Delayed breast cancer presentation, diagnosis, and treatment in Kenya.

PURPOSE: In this mixed-methods study, we evaluated the factors that contribute to delayed breast cancer (BC) diagnosis and treatment at a Kenyan hospital. METHODS: Individuals with a diagnosis of BC, either as a referral or index patient, were recruited to participate in this study through convenience sampling. Data were collected on sociodemographics, health history, and cancer history, diagnosis, and treatment of patients at Kenyatta National Hospital (KNH). For the quantitative analyses, the relationship between sociodemographic and health history factors with stage at diagnosis, number of visits before diagnosis, time to diagnosis, and time to initial intervention, stratified by time to onset of symptoms, were examined using regression analyses. For the qualitative analysis, in-depth interviews of every fifth patient were completed to assess reasons for delayed diagnosis and treatment. RESULTS: The final analytic sample comprised of 378 female BC patients with an average age of 50. These females were generally of lower SES: 49.2% attained no or only primary-level education, 57.4% were unemployed, and the majority (74.6%) had a monthly household income of < 5000 Kenyan shillings (equivalent to ~ $41 USD). The median time from BC symptom onset to presentation at KNH was 13 (IQR = 3-36) weeks, from presentation to diagnosis was 17.5 (IQR = 7-36.5) weeks, and from diagnosis to receipt of the initial intervention was 6 (IQR = 3-13) weeks. Female BC patients who were never/unmarried, less educated, less affluent, users of hormonal contraception, and had ≥ 3 children were more likely to experience diagnosis and treatment delays. Qualitative data showed that financial constraints, lack of patient BC awareness, and healthcare practitioner misdiagnosis and/or strikes delayed patient diagnosis and treatment. CONCLUSIONS: BC patients experience long healthcare system delays before diagnosis and treatment. Educating communities and providers about BC and expediting referrals may minimize such delays and subsequently BC mortality rates in Kenya.

Cancer-bone microenvironmental interactions promotes STAT3 signaling.

Prostate cancer (PCa) patients' mortality is mainly attributed to complications caused by metastasis of the tumor cells to organs critical for survival, such as bone. We hypothesized that PCa cell-bone interactions would promote paracrine signaling. A panel of PCa cell lines were cocultured with hydroxyapatite ([HA]; inorganic component of bone) of different densities. Conditioned media (CM) was collected and analyzed for calcium levels and effect on paracrine signaling, cell migration, and viability in vitro and in vivo. Our results showed that calcium levels were elevated in CM from cancer cell-bone cocultures, compared to media or cancer cells alone, and this could be antagonized by ethylene glycol-bis(2-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA), a calcium chelator, or knockdown of Snail protein. We also observed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation and paracrine cell proliferation and migration in LNCaP cells incubated with CM from various cell lines; this phosphorylation and cell migration could be antagonized by Snail knockdown or various inhibitors including EGTA, STAT3 inhibitor (WP1066) or cathepsin L inhibitor (Z-FY-CHO). In vivo, higher HA bone density increased tumorigenicity and migration of tumor cells to HA implant. Our study shows that cancer-bone microenvironment interactions lead to calcium-STAT3 signaling, which may present an area for therapeutic targeting of metastatic PCa.

Proteomics-Metabolomics Combined Approach Identifies Peroxidasin as a Protector against Metabolic and Oxidative Stress in Prostate Cancer.

Peroxidasin (PXDN), a human homolog of Drosophila PXDN, belongs to the family of heme peroxidases and has been found to promote oxidative stress in cardiovascular tissue, however, its role in prostate cancer has not been previously elucidated. We hypothesized that PXDN promotes prostate cancer progression via regulation of metabolic and oxidative stress pathways. We analyzed PXDN expression in prostate tissue by immunohistochemistry and found increased PXDN expression with prostate cancer progression as compared to normal tissue or cells. PXDN knockdown followed by proteomic analysis revealed an increase in oxidative stress, mitochondrial dysfunction and gluconeogenesis pathways. Additionally, Liquid Chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomics confirmed that PXDN knockdown induced global reprogramming associated with increased oxidative stress and decreased nucleotide biosynthesis. We further demonstrated that PXDN knockdown led to an increase in reactive oxygen species (ROS) associated with decreased cell viability and increased apoptosis. Finally, PXDN knockdown decreased colony formation on soft agar. Overall, the data suggest that PXDN promotes progression of prostate cancer by regulating the metabolome, more specifically, by inhibiting oxidative stress leading to decreased apoptosis. Therefore, PXDN may be a biomarker associated with prostate cancer and a potential therapeutic target.

High mobility group A2 (HMGA2) promotes EMT via MAPK pathway in prostate cancer.

Studies have shown that High mobility group A2 (HMGA2), a non-histone protein, can promote epithelial-mesenchymal transition (EMT), which plays a critical role in prostate cancer progression and metastasis. Interestingly, full-length or wild-type HMGA2 and truncated (lacking the 3'UTR) HMGA2 isoforms are overexpressed in several cancers. However, there are no studies investigating the expression and differential roles of WT vs truncated HMGA2 isoforms in prostate cancer. Immunohistochemical staining of prostate tissue microarray revealed low membrane expression in normal epithelial prostate cells, and that expression increased with tumor grade as well as a switch from predominantly cytoplasmic HMGA2 in lower tumor grades, to mostly nuclear in high grade and bone metastatic tissue. LNCaP cells stably overexpressing wild-type HMGA2 displayed nuclear localization of HMGA2 and induction of EMT associated with increased Snail, Twist and vimentin expression compared to LNCaP Neo control cells, as shown by immunofluorescence and western blot analyses. This was associated with increased cell migration on collagen shown using boyden chamber assay. Conversely, LNCaP cells overexpressing truncated HMGA2 showed cytoplasmic HMGA2 expression that did not induce EMT yet displayed increased cell proliferation and migration compared to LNCaP Neo. Both wild-type and truncated HMGA2 increased levels of phospho-ERK, and interestingly, treatment with U0126, MAPK inhibitor, antagonized wild-type HMGA2-mediated EMT and cell migration, but did not affect truncated HMGA2-mediated cell proliferation or migration. Therefore, although both wild-type and truncated HMGA2 may promote prostate tumor progression, wild-type HMGA2 acts by inducing EMT via MAPK pathway.

Epithelial-Mesenchymal Transition (EMT) and Prostate Cancer.

Typically the normal epithelial cells are a single layer, held tightly by adherent proteins that prevent the mobilization of the cells from the monolayer sheet. During prostate cancer progression, the epithelial cells can undergo epithelial-mesenchymal transition or EMT, characterized by morphological changes in their phenotype from cuboidal to spindle-shaped. This is associated with biochemical changes in which epithelial cell markers such as E-cadherin and occludins are down-regulated, which leads to loss of cell-cell adhesion, while mesenchymal markers such as vimentin and N-cadherin are up-regulated, thereby allowing the cells to migrate or metastasize to different organs. The EMT transition can be regulated directly and indirectly by multiple molecular mechanisms including growth factors and cytokines such as transforming growth factor-beta (TGF-ß), epidermal growth factor (EGF) and insulin-like growth factor (IGF), and signaling pathways such as mitogen-activated protein kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3K). This signaling subsequently induces expression of various transcription factors like Snail, Twist, Zeb1/2, that are also known as master regulators of EMT. Various markers associated with EMT have been reported in prostate cancer patient tissue as well as a possible association with health disparities. There has been consideration to therapeutically target EMT in prostate cancer patients by targeting the EMT signaling pathways.

Snail transcription factor NLS and importin ß1 regulate the subcellular localization of Cathepsin L and Cux1.

Several recent studies have highlighted an additional unexpected localization and site of action for Cathepsin L (Cat L) protease within the nucleus in breast, colon and prostate cancer, however, its role in the nucleus was unclear. It was proposed to mediate proteolytic processing of the transcription factor CCAAT-displacement protein/cut homeobox transcription factor (Cux1) from the full-length p200 isoform to generate the p110 and p90 isoforms, of which the p110 isoform was shown to act as a cell cycle regulator to accelerate entry into the S phase. The p110 isoform has also been shown to bind to the promoter regions of Snail and E-cadherin to activate Snail and inactivate E-cadherin transcription, thus promoting epithelial mesenchymal transition (EMT). Mechanistic studies on what drives Cat L nuclear localization have not been reported. Our hypothesis is that Snail shuttles into the nucleus with Cat L through binding to importin-ß. Snail knockdown with siRNA in MDA-MB-468 breast cancer cells led to nuclear to cytoplasmic shuttling of Cat L and decreased levels of Cux1, while overexpression of Snail in MCF-7 breast cancer cells or HEK-293 human embryonic kidney cells led to increased nuclear expression of both Cat L and Cux1. Additionally, transient transfection of Snail NLS mutants not only abrogated Snail nuclear localization but also nuclear localization of Cat L and Cux1. Interestingly, importin ß1 knockdown with siRNA decreased Snail and Cux1 levels, as well as nuclear localization of Cat L. Therefore, we show for the first time that the nuclear localization of Cat L and its substrate Cux1can be positively regulated by Snail NLS and importin ß1, suggesting that Snail, Cat L and Cux1 all utilize importin ß1 for nuclear import.

Muscadine grape skin extract can antagonize Snail-cathepsin L-mediated invasion, migration and osteoclastogenesis in prostate and breast cancer cells.

To develop new and effective chemopreventive agents against bone metastasis, we assessed the effects of muscadine grape skin extract (MSKE), whose main bioactive component is anthocyanin, on bone turnover, using prostate and breast cancer cell models overexpressing Snail transcription factor. MSKE has been shown previously to promote apoptosis in prostate cancer cells without affecting normal prostate epithelial cells. Snail is overexpressed in prostate and breast cancer, and is associated with increased invasion, migration and bone turnover/osteoclastogenesis. Cathepsin L (CatL) is a cysteine cathepsin protease that is overexpressed in cancer and involved in bone turnover. Snail overexpression in prostate (LNCaP, ARCaP-E) and breast (MCF-7) cancer cells led to increased CatL expression/activity and phosphorylated STAT-3 (pSTAT-3), compared to Neo vector controls, while the reverse was observed in C4-2 (the aggressive subline of LNCaP) cells with Snail knockdown. Moreover, CatL expression was higher in prostate and breast tumor tissue compared to normal tissue. MSKE decreased Snail and pSTAT3 expression, and abrogated Snail-mediated CatL activity, migration and invasion. Additionally, Snail overexpression promoted osteoclastogenesis, which was significantly inhibited by the MSKE as effectively as Z-FY-CHO, a CatL-specific inhibitor, or osteoprotegerin, a receptor activator of nuclear factor kappa B ligand (RANKL) antagonist. Overall, these novel findings suggest that Snail regulation of CatL may occur via STAT-3 signaling and can be antagonized by MSKE, leading to decreased cell invasion, migration and bone turnover. Therefore, inhibition using a natural product such as MSKE could potentially be a promising bioactive compound for bone metastatic cancer.

The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis.

The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis.

Muscadine grape skin extract reverts snail-mediated epithelial mesenchymal transition via superoxide species in human prostate cancer cells.

BACKGROUND: Snail transcription factor can induce epithelial-mesenchymal transition (EMT), associated with decreased cell adhesion-associated molecules like E-cadherin, increased mesenchymal markers like vimentin, leading to increased motility, invasion and metastasis. Muscadine grape skin extract (MSKE) has been shown to inhibit prostate cancer cell growth and induce apoptosis without affecting normal prostate epithelial cells. We investigated novel molecular mechanisms by which Snail promotes EMT in prostate cancer cells via Reactive Oxygen Species (ROS) and whether it can be antagonized by MSKE. METHODS: ARCaP and LNCaP cells overexpressing Snail were utilized to examine levels of reactive oxygen species (ROS), specifically, superoxide, in vitro using Dihydroethidium (DHE) or HydroCy3 dyes. Mitosox staining was performed to determine whether the source of ROS was mitochondrial in origin. We also investigated the effect of Muscadine grape skin extract (MSKE) on EMT marker expression by western blot analysis. Migration and cell viability using MTS proliferation assay was performed following MSKE treatments. RESULTS: Snail overexpression in ARCaP and LNCaP cells was associated with increased concentration of mitochondrial superoxide, in vitro. Interestingly, MSKE decreased superoxide levels in ARCaP and LNCaP cells. Additionally, MSKE and Superoxide Dismutase (SOD) reverted EMT as evidenced by decreased vimentin levels and re-induction of E-cadherin expression in ARCaP-Snail cells after 3 days, concomitant with reduced cell migration. MSKE also decreased Stat-3 activity in ARCaP-Snail cells. CONCLUSIONS: This study shows that superoxide species may play a role in Snail transcription factor-mediated EMT. Therefore, therapeutic targeting of Snail with various antioxidants such as MSKE may prove beneficial in abrogating EMT and ROS-mediated tumor progression in human prostate cancer.

Camalexin-induced apoptosis in prostate cancer cells involves alterations of expression and activity of lysosomal protease cathepsin D.

Camalexin, the phytoalexin produced in the model plant Arabidopsis thaliana, possesses antiproliferative and cancer chemopreventive effects. We have demonstrated that the cytostatic/cytotoxic effects of camalexin on several prostate cancer (PCa) cells are due to oxidative stress. Lysosomes are vulnerable organelles to Reactive Oxygen Species (ROS)-induced injuries, with the potential to initiate and or facilitate apoptosis subsequent to release of proteases such as cathepsin D (CD) into the cytosol. We therefore hypothesized that camalexin reduces cell viability in PCa cells via alterations in expression and activity of CD. Cell viability was evaluated by MTS cell proliferation assay in LNCaP and ARCaP Epithelial (E) cells, and their respective aggressive sublines C4-2 and ARCaP Mesenchymal (M) cells, whereby the more aggressive PCa cells (C4-2 and ARCaPM) displayed greater sensitivity to camalexin treatments than the lesser aggressive cells (LNCaP and ARCaPE). Immunocytochemical analysis revealed CD relocalization from the lysosome to the cytosol subsequent to camalexin treatments, which was associated with increased protein expression of mature CD; p53, a transcriptional activator of CD; BAX, a downstream effector of CD, and cleaved PARP, a hallmark for apoptosis. Therefore, camalexin reduces cell viability via CD and may present as a novel therapeutic agent for treatment of metastatic prostate cancer cells.

Unveiling the potential of Muscadine grape Skin extract as an innovative therapeutic intervention in cancer treatment.

The use of muscadine grape extracts (MGSE). in cancer treatment has gained attention due to its distinctive composition of polyphenols and antioxidants. This review analyses the reported anti-cancer properties of MGSE. The study commences by reviewing the phytochemical composition of MGSE, highlighting the presence of resveratrol and ellagic acid. Furthermore, the review underscores the mechanism of action of these active compounds in MGSE in combating cancer cells. The anti-cancer potential of MGSE compared to other plant extracts is also discussed. In addition, it highlights MGSE's superiority and distinct phytochemical composition in preventing cancer growth by comparing its anti-cancer compounds with those of other anti-cancer medicinal plants. Lastly, the combinatory approaches of MGSE with traditional cancer therapies, its safety, and its possible side effects were highlighted. This work provides an understanding of the anti-cancer properties of MGSE, positioning it as a valuable and unique challenge within the field of cancer therapy.

A Hybrid Learning-Architecture for Mental Disorder Detection Using Emotion Recognition.

Mental illness has grown to become a prevalent and global health concern that affects individuals across various demographics. Timely detection and accurate diagnosis of mental disorders are crucial for effective treatment and support as late diagnosis could result in suicidal, harmful behaviors and ultimately death. To this end, the present study introduces a novel pipeline for the analysis of facial expressions, leveraging both the AffectNet and 2013 Facial Emotion Recognition (FER) datasets. Consequently, this research goes beyond traditional diagnostic methods by contributing a system capable of generating a comprehensive mental disorder dataset and concurrently predicting mental disorders based on facial emotional cues. Particularly, we introduce a hybrid architecture for mental disorder detection leveraging the state-of-the-art object detection algorithm, YOLOv8 to detect and classify visual cues associated with specific mental disorders. To achieve accurate predictions, an integrated learning architecture based on the fusion of Convolution Neural Networks (CNNs) and Visual Transformer (ViT) models is developed to form an ensemble classifier that predicts the presence of mental illness (e.g., depression, anxiety, and other mental disorder). The overall accuracy is improved to about 81% using the proposed ensemble technique. To ensure transparency and interpretability, we integrate techniques such as Gradient-weighted Class Activation Mapping (Grad-CAM) and saliency maps to highlight the regions in the input image that significantly contribute to the model's predictions thus providing healthcare professionals with a clear understanding of the features influencing the system's decisions thereby enhancing trust and more informed diagnostic process.

High Mobility Group AT-hook 2: A Biomarker Associated with Resistance to Enzalutamide in Prostate Cancer Cells.

Metastatic prostate cancer (mPCa) is a leading cause of mortality, partly due to its resistance to anti-androgens like enzalutamide. Snail can promote this resistance by increasing full-length AR and AR-V7. High Mobility Group AT-hook 2 (HMGA2), a DNA-binding protein upstream of Snail, is crucial in proliferation and epithelial-mesenchymal transition (EMT). This study examines HMGA2's role in enzalutamide resistance. LNCaP and 22Rv1 cells overexpressing wild-type HMGA2, but not truncated HMGA2, showed EMT. Both variants led to a decreased sensitivity to enzalutamide but not alisertib compared to Neo control cells. The overexpression of HMGA2 did not alter AR expression. Enzalutamide-resistant C4-2B cells (C4-2B MDVR) had higher HMGA2 and AR/AR variant expression than enzalutamide-sensitive C4-2B cells but remained sensitive to alisertib. The HMGA2 knockdown in C4-2B MDVR cells increased sensitivity to both enzalutamide and alisertib without changing AR expression. A clinical analysis via cBioPortal revealed HMGA2 alterations in 3% and AR alterations in 59% of patients. The HMGA2 changes were linked to treatments like enzalutamide, abiraterone, or alisertib, with amplifications more prevalent in bone, lymph node, and liver metastases. Conclusively, HMGA2 is a potential biomarker for enzalutamide resistance in mPCa, independent of Snail and AR signaling, and alisertib may be an effective treatment for mPCa that expresses HMGA2.

ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells.

Reactive oxygen species (ROS) play a central role in oxidative stress, which leads to the onset of diseases, such as cancer. Furthermore, ROS contributes to the delicate balance between tumor cell survival and death. However, the mechanisms by which tumor cells decide to elicit survival or death signals during oxidative stress are not completely understood. We have previously reported that ROS enhanced tumorigenic functions in prostate cancer cells, such as transendothelial migration and invasion, which depended on CXCR4 and AKT signaling. Here, we report a novel mechanism by which ROS facilitated cell death through activation of AKT. We initially observed that ROS enhanced the expression of phosphorylated AKT (p-AKT) in 22Rv1 human prostate cancer cells. The tumor suppressor PTEN, a negative regulator of AKT signaling, was rendered catalytically inactive through oxidation by ROS, although the expression levels remained consistent. Despite these events, cells still underwent apoptosis. Further investigation into apoptosis revealed that expression of the tumor suppressor pVHL increased, and contains a target site for p-AKT phosphorylation. pVHL and p-AKT associated in vitro, and knockdown of pVHL rescued HIF1α expression and the cells from apoptosis. Collectively, our study suggests that in the context of oxidative stress, p-AKT facilitated apoptosis by inducing pVHL function.

Prostate cancer metastasis and health disparities: a systematic review.

BACKGROUND: Prostate cancer (PCa), one of the most prevalent malignancies affecting men, significantly contributes to increased mortality rates worldwide. While the causative death is due to advanced metastatic disease, this occurrence disproportionately impacts men of African descent compared to men of European descent. In this review, we describe potential mechanisms underlying PCa metastases disparities and current treatments for metastatic disease among these populations, differences in treatment outcomes, and survival rates, in hopes of highlighting a need to address disparities in PCa metastases. METHODS: We reviewed existing literature using databases such as PubMed, Google Scholar, and Science Direct using the following keywords: "prostate cancer metastases", "metastatic prostate cancer disparity", "metastatic prostate cancer diagnosis and treatment", "prostate cancer genetic differences and mechanisms", "genetic differences and prostate tumor microenvironment", and "men of African descent and access to clinical treatments". The inclusion criteria for literature usage were original research articles and review articles. RESULTS: Studies indicate unique genetic signatures and molecular mechanisms such as Epithelial-Mesenchymal Transition (EMT), inflammation, and growth hormone signaling involved in metastatic PCa disparities. Clinical studies also demonstrate differences in treatment outcomes that are race-specific, for example, patients of African descent have a better response to enzalutamide and immunotherapy yet have less access to these drugs as compared to patients of European descent. CONCLUSIONS: Growing evidence suggests a connection between a patient's genetic profile, the prostate tumor microenvironment, and social determinants of health that contribute to the aggressiveness of metastatic disease and treatment outcomes. With several potential pathways highlighted, the limitations in current diagnostic and therapeutic applications that target disparity in PCa metastases warrant rigorous research attention.

Post biphosphonate mandible osteonecrosis: A case study and literature review.

Purpose: Bisphosphonates have proven effective in reducing pain and skeletal events in bone metastases treatment. However, there is a long-term complication called osteonecrosis of the jaw, which has been reported for more than a decade. Despite various professional recommendations, there is no international consensus on the best therapeutic strategy. Prevention is crucial, and a multidisciplinary approach must be tailored to each stage of the condition. Design: We present a case of osteonecrosis of the jaw in a patient with metastatic breast cancer who was receiving 4 mg injectable zoledronic acid. Result: The patient stopped treatment with zoledronic acid and received systemic treatment (analgesics, antibiotics), with the resolution of symptoms. Conclusion: ONJ is a serious condition associated with taking BP that can impact oral health and quality of life. Our study highlights the effectiveness of systematic treatment in managing ONJ with BP-related alterations. Preventative measures, such as regular dental consultations, play a vital role in reducing the risk of ONJ. Multidisciplinary management is essential to addressing the different stages of the condition.

Novel roles for HMGA2 isoforms in regulating oxidative stress and sensitizing to RSL3-Induced ferroptosis in prostate cancer cells.

Oxidative stress is increased in several cancers including prostate cancer, and is currently being exploited in cancer therapy to induce ferroptosis, a novel nonapoptotic form of cell death. High mobility group A2 (HMGA2), a non-histone protein up-regulated in several cancers, can be truncated due to chromosomal rearrangement or alternative splicing of HMGA2 gene. The purpose of this study is to investigate the role of wild-type vs. truncated HMGA2 in prostate cancer (PCa). We analyzed the expression of wild-type vs. truncated HMGA2 and showed that prostate cancer patient tissue and some cell lines expressed increasing amounts of both wild-type and truncated HMGA2 with increasing tumor grade, compared to normal epithelial cells. RNA-Seq analysis of LNCaP prostate cancer cells stably overexpressing wild-type HMGA2 (HMGA2-WT), truncated HMGA2 (HMGA2-TR) or empty vector (Neo) control revealed that HMGA2-TR cells exhibited higher oxidative stress compared to HMGA2-WT or Neo control cells, which was also confirmed by analysis of basal reactive oxygen species (ROS) levels using 2', 7'-dichlorofluorescin diacetate (DCFDA) dye, the ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) and NADP/NADPH using metabolomics. This was associated with increased sensitivity to RAS-selective lethal 3 (RSL3)-induced ferroptosis that could be antagonized by ferrostatin-1. Additionally, proteomic and immunoprecipitation analyses showed that cytoplasmic HMGA2 protein interacted with Ras GTPase-activating protein-binding protein 1 (G3BP1), a cytoplasmic stress granule protein that responds to oxidative stress, and that G3BP1 transient knockdown increased sensitivity to ferroptosis even further. Endogenous knockdown of HMGA2 or G3BP1 in PC3 cells reduced proliferation which was reversed by ferrostatin-1. In conclusion, we show a novel role for HMGA2 in oxidative stress, particularly the truncated HMGA2, which may be a therapeutic target for ferroptosis-mediated prostate cancer therapy.

Snail transcription factor negatively regulates maspin tumor suppressor in human prostate cancer cells.

BACKGROUND: Maspin, a putative tumor suppressor that is down-regulated in breast and prostate cancer, has been associated with decreased cell motility. Snail transcription factor is a zinc finger protein that is increased in breast cancer and is associated with increased tumor motility and invasion by induction of epithelial-mesenchymal transition (EMT). We investigated the molecular mechanisms by which Snail increases tumor motility and invasion utilizing prostate cancer cells. METHODS: Expression levels were analyzed by RT-PCR and western blot analyses. Cell motility and invasion assays were performed, while Snail regulation and binding to maspin promoter was analyzed by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RESULTS: Snail protein expression was higher in different prostate cancer cells lines as compared to normal prostate epithelial cells, which correlated inversely with maspin expression. Snail overexpression in 22Rv1 prostate cancer cells inhibited maspin expression and led to increased migration and invasion. Knockdown of Snail in DU145 and C4-2 cancer cells resulted in up-regulation of maspin expression, concomitant with decreased migration. Transfection of Snail into 22Rv1 or LNCaP cells inhibited maspin promoter activity, while stable knockdown of Snail in C4-2 cells increased promoter activity. ChIP analysis showed that Snail is recruited to the maspin promoter in 22Rv1 cells. CONCLUSIONS: Overall, this is the first report showing that Snail can negatively regulate maspin expression by directly repressing maspin promoter activity, leading to increased cell migration and invasion. Therefore, therapeutic targeting of Snail may be useful to re-induce expression of maspin tumor suppressor and prevent prostate cancer tumor progression.

Building Capacity for Community-Academia Research Partnerships by Establishing a Physical Infrastructure for Community Engagement: Morgan CARES.

Research partnerships between universities and communities following the principles of community-based participatory research (CBPR) have the potential to eliminate cycles of health disparities. The purpose of this article is to describe the process of establishing a community-campus network with a distinct mission and vision of developing trusting and successful research partnerships that are sustained and effective. In 2019, Morgan CARES was established to facilitate community engagement by founding a community center "within" a low-income residential neighborhood as a safe and accessible hub for creating a vibrant learning community. A community needs assessment and asset mapping was conducted and several necessary resources and services were provided to maximize networking opportunities, nurture innovative ideas and proposals, and provide seed funding. Lessons learned informed the optimization of a theoretical model that has guided the development and implementation of the program's key components. By December 2021, Morgan CARES had recruited 222 community and 137 academic members representing diverse expertise from across Baltimore City. We also successfully established new partnerships and funded a total of 17 small community-academic awards. Although in its early stages, Morgan CARES has established a dynamic learning community following a conceptual framework that could guide future similar initiatives.

Snail-mediated regulation of reactive oxygen species in ARCaP human prostate cancer cells.

Reactive oxygen species increases in various diseases including cancer and has been associated with induction of epithelial-mesenchymal transition (EMT), as evidenced by decrease in cell adhesion-associated molecules like E-cadherin, and increase in mesenchymal markers like vimentin. We investigated the molecular mechanisms by which Snail transcription factor, an inducer of EMT, promotes tumor aggressiveness utilizing ARCaP prostate cancer cell line. An EMT model created by Snail overexpression in ARCaP cells was associated with decreased E-cadherin and increased vimentin. Moreover, Snail-expressing cells displayed increased concentration of reactive oxygen species (ROS), specifically, superoxide and hydrogen peroxide, in vitro and in vivo. Real Time PCR profiling demonstrated increased expression of oxidative stress-responsive genes, such as aldehyde oxidase I, in response to Snail. The ROS scavenger, N-acetyl cysteine partially reversed Snail-mediated EMT after 7 days characterized by increased E-cadherin levels and decreased ERK activity, while treatment with the MEK inhibitor, UO126, resulted in a more marked effect by 3 days, characterized by cells returning back to the epithelial morphology and increased E-cadherin. In conclusion, this study shows for the first time that Snail transcription factor can regulate oxidative stress enzymes and increase ROS-mediated EMT regulated in part by ERK activation. Therefore, Snail may be an attractive molecule for therapeutic targeting to prevent tumor progression in human prostate cancer.