Search Results (189)

Prostate cancer (PCa) is a highly heterogeneous disease, with castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) representing its most aggressive and therapy-resistant forms. Emerging evidence indicates that lineage plasticity—driven by key transcription factors such as Octamer Binding Factor 4 (OCT4)—plays a crucial role in therapeutic resistance and disease progression. OCT4, in coordination with SOX2 and NANOG, acts as a master regulator of stemness and is frequently upregulated in prostate cancer stem cells (PCSCs). This upregulation contributes to tumor initiation, metastasis, and resistance to both androgen deprivation therapy (ADT) and chemotherapy. In this review, we explore the role of OCT4 in mediating lineage plasticity in prostate cancer, with particular emphasis on its involvement in treatment resistance and neuroendocrine differentiation. We also examine therapeutic strategies aimed at targeting OCT4 directly, such as microRNA-mediated suppression, small-molecule inhibitors, and suicide gene therapy, as well as indirect approaches that modulate OCT4 expression via FGFR and NF-κB signaling pathways. While these strategies offer promising avenues, challenges such as adaptive resistance and the intricate signaling networks within PCSCs remain significant hurdles. A deeper understanding of the molecular mechanisms underlying OCT4-driven plasticity may pave the way for novel therapeutic approaches and improved outcomes in advanced prostate cancer. Full article

Isoforms of prostate transmembrane protein, androgen induced 1 (PMEPA1), are regulated either by TGF-beta or AR activation and provide negative loop-regulation of these signaling pathways. High levels of PMEPA1 protein have been observed in various tumor types, including prostate, bladder, colorectal cancers, and glioblastoma. Direct oncogenic role of PMEPA1 in hepatocellular carcinoma has been recently shown on an animal model. New studies also indicate an upregulation of PMEPA1 in tumor-associated immune and stromal cells; however, its specific role in tumor stromal cells remains largely unexplored. In our previous research, we developed a cancer-stroma sphere (CSS) model that integrates tumor cells with mesenchymal stem cells (MSCs). Evaluations of chemotherapy and CAR-T therapies on CSSs have demonstrated that this model closely mimics in vivo data regarding cytotoxicity and adverse effects of therapy. In the present study, we reveal that PMEPA1 is significantly overexpressed in MSCs within the CSS. Moreover, this overexpression has been induced under short-term co-culture conditions. Among the five isoforms of PMEPA1, PMEPA1a and PMEPA1b isoforms have been detected in MSCs. These findings underscore the potential role of PMEPA1 in the tumor microenvironment modulation by MSCs. Full article

Bardoxolone methyl, also known as CDDO-Me or RTA 402, is a synthetic oleanane triterpenoid that has garnered significant attention as a potent pharmacological activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is a master regulator of cellular redox homeostasis, controlling the expression of genes involved in antioxidant defense, detoxification, and mitochondrial function. By inducing Nrf2 and promoting the transcription of downstream antioxidant response element (ARE)-driven genes, bardoxolone methyl enhances cellular resilience to oxidative stress and inflammation. This mechanism is central not only to its cytoprotective effects but also to its emerging role in oncology. A number of studies investigated the effects of bardoxolone methyl in several malignancies including breast cancer, lung cancer, pancreatic ductal adenocarcinoma, prostate cancer, colorectal cancer, oral and esophageal squamous cell carcinoma, ovarian cancer and glioblastoma. Studies in the literature indicate that bardoxolone methyl exhibits anticancer activity through several mechanisms, including the suppression of cell proliferation, induction of cell cycle arrest and apoptosis, inhibition of epithelial–mesenchymal transition (EMT), and impairment of cancer cell stemness. Additionally, bardoxolone methyl modulates mitochondrial function, reduces glycolytic and oxidative phosphorylation capacities, and induces reactive oxygen species (ROS)-mediated stress responses. In this review, we summarize the available literature regarding the studies which investigated the effects of bardoxolone methyl as anticancer agent. Full article

The treatment of choice for prostate cancer is androgen deprivation (ADT) and novel hormonal agents such as Abiraterone, Enzalutamide, or Apalutamide. Initially, this therapy is highly effective, but a significant challenge arises as most patients eventually develop resistance, resulting in castration-resistant prostate cancer (CRPC). Furthermore, the sequential use of these drugs can lead to cross-resistance, diminishing their efficacy. Tumor heterogeneity plays a pivotal role in the development of resistance to different treatments. This study utilized cellular models of CRPC to assess the response to Apalutamide when it was administered as a second- or third-line treatment. Functional and genetic analyses were conducted in various CRPC cell models exposed to Apalutamide. These analyses included real-time cell monitoring assays, flow cytometry, clonogenicity assays, and RT-qPCR. CRPC cell models were capable of continued proliferation, maintained cell cycle profiles similar to those of untreated cells, and retained their clonogenic potential. Cross-resistance to Apalutamide in models of ADT, ADT plus Enzalutamide, or Abiraterone resistance did not correlate with the expression levels of AR-V7 and AR-V9 variants. Gene expression analysis of resistant prostate cancer cell lines revealed that treatment with Apalutamide induced the emergence of more aggressive phenotypes, including cancer stem cells or neuroendocrine differentiation profiles. Most CRPC cell models developed cross-resistance to Apalutamide and were able to proliferate and retain their clonogenic capability. Apalutamide resistance was not linked to the expression of AR-V7 or AR-V9 variants but was instead associated to bypass of AR signaling pathway and the emergence of more aggressive expression profiles. Full article

Radiotherapy resistance represents a critical aspect of cancer treatment, and molecular characterization is needed to explore the pathways and mechanisms involved. DNA repair, hypoxia, metabolic reprogramming, apoptosis, tumor microenvironment modulation, and activation of cancer stem cells are the primary mechanisms that regulate radioresistance, and understanding their complex interactions is essential for planning the correct therapeutic strategy. Proteomics has emerged as a key approach in precision medicine to study tumor heterogeneity and treatment response in cancer patients. The integration of mass spectrometry-based techniques with bioinformatics has enabled high-throughput, quantitative analyses to identify biomarkers, pathways, and new potential therapeutic targets. This review highlights recent advances in proteomic technologies and their application in identifying biomarkers predictive of radiosensitivity and radioresistance in different tumors, including head and neck, breast, lung, and prostate cancers. Sample variability, data interpretation, and the translation of findings into clinical practice remain challenging elements of proteomics. However, technological advancements support its application in a wide range of topics, allowing a comprehensive approach to radiobiology, which helps overcome radiation resistance. Ultimately, incorporating proteomics into the radiotherapy workflow offers significant potential for enhancing treatment efficacy, minimizing toxicity, and guiding precision oncology strategies. Full article

Retinoic acid receptor (RAR) γ expression is restricted during adult haematopoiesis to haematopoietic stem cells and their immediate offspring and is required for their maintenance. From zebrafish studies, RARγ is selectively expressed by stem cells and agonism in the absence of exogenous all-trans retinoic acid blocked stem cell development. Recent findings for the expression of RARγ have revealed an oncogenic role in acute myeloid leukaemia and cholangiocarcinoma and colorectal, head and neck, hepatocellular, ovarian, pancreatic, prostate, and renal cancer. Overexpression and agonism of RARγ enhanced cell proliferation for head and neck, hepatocellular, and prostate cancer. RARγ antagonism, pan-RAR antagonism, and RARγ downregulation led to cell growth which was often followed by cell death for acute myeloid leukaemia, astrocytoma, and cholangiocarcinoma as well as hepatocellular, primitive, neuroectodermal ovarian, and prostate cancer. Histological studies have associated high level RARγ expression with high-grade disease, metastasis, and a poor prognosis for cholangiocarcinoma and ovarian, pancreatic, and prostate cancer. RARγ is expressed by cancer stem cells and is a targetable drive of cancer cell growth and survival. Full article

Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that promote proliferation, invasion, and metastasis. The CXCR4/CXCL12 signaling pathway is gaining attention as a promising target for cancer therapy. CXCR4, a chemokine receptor, is often overexpressed in various types of cancer, including kidney, lung, brain, prostate, breast, pancreas, ovarian, and melanomas. When it binds to its endogenous ligand, CXCL12, it promotes cell survival, proliferation, and migration, crucial mechanisms for the retention of hematopoietic stem cells in the bone marrow and the movement of lymphocytes. The extensive expression of CXCR4 in cancer, coupled with the constant presence of CXCL12 in various organs, drives the activation of this axis, which in turn facilitates angiogenesis, tumor progression, and metastasis. Given the detrimental role of the CXCR4/CXCL12 axis, the search for drugs acting selectively against this protein represents an open challenge. This review aims to summarize the recent advancements in the design and development of CXCR4 antagonists as potential anticancer agents. Full article

Background/Objectives: MIDN (midnolin) is newly discovered method for critically regulating a ubiquitin-independent proteasomal degradation pathway. This study aims to examine the expression, prognostic value, genomic changes, interacting proteins, methylation status, and correlations with the tumor immune microenvironment of MIDN in various cancers. Methods: The GTEx, Depmap, GEPIA2, and Kaplan–Meier Plotter databases are applied to evaluate the MIDN level in tumor and normal tissues and the MIDN prognostic value in cancers. The genetic alterations of MIDN in cancers are investigated using the cBioPortal database. The STRING, GeneMANIA, DAVID, and Human Protein Atlas are harnessed to identify and analyze MIDN-interacted proteins. The Sangerbox 3.0 platform (a pan-cancer analysis module) is used to measure the correlations between the MIDN level and the tumor immune microenvironment, stemness, immune cell infiltration, tumor mutational burden, immune checkpoint genes, and RNA modification genes. Immunofluorescence, qRT-PCR, and Western blotting assays were used to evaluate the biological roles of MIDN in breast and gastric cancer cells. Results: MIDN expression was dysregulated in many cancers and associated with prognosis in several cancers, such as esophageal cancer. MIDN was mutated in 1.7% of cancers, and deep deletion was the dominant mutation type. NR4A1, PSMC1, and EGR1 were selected as MIDN-interacted proteins, and these four molecules were co-expressed in pancreatic cancer, liver cancer, urothelial cancer, melanoma, and breast cancer. MIDN expression was significantly correlated with the infiltration of CD8+ T cell, CD4+ T cell, B cell, macrophage, neutrophil, and DC both in prostate adenocarcinoma and liver hepatocellular carcinoma. The MIDN level was correlated with several immune checkpoint genes, such as VEGFA, and RNA modification genes such as YTHDF1, YTHDF2, YTHDF3, and YTHDC1 in cancers. Furthermore, in breast cancer cells, the downregulation of MIDN suppressed the colony formation abilities and lessened cell-cycle-associated and stemness-associated genes; in gastric cancer, the knockdown of MIDN diminished the mRNA levels of Nanog and LDHA. Strikingly, silence of MIDN upregulated FTO protein expression in both breast and gastric cancer cells. Conclusions: Our findings demonstrate the expression, prognostic value, mutation status, interacting proteins, methylation status, and correlations with the tumor immune microenvironment of MIDN. MIDN will be developed as a potential therapeutic target and a prognosis biomarker. Full article

Cancer stem cells (CSC) are known to be the main source of tumor relapse, metastasis, or multidrug resistance and the mechanisms to counteract or eradicate them and their activity remain elusive. There are different hypotheses that claim that the origin of CSC might be in regular stem cells (SC) and, due to accumulation of mutations, these normal cells become malignant, or the source of CSC might be in any malignant cell that, under certain environmental circumstances, acquires all the qualities to become CSC. Multiple studies indicate that lifestyle and diet might represent a source of wellbeing that can prevent and ameliorate the malignant phenotype of CSC. In this review, after a brief introduction to SC and CSC, we analyze the effects of phenolic and non-phenolic dietary compounds and we highlight the molecular mechanisms that are shown to link diets to CSC activation in colon, breast, and prostate cancer. We focus the analysis on specific markers such as sphere formation, CD surface markers, epithelial–mesenchymal transition (EMT), Oct4, Nanog, Sox2, and aldehyde dehydrogenase 1 (ALDH1) and on the major signaling pathways such as PI3K/Akt/mTOR, NF-κB, Notch, Hedgehog, and Wnt/β-catenin in CSC. In conclusion, a better understanding of how bioactive compounds in our diets influence the dynamics of CSC can raise valuable awareness towards reducing cancer risk. Full article

Background/Objectives: Photoimmunotherapy (PIT) is an innovative approach for the targeted therapy of cancer. In PIT, photosensitizer dyes are conjugated to tumor-specific antibodies for targeted delivery into cancer cells. Upon irradiation with visible light, the photosensitizer dye is activated and induces cancer-specific cell death. In the present article, we describe the PIT of prostate cancer (PC) as a therapeutic option for the targeted treatment of localized prostate cancer. Methods: We conjugated the silicon phthalocyanine dye WB692-CB2 to recombinant cysteine-modified anti-CD44 and anti-EpCAM antibodies via a maleimide linker and tested the antibody dye conjugates for PIT on PC cells and prostate cancer stem cell (PCSC)-like cells. Results: The anti-CD44 and anti-EpCAM antibody dye conjugates showed specific binding and high cytotoxicity against PC and PCSC-like cells following irradiation with red light. Combined treatment with both conjugates led to enhanced cytotoxic effects. Conclusions: PIT with our dye WB692-CB2 can serve as an effective focal therapy against prostate cancer, preserving the prostate gland and minimizing side effects. It can be employed during radical prostatectomy (RP) to treat residual tumor cells or lymph node metastases in areas where further surgical intervention is not feasible. Utilizing multiple conjugates against antigens expressed on differentiated PC and PCSC-like cells, such as CD44 and EpCAM, could be an effective method to eradicate residual cancer cells in heterogeneous tumors. This approach could reduce the risk of local recurrence after RP and thus increase the therapeutic outcome of PC patients. Full article

The goal of this paper is to discuss the role of ALDH isozymes in different cancers, review advances in ALDH1-targeting cancer therapies, and explore a mechanism that explains how ALDH expression becomes elevated during cancer development. ALDH is often overexpressed in cancer, and each isoform has a unique expression pattern and a distinct role in different cancers. The abnormal expression of ALDHs in different cancer types (breast, colorectal, lung, gastric, cervical, melanoma, prostate, and renal) is presented and correlated with patient prognosis. ALDH plays a significant role in various cellular functions, such as metabolism, oxidative stress response, detoxification, and cellular differentiation. Among the ALDH families, ALDH1 has gained considerable attention as a cancer stem cell (CSC) marker due to its significant role in the maintenance of stemness and the differentiation of stem cells (SCs), along with its involvement in tumorigenesis. A description of the cellular mechanisms and physiology of ALDH1 that underlies cancer development is provided. Moreover, current advances in ALDH1-targeting cancer therapies are discussed. Full article

CAR-T therapy has revolutionized the field of oncology, offering a promising treatment option for cancer patients. However, the significant morbidity associated with therapy-related toxicity presents a major challenge to its widespread use. Despite extensive research into the underlying mechanisms of CAR-T therapy-related toxicity, there are still many unknowns. Furthermore, the lack of adequate in vitro models for assessing immunotoxicity and neurotoxicity further complicates the development of safer cellular therapies. Previously in our laboratory, we developed cancer-stroma spheres (CSS) composed of prostate adenocarcinoma PC3 cells and mesenchymal stem cells (MSC). Herein we present evidence that multicellular CSS could serve as a valuable in vitro model for toxicity studies related to CAR-T therapy. CSS containing CD19-overexpressing PC3M cells exhibited increased secretion of CAR-T cell toxicity-associated IL-8, MCP-1, and IP-10 in the presence of anti-CD19 CAR-T cells, compared to spheres derived from single cell types. Full article

Background/Objectives: The development of therapies targeting unregulated Src signaling through selective kinase inhibition using small-molecule inhibitors presents a significant challenge for the scientific community. Among these inhibitors, pyrazolo[3,4-d]pyrimidine heterocycles have emerged as potent agents; however, their clinical application is hindered by low solubility in water. To overcome this limitation, some carrier systems, such as halloysite nanotubes (HNTs), can be used. Methods: Herein, we report the development of HNT-based nanomaterials as carriers for pyrazolo[3,4-d]pyrimidine molecules. To achieve this objective, the clay was modified by two different approaches: supramolecular loading into the HNT lumen and covalent grafting onto the HNT external surface. The resulting nanomaterials were extensively characterized, and their morphology was imaged by high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM). In addition, the kinetic release of the molecules supramolecularly loaded into the HNTs was also evaluated. QSAR studies were conducted to elucidate the physicochemical and pharmacokinetic properties of these inhibitors, and structure-based virtual screening (SBVS) was performed to analyze their binding poses in protein kinases implicated in cancer. Results: The characterization methods demonstrate successful encapsulation of the drugs and the release properties under physiological conditions. Furthermore, QSAR studies and SBVS provide valuable insights into the physicochemical, pharmacokinetic, and binding properties of these inhibitors, reinforcing their potential efficacy. Conclusions: The cytotoxicity of these halloysite-based nanomaterials, and of pure molecules for comparison, was tested on RT112, UMUC3, and PC3 cancer cell lines, demonstrating their potential as effective agents for prostate and bladder cancer treatment. Full article

The delivery of anticancer drugs using nanotechnology is a promising approach aimed at improving the therapeutic efficacy and reducing the toxicity of chemotherapeutic agents. Liposomes were prepared using HSPC: DSPE–PEG–2000: DSPE–PEG2000–maleimide in the ratio of 4:1:0.2 and conjugated with a PSA antibody. Euphorbia milii extract (EME), doxorubicin (Dox), and docetaxel (Doc) encapsulated in temperature–sensitive immunoliposomes were investigated for their activities against the prostate cancer LNCap and DU145 cell lines. Organic extracts of EME leaves, roots, and stems were screened against both cell lines, inhibiting more than 50% of cell culture at concentrations of 10 μg/mL. The immunoliposomes incorporating the EME and docetaxel were active against the LNCap cells when exposed to heat at 39–40 °C. The liposomes not exposed to heat were inactive against the LNCap cells. The developed heat-sensitive immunoliposomes used for the delivery of both the EME and chemotherapeutic agents was able to successfully release the entrapped contents upon heat exposure above the phase transition temperature of the liposome membrane. The heat-sensitive immunoliposomes conjugated with a PSA antibody encapsulated the extract successfully and showed better cell antiproliferation efficacy against the prostate cancer cell lines in the presence of heat. Full article

Prostate cancer (PCa) poses a significant global health challenge, particularly due to its progression into aggressive forms like neuroendocrine prostate cancer (NEPC). This study developed and validated a stemness-associated gene signature using advanced machine learning techniques, including Random Forest and Lasso regression, applied to large-scale transcriptomic datasets. The resulting seven-gene signature (KMT5C, DPP4, TYMS, CDC25B, IRF5, MEN1, and DNMT3B) was validated across independent cohorts and patient-derived xenograft (PDX) models. This signature demonstrated strong prognostic value for progression-free, disease-free, relapse-free, metastasis-free, and overall survival. Importantly, the signature not only identified specific NEPC subtypes, such as large-cell neuroendocrine carcinoma, which is associated with very poor outcomes, but also predicted a poor prognosis for PCa cases that exhibit this molecular signature, even when they were not histopathologically classified as NEPC. This dual prognostic and classifier capability makes the seven-gene signature a robust tool for personalized medicine, providing a valuable resource for predicting disease progression and guiding treatment strategies in PCa management. Full article