, plays a role in prostate cancer (PCa) progression. Firstly, SIRT4 expression was verified in PCa tissues and cell lines by quantitative real-time PCR (qRT-PCR) and western blotting. Subsequently, we established stable PC-3 and 22rv1 cells that overexpressed SIRT4 and knocked down SIRT4, respectively. The functions of SIRT4 in PCa were explored through various phenotype experiments. The mechanism underlying the functions of SIRT4 was investigated through western blotting, immunoprecipitation, immunofluorescence, and nuclear and cytoplasmic extraction assays. We revealed that SIRT4 inhibited cell progression both in vivo and in vitro. Mechanistically, on the one hand, SIRT4 promoted the ADP-ribosylation of glutamate dehydrogenase 1 to inhibit the glutamine metabolism pathways. On the other hand, SIRT4 inhibited the phosphorylation of AKT, thereby affecting p21 phosphorylation and its cellular localization for cell cycle arrest. In conclusion, our study indicates that SIRT4 is directly associated with PCa progression and could be a novel target for PCa therapy.

Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition.

Metastatic prostate cancer (PCa) in bone induces bone-forming lesions that enhance PCa progression. How tumor-induced bone formation enhances PCa progression is not known. We have previously shown that PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition by tumor-secreted BMP4. Here, we show that EC-to-OSB transition leads to changes in the tumor microenvironment that increases the metastatic potential of PCa cells. We found that conditioned medium (CM) from EC-OSB hybrid cells increases the migration, invasion and survival of PC3-mm2 and C4-2B4 PCa cells. Quantitative mass spectrometry (iTRAQ) identified Tenascin C (TNC) as one of the major proteins secreted from EC-OSB hybrid cells. TNC expression in tumor-induced osteoblasts was confirmed by immunohistochemistry of MDA-PCa118b xenograft and human bone metastasis specimens. Mechanistically, BMP4 increases TNC expression in EC-OSB cells through the Smad1-Notch/Hey1 pathway. How TNC promotes PCa metastasis was next interrogated by in vitro and in vivo studies. In vitro studies showed that a TNC neutralizing antibody inhibits EC-OSB-CM-mediated PCa cell migration and survival. TNC knockdown decreased, while addition of recombinant TNC or TNC overexpression increased migration and anchorage-independent growth of PC3 or C4-2b cells. When injected orthotopically, PC3-mm2-shTNC clones decreased metastasis to bone, while C4-2b-TNC overexpressing cells increased metastasis to lymph nodes. TNC enhances PCa cell migration through α5β1 integrin-mediated YAP/TAZ inhibition. These studies elucidate that tumor-induced stromal reprogramming generates TNC that enhances PCa metastasis and suggest that TNC may be a target for PCa therapy.

The non-canonical mechanism of ER stress-mediated progression of prostate cancer

BackgroundThe development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation.MethodsCell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP, and 22RV1 cells, as well as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy.ResultsHerein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites.ConclusionsWe found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.

Combination Therapy of Metastatic Castration-Recurrent Prostate Cancer: Hyaluronic Acid Decorated, Cabazitaxel-Prodrug and Orlistat Co-Loaded Nano-System.

PurposeProstate cancer (PCa) is the second leading cause of cancer-related death among men in developed countries. Cabazitaxel (CBZ) is recommended as one of the most active chemotherapy agents for PCa. This study aimed to develop a hyaluronic acid (HA) decorated, cabazitaxel-prodrug (HA-CBZ) and orlistat (ORL) co-loaded nano-system against the prostate cancer in vitro and in vivo.MethodsCabazitaxel-prodrug was firstly synthesized by conjugating HA with CBZ through the formation of ester bonds. HA contained ORL and CBZ prodrug co-loaded lipid-polymer hybrid nanoparticles (ORL/HA-CBZ/LPNs) were constructed and characterized in terms of particle size, zeta potential, drug loading capacity and stability. The antitumor efficiency and systemic toxicity of LPNs were evaluated in vitro and in vivo.ResultsThe resulting ORL/HA-CBZ/LPNs were 150.9 nm in particle size with narrow distribution and high entrapment efficiency. The minimum combination index of 0.57 was found at a drug ratio of 1:2 (ORL:HA-CBZ, w/w) in the drug co-loaded formulations, indicating the strongest synergism effect. ORL/HA-CBZ/LPNs demonstrated an enhanced in vitro and in vivo antitumor effect compared with single drug loaded LPNs and free drug formulations.ConclusionORL/HA-CBZ/LPNs showed remarkable synergism cytotoxicity and the best tumor inhibition efficiency in mice with negligible systemic toxicity. ORL/HA-CBZ/LPNs can be highly useful for targeted prostate cancer therapy.

FGF21 facilitates autophagy in prostate cancer cells by inhibiting the PI3K\u2013Akt\u2013mTOR signaling pathway

Fibroblast growth factor 21 (FGF21) plays an important role in regulating glucose and lipid metabolism, but its role in cancer is less well-studied. We aimed to investigate the action of FGF21 in the development of prostate cancer (PCa). Herein, we found that FGF21 expression was markedly downregulated in PCa tissues and cell lines. FGF21 inhibited the proliferation and clone formation of LNCaP cells (a PCa cell line) and promoted apoptosis. FGF21 also inhibited PCa cell migration and invasiveness. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that FGF21 was related to autophagy and the phosphatidylinositol 3-kinase–Akt kinase–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway. Mechanistically, FGF21 promoted autophagy in LNCaP cells by inhibiting the PI3K–Akt–mTOR–70S6K pathway. In addition, FGF21 inhibited PCa tumorigenesis in vivo in nude mice. Altogether, our findings show that FGF21 inhibits PCa cell proliferation and promoted apoptosis in PCa cells through facilitated autophagy. Therefore, FGF21 might be a potential novel target in PCa therapy.

Bioconjugated solid lipid nanoparticles (SLNs) for targeted prostate cancer therapy

Prostate cancer is one of the prominent causes of cancer mortality in men all over the world and a challenge to treat. In this study, transferrin (Tf) bioconjugated solid lipid nanoparticles (SLNs) were developed and loaded with curcumin (CRC) for active targeting of prostate cancer cells. Curcumin is an anticancer agent, but its clinical applications are impeded due to the poor water solubility and bioavailability. Prepared blank Tf-SLNs showed minimal cytotoxicity while Tf-CRC-SLNs demonstrated significant in-vitro anti-proliferative activity compared to CRC-SLNs alone. Cellular uptake of Tf-CRC-SLNs were found to be significantly higher (p < 0.05/=0.01) compared to unconjugated SLNs or pure drug alone. Bioconjugated Tf-CRC-SLNs also showed improved early apoptotic and late apoptotic or early necrotic populations (6.4% and 88.9% respectively) to CRC-SLNs and CRC solution. Most importantly, in-vivo studies with Tf-CRC-SLNs in mice bearing prostate cancer revealed significant tumour regression (392.64 mm3 after 4 weeks, p < 0.001) compared to the control group. The findings of this work encourage future investigations and further in-vivo clinical studies on the potential of bioconjugated SLNs for cancer cure.

Long noncoding RNA SNHG1 promotes human prostate cancer progression by sponging miR-383-5p.

Prostate cancer is the most common urinary malignancy in males. Long noncoding RNA small nucleolar RNA host gene 1 (lncRNA SNHG1) has been reported to play a crucial role in the development of various cancers. However, the understanding of SNHG1 in prostate cancer is still limited and needs further investigation. In this study, we found the level of SNHG1 was significantly upregulated in prostate cancer tissues and cells. Knockdown of SNHG1 significantly suppressed proliferation, migration and invasion and promoted cell apoptosis in prostate cancer cells. In addition, knockdown of SNHG1 significantly downregulated proliferating cell nuclear antigen and upregulated cleaved caspase-3. MiR-383-5p was identified to be a target of SNHG1 by bioinformatics analysis, dual-luciferase reporter assay, RNA immunoprecipitation assay and RNA pull-down assay. MiR-383-5p was significantly downregulated in prostate cancer tissues and cells. Inhibition of miR-383-5p could partially restore the effects of SNHG1 knockdown on prostate cancer cell proliferation, apoptosis, migration and invasion. Furthermore, murine xenograft models were established to investigate the effects of SNHG1 and miR-383-5p in tumorigenesis in vivo. We found SNHG1 knockdown or miR-383-5p overexpression repressed tumor growth in vivo. In conclusion, SNHG1 contributed to prostate cancer progression by targeting miR-383-5p, elucidating that SNHG1 might be a target for prostate cancer therapy.

Extracellular Vesicles-Mediated Transfer of miRNA Let-7b from PC3 Cells to Macrophages.

Prostate-derived extracellular vesicles (pEVs) may represent a way to selectively transport cargo molecules from the producing cells to the target cells to allow biological events, both in physiological and pathological circumstances. pEVs cargo participates in the modulation of the inflammatory responses in physiological conditions and during cancer progression. In the present study, we examined the expression levels of miRNA Let-7b, in both precursor and mature forms, in noncancerous and cancerous prostate cell lines, PNT2 and PC3 respectively, and in their extracellular vesicles (EVs) using reverse-transcription quantitative PCR strategies. We showed that miRNA Let-7b was highly expressed in noncancerous cells and strongly decreased in cancerous PC3 cells, while the opposite was observed in the respective EVs, thus supporting the tumor suppressor role of miRNA Let7-b. We also demonstrated that miRNA Let-7b can be transferred to THP-1 cells via EVs, which are known to induce TAM-like polarization. Our results support the view that miRNA Let-7 b, contained in PC3-derived EVs, is associated with the increase in the miRNA Let7-b observed in TAM-like macrophages. Overall, our results indicate that circulating EV-loaded miRNA might be useful biomarkers for prostate cancer progression and might also support a possible use of pEVs as targets for prostate cancer therapy.

Prostate Cancer Proliferation Is Affected by the Subcellular Localization of MCT2 and Accompanied by Significant Peroxisomal Alterations.

Simple SummaryFatty acid β-oxidation is a dominant bioenergetic pathway in prostate cancer. It has recently been suggested that the specific targeting of monocarboxylate transporter 2 (MCT2) to peroxisomes contributed to an increase in β-oxidation rates and maintenance of the redox balance in prostate cancer cells. Here we provide evidence demonstrating that prostate cancer streamlines peroxisome metabolism by upregulating distinct pathways involved in lipid metabolism. Importantly, we show that the localization of MCT2 at peroxisomes is required for prostate cancer cell proliferation. Our results emphasize the importance of peroxisomes for prostate cancer development and highlight different cellular mechanisms that may be further explored as possible targets for prostate cancer therapy.Reprogramming of lipid metabolism directly contributes to malignant transformation and progression. The increased uptake of circulating lipids, the transfer of fatty acids from stromal adipocytes to cancer cells, the de novo fatty acid synthesis, and the fatty acid oxidation support the central role of lipids in many cancers, including prostate cancer (PCa). Fatty acid β-oxidation is the dominant bioenergetic pathway in PCa and recent evidence suggests that PCa takes advantage of the peroxisome transport machinery to target monocarboxylate transporter 2 (MCT2) to peroxisomes in order to increase β-oxidation rates and maintain the redox balance. Here we show evidence suggesting that PCa streamlines peroxisome metabolism by upregulating distinct pathways involved in lipid metabolism. Moreover, we show that MCT2 is required for PCa cell proliferation and, importantly, that its specific localization at the peroxisomal membranes is essential for this role. Our results highlight the importance of peroxisomes in PCa development and uncover different cellular mechanisms that may be further explored as possible targets for PCa therapy.

Long Non-coding RNA AGAP2-AS1 Silencing Inhibits PDLIM5 Expression Impeding Prostate Cancer Progression via Up-Regulation of MicroRNA-195-5p

Prostate cancer remains a significant cause of cancer-related deaths in male population. More recently, accumulating evidence continues to implicate long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in various types of cancers, including prostate cancer. The current study aimed to elucidate the role of lncRNA AGAP2-AS1/miR-195-5p/PDZ and LIM domain 5 (PDLIM5) in prostate cancer progression. Initially, microarray expression profiles were applied to screen differentially expressed lncRNAs/miRNAs/genes associated with prostate cancer. Dual-luciferase reporter and RNA pull-down/RIP assays were subsequently performed to explore the interactions among lncRNA AGAP2-AS1, miR-195-5p, and PDLIM5, after which their expression was detected in cancer tissues and cells. Next, gain- and loss-of-function approaches were employed to elucidate the mechanism of lncRNA AGAP2-AS1/miR-195-5p/PDLIM5 in the processes of cell proliferation, migration and invasion as well as tumor growth. LncRNA AGAP2-AS1 was found to be highly expressed in prostate cancer. Silencing of lncRNA AGAP2-AS1 contributed to the suppression of proliferation, migration and invasion of cancer cells in vitro. Besides, lncRNA AGAP2-AS1 could bind to miR-195-5p which targeted PDLIM5 and subsequently downregulated its expression, ultimately impeding the progression of prostate cancer. Additionally, lncRNA AGAP2-AS1 inhibition led to an up-regulated expression of miR-195-5p and down-regulated PDLIM5 expression, resulting in delayed tumor growth in vivo. Taken together, the key findings of our study demonstrated that lncRNA AGAP2-AS1 silencing exerted suppressive effects on the development of prostate cancer via the miR-195-5p-dependent downregulation of PDLIM5. Our findings highlighted the potential of lncRNA AGAP2-AS1 as a promising novel molecular target for prostate cancer therapy.

LncRNA MCM3AP-AS1 Promotes Cell Proliferation and Invasion Through Regulating miR-543-3p/SLC39A10/PTEN Axis in Prostate Cancer.

ObjectiveLong-chain noncoding RNAs (lncRNAs) are key players in a wide range of biological processes, especially the pathogenesis and development of tumors. LncRNA MCM3AP-AS1 has been demonstrated to be involved in the invasion of various tumors including prostate cancer (PCa). However, its functions in PCa have not been fully elucidated.MethodsqRT-PCR was conducted to measure the expression levels of lncRNA MCM3AP-AS1 and miR-543-3p in PCa tissue samples and cell lines. The expression levels of E-cadherin and SLC39A10 proteins were detected by Western blots. CCK-8 test, cell scratch test and trans-well test were used to evaluate the proliferation, invasion and migration abilities of PCa cells, respectively. Annexin V-FITC/PI experiments were carried out to determine the status of apoptosis. Bioinformatics analysis and Luciferase assay were used to explore the relationship between lncRNA MCM3AP-AS1, miR-543-3p and SLC39A10.ResultsIn PCa tissue samples and cell lines, lncRNA MCM3AP-AS1 was up-regulated while miR-543-3p was down-regulated. Over-expression of MCM3AP-AS1 could promote the proliferation and invasion of PCa cells. Correlation analysis showed that the expression of MCM3AP-AS1 and miR-543-3p was significantly and inversely correlated. We further verified that miR-543-3p inhibitor was able to reverse si-MCM3AP-AS1-mediated inhibitory effects on the PCa cell proliferation, migration and invasion through regulating the downstream protein axis SLC39A10/PTEN/Akt. Finally, in vivo experiments indicated that knocking down of MCM3AP-AS1 could largely reduce tumor volumes, and decreased the ratio of Ki67-positive cells and the expression of SLC39A10 in tumor samples.ConclusionLncRNA MCM3AP-AS1 can promote the proliferation, migration and invasion abilities of PCa cells through regulating the miR-543-3p/SLC39A10/PTEN axis, which suggests that lncRNA MCM3AP-AS1 might be a potential target for prostate cancer therapy.