Multiple Cell Signaling Pathways Research Articles

A novel combinatorial approach usingsulforaphane- and withaferin A-rich extracts for prevention of estrogen receptor-negative breast cancer through epigenetic and gut microbial mechanisms.

Estrogen receptor-negative [ER(-)] mammary cancer is the most aggressive type of breast cancer (BC) with higher rate of metastasis and recurrence. In recent years, dietary prevention of BC with epigenetically active phytochemicals has received increased attention due to its feasibility, effectiveness, and ease of implementation. In this regard, combinatorial phytochemical intervention enables more efficacious BC inhibition by simultaneously targeting multiple tumorigenic pathways. We, therefore, focused on investigation of the effect of sulforaphane (SFN)-rich broccoli sprouts (BSp) and withaferin A (WA)-rich Ashwagandha (Ash) combination on BC prevention in estrogen receptor-negative [ER(-)] mammary cancer using transgenic mice. Our results indicated that combinatorial BSp + Ash treatment significantly reduced tumor incidence and tumor growth (~ 75%) as well as delayed (~ 21%) tumor latency when compared to the control treatment and combinatorial BSp + Ash treatment was statistically more effective in suppressing BC compared to single BSp or Ash intervention. At the molecular level, the BSp and Ash combination upregulated tumor suppressors (p53, p57) along with apoptosis associated proteins (BAX, PUMA) and BAX:BCL-2 ratio. Furthermore, our result indicated an expressional decline of epigenetic machinery HDAC1 and DNMT3A in mammary tumor tissue because of combinatorial treatment. Interestingly, we have reported multiple synergistic interactions between BSp and Ash that have impacted both tumor phenotype and molecular expression due to combinatorial BSp and Ash treatment. Our RNA-seq analysis results also demonstrated a transcriptome-wide expressional reshuffling of genes associated with multiple cell-signaling pathways, transcription factor activity and epigenetic regulations due to combined BSp and Ash administration. In addition, we discovered an alteration of gut microbial composition change because of combinatorial treatment. Overall, combinatorial BSp and Ash supplementation can prevent ER(-) BC through enhanced tumor suppression, apoptosis induction and transcriptome-wide reshuffling of gene expression possibly influencing multiple cell signaling pathways, epigenetic regulation and reshaping gut microbiota.

VDX-111 targets proliferative pathways in canine cancer cell lines.

VDX-111 (also identified as AMPI-109) is a vitamin D derivative which has shown anticancer activity. To further assess the function of this compound against multiple cancer types, we examined the efficacy of VDX-111 against a panel of 30 well characterized canine cancer cell lines. Across a variety of cancer types, VDX-111 induced widely variable growth inhibition, cell death, and migration inhibition, at concentrations ranging from 10 nM to 1 μM. Growth inhibition sensitivity did not correlate strongly with tumor cell histotype; however, it was significantly correlated with the expression of genes in multiple cell signaling pathways, including the MAPK and PI3K-AKT pathways. We confirmed inhibition of these signaling pathways as likely participants in the effects of VDX-111. These results suggest that a subset of canine tumors may be sensitive to treatment with VDX-111, and suggests possible predictive markers of drug sensitivity and pharmacodynamic biomarkers of drug exposure that could be employed in future clinical trials.

Insights into Nimbolide molecular crosstalk and its anticancer properties.

Nimbolide, one of the main ingredients constituent of Azadirachta indica (neem) leaf extract, has garnered attention for its potential as an anticancer agent. Its efficacy against various cancers and chemopreventive action has been demonstrated through numerous in vivo and in vitro studies. This updated review aims to comprehensively explore the chemopreventive and anticancer properties of nimbolide, emphasizing its molecular mechanisms of action and potential therapeutic applications in oncology. The review synthesizes evidence from various studies that examine nimbolide's roles in apoptosis induction, anti-proliferation, cell death, metastasis inhibition, angiogenesis suppression, and modulation of carcinogen-metabolizing enzymes. Nimbolide exhibits multifaceted anticancer activities, including the modulation of multiple cell signaling pathways related to inflammation, invasion, survival, growth, metastasis, and angiogenesis. However, its pharmacological development is still in the early stages, mainly due to limited pharmacokinetic and comprehensive long-term toxicological studies. Nimbolide shows promising anticancer and chemopreventive properties, but there is need for systematic preclinical pharmacokinetic and toxicological research. Such studies are essential for establishing safe dosage ranges for first-in-human clinical trials and further advancing nimbolide's development as a therapeutic agent against various cancers. The review highlights the potential of nimbolide in cancer treatment and underscores the importance of rigorous preclinical evaluation to realize its full therapeutic potential.

Abstract 6956: Role of soluble CD109 in the progression of head and neck squamous cell carcinoma

Abstract Introduction: About five percent of global cancer deaths are attributed to Head and Neck Squamous Cell Carcinoma (HNSCC), and its annual incidence is predicted to skyrocket by thirty percent by 2030 (according to GLOBOCAN estimates). HNSCC originates from squamous cells in the oral cavity, lips, tongue, larynx, pharynx, and salivary glands. Despite the comparatively easy tumor diagnosis, the number of patients diagnosed at an advanced stage with metastatic spread is substantial. Multiple cell-signaling pathways have been proven to be dysregulated in HNSCC, including the epidermal growth factor receptor (EGFR). Our group has identified CD109, a GPI-anchored membrane-associated protein, as a TGF-β co-receptor that inhibits TGF-β signaling. CD109 expression is upregulated in SCC, and its elevated expression in premalignant lesions is associated with an increased risk of metastatic progression. Recent studies by our team have revealed that CD109 promotes tumor growth in vivo, likely by enhancing EGFR signaling. Interestingly, we have also discovered that membrane CD109 (mCD109) is endogenously released from the cell surface; however, the mechanism of action of the released/soluble form of CD109 (sCD109) remains unknown. In the current study, we examined whether sCD109 opposes the mCD109/EGFR-mediated pro-tumorigenic signaling and HNSCC progression. Research Questions: 1.Does sCD109 regulate EGF-induced EGFR signaling and downstream stem cell marker expression?2.Does sCD109 regulate EGFR expression levels on the HNSCC cell surface?3.Does sCD109 affect the nuclear localization of EGFR?4.Does sCD109 promote EGFR internalization and degradation? Methodology: HNSCC cells and patient-derived primary cells were treated with/without sCD109 recombinant protein (1nM, 5nM, and 10nM) without and with the EGF induction (10ng/ml for 15 mins) and were analyzed by western blotting, immunofluorescence, and immunocytochemistry. The role of sCD109 in regulating membrane EGFR levels was assessed by flow cytometry and surface protein biotinylation assay. Results: Our findings demonstrated that sCD109 inhibited EGF-induced phosphorylation of EGFR (Y1068), STAT3, AKT, and ERK. The sCD109 suppressed the stem cell marker expression (Nanog, OCT4, SOX2). Additionally, sCD109 hindered the nuclear localization of activated EGFR. The sCD109 decreased the membrane EGFR expression levels and activated the phosphorylation of EGFR (Y1045), suggesting a role for sCD109 in promoting EGFR degradation. Conclusion: Our team has previously reported that mCD109 is pro-tumorigenic, and our current findings suggest that sCD109 opposes the pro-tumorigenic effects of mCD109. This study aimed to determine how sCD109 regulates cellular signaling pathways and will provide key insights into the molecular mechanisms underlying the progression of HNSCC, a highly prevalent malignancy. Citation Format: Varsha Reddy Durgempudi, Tenzin Kungyal, Anie Philip. Role of soluble CD109 in the progression of head and neck squamous cell carcinoma [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 6956.

Allyl isothiocyanate regulates oxidative stress, inflammation, cell proliferation, cell cycle arrest, apoptosis, angiogenesis, invasion and metastasis via interaction with multiple cell signaling pathways.

Cancer growth is a molecular mechanism initiated by genetic and epigenetic modifications that are involved in cell proliferation, differentiation, apoptosis, and senescence pathways. Chemoprevention is an important strategy for cancer treatment that leads to blocking, reversing, or impeding the multistep process of tumorigenesis, including the blockage of its vital morphogenetic milestones viz. normal, preneoplasia, neoplasia, and metastasis. Naturally occurring phytochemicals are becoming ever more popular compared to synthetic drugs for many reasons, including safety, bioavailability, efficacy, and easy availability. Allyl isothiocyanate (AITC) is a natural compound present in all plants of the Cruciferae family, such as Brussels sprouts, cauliflower, mustard, cabbage, kale, horseradish, and wasabi. In vitro and in vivo studies carried out over the decades have revealed that AITC inhibits tumorigenesis without any toxicity and undesirable side effects. The bioavailability of AITC is exceedingly high, as it was reported that nearly 90% of orally administered AITC is absorbed. AITC exhibits multiple pharmacological properties among which its anticancer activity is the most significant for cancer treatment. Its anticancer activity is exerted via selective modulation of multiple cell signaling pathways related to oxidative stress, inflammation, cell proliferation, cell cycle arrest, apoptosis, angiogenesis, invasion, and metastasis. This review highlights the current knowledge on molecular targets that are involved in the anticancer effect of AITC associated with (i) inhibition of carcinogenic activation and induction of antioxidants, (ii) suppression of pro-inflammatory and cell proliferative signals, (iii) induction of cell cycle arrest and apoptosis, and (iv) inhibition of angiogenic and invasive signals related to metastasis.

Stimuli-Responsive 3D Printable Conductive Hydrogel: A Step toward Regulating Macrophage Polarization and Wound Healing.

Conductive hydrogels (CHs) are promising alternatives for electrical stimulation of cells and tissues in biomedical engineering. Wound healing and immunomodulation are complex processes that involve multiple cell types and signaling pathways. 3D printable conductive hydrogels have emerged as an innovative approach to promote wound healing and modulate immune responses. CHs can facilitate electrical and mechanical stimuli, which can be beneficial for altering cellular metabolism and enhancing the efficiency of the delivery of therapeutic molecules. This review summarizes the recent advances in 3D printable conductive hydrogels for wound healing and their effect on macrophage polarization. This report also discusses the properties of various conductive materials that can be used to fabricate hydrogels to stimulate immune responses. Furthermore, this review highlights the challenges and limitations of using 3D printable CHs for future material discovery. Overall, 3D printable conductive hydrogels hold excellent potential for accelerating wound healing and immune responses, which can lead to the development of new therapeutic strategies for skin and immune-related diseases.

Pax-8: Molecular biology, pathophysiology, and potential pathogenesis.

Transcription factors, as the convergence points of multiple signaling pathways in eukaryotic cells, are closely involved in disease development. Pax-8, an important transcription factor belonging to the Pax family, exerts a crucial influence on the regulation of gene expression required for both physiological conditions and pathological processes. Pax-8 contributes to the pathogenesis of many human diseases, ranging from cardiovascular disease to many cancers, and therefore, it can be imagined that Pax-8 holds great therapeutic potential. In this review, we summarize the structure, distribution, function, and regulatory mechanisms of Pax-8 to provide a new research direction for Pax-8.

Mask exhibits trxG-like behavior and associates with H3K27ac marked chromatin

The Trithorax group (trxG) proteins counteract the repressive effect of Polycomb group (PcG) complexes and maintain transcriptional memory of active states of key developmental genes. Although chromatin structure and modifications appear to play a fundamental role in this process, it is not clear how trxG prevents PcG-silencing and heritably maintains an active gene expression state. Here, we report a hitherto unknown role of Drosophila Multiple ankyrin repeats single KH domain (Mask), which emerged as one of the candidate trxG genes in our reverse genetic screen. The genome-wide binding profile of Mask correlates with known trxG binding sites across the Drosophila genome. In particular, the association of Mask at chromatin overlaps with CBP and H3K27ac, which are known hallmarks of actively transcribed genes by trxG. Importantly, Mask predominantly associates with actively transcribed genes in Drosophila. Depletion of Mask not only results in the downregulation of trxG targets but also correlates with diminished levels of H3K27ac. The fact that Mask positively regulates H3K27ac levels in flies was also found to be conserved in human cells. Strong suppression of Pc mutant phenotype by mutation in mask provides physiological relevance that Mask contributes to the anti-silencing effect of trxG, maintaining expression of key developmental genes. Since Mask is a downstream effector of multiple cell signaling pathways, we propose that Mask may connect cell signaling with chromatin mediated epigenetic cell memory governed by trxG.

Anticancer activity and other biomedical properties of β-sitosterol: Bridging phytochemistry and current pharmacological evidence for future translational approaches.

Sterols, including β-sitosterol, are essential components of cellular membranes in both plant and animal cells. Despite being a major phytosterol in various plant materials, comprehensive scientific knowledge regarding the properties of β-sitosterol and its potential applications is essential for scholarly pursuits and utilization purposes. β-sitosterol shares similar chemical characteristics with cholesterol and exhibits several pharmacological activities without major toxicity. This study aims to bridge the gap between phytochemistry and current pharmacological evidence of β-sitosterol, focusing on its anticancer activity and other biomedical properties. The goal is to provide a comprehensive understanding of β-sitosterol's potential for future translational approaches. A thorough examination of the literature was conducted to gather relevant information on the biological properties of β-sitosterol, particularly its anticancer therapeutic potential. Various databases were searched, including PubMed/MedLine, Scopus, Google Scholar, and Web of Science using appropriate keywords. Studies investigating the effects of β-sitosterol on different types of cancer were analyzed, focusing on mechanisms of action, pharmacological screening, and chemosensitizing properties. Modern pharmacological screening studies have revealed the potential anticancer therapeutic properties of β-sitosterol against various types of cancer, including leukemia, lung, stomach, breast, colon, ovarian, and prostate cancer. β-sitosterol has demonstrated chemosensitizing effects on cancer cells, interfering with multiple cell signaling pathways involved in proliferation, cell cycle arrest, apoptosis, survival, metastasis invasion, angiogenesis, and inflammation. Structural derivatives of β-sitosterol have also shown anti-cancer effects. However, research in the field of drug delivery and the detailed mode of action of β-sitosterol-mediated anticancer activities remains limited. β-sitosterol, as a non-toxic compound with significant pharmacological potential, exhibits promising anticancer effects against various cancer types. Despite being relatively less potent than conventional cancer chemotherapeutics, β-sitosterol holds potential as a safe and effective nutraceutical against cancer. Further comprehensive studies are recommended to explore the biological properties of β-sitosterol, including its mode of action, and develop novel formulations for its potential use in cancer treatment. This review provides a foundation for future investigations and highlights the need for further research on β-sitosterol as a potent superfood in combating cancer.

Klotho in Cancer: Potential Diagnostic and Prognostic Applications

Klotho proteins, αKlotho, βKlotho, and γKlotho, exert tumor-suppressive activities via the fibroblast growth factor receptors and multiple cell-signaling pathways. There is a growing interest in Klotho proteins as potential diagnostic and prognostic biomarkers for multiple diseases. However, recent advances regarding their roles and potential applications in cancer remain disperse and require an integrated analysis. The present review analyzed research articles published between 2012 and 2022 in the Cochrane and Scopus scientific databases to study the role of Klotho in cancer and their potential as tools for diagnosing specific cancer types, predicting tumor aggressiveness and prognosis. Twenty-six articles were selected, dealing with acute myeloid leukemia and with bladder, breast, colorectal, esophageal, gastric, hepatocellular, ovarian, pancreatic, prostatic, pulmonary, renal, and thyroid cancers. αKlotho was consistently associated with improved prognosis and may be useful in estimating patient survival. A single study reported the use of soluble αKlotho levels in blood serum as a tool to aid the diagnosis of esophageal cancer. γKlotho was associated with increased aggressiveness of bladder, breast, and prostate cancer, and βKlotho showed mixed results. Further clinical development of Klotho-based assays will require careful identification of specific tumor subtypes where Klotho proteins may be most valuable as diagnostic or prognostic tools.

Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing

Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and progression of LUAD. Pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are two key enzymes involved in glucose metabolism, whilst their aberrant expressions are often associated with tumorigenesis. Herein, we investigated the anticancer effects of combined inhibition of PDK1 and LDHA in LUAD in vitro and in vivo and its underlying mechanisms of action. The combination of a PDK1 inhibitor, 64, and a LDHA inhibitor, NHI-Glc-2, led to a synergistic growth inhibition in 3 different LUAD cell lines and more than additively suppressed tumor growth in the LUAD xenograft H1975 model. This combination also inhibited cellular migration and colony formation, while it induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) resulting in mitochondrial depolarization and apoptosis in LUAD cells. These effects were related to modulation of multiple cell signaling pathways, including AMPK, RAS/ERK, and AKT/mTOR. Our findings demonstrate that simultaneous inhibition of multiple glycolytic enzymes (PDK1 and LDHA) is a promising novel therapeutic approach for LUAD.

Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation.

Cancer is a multifactorial disorder with extremely complex genetics and progression. The major challenge in cancer therapy is the development of cancer resistance and relapse. Conventional anticancer drugs directly target the DNA of the cell, while modern chemotherapeutic drugs include molecular-targeted therapy, such as targeting the abnormal cell signaling inside the cancer cells. Targeted chemotherapy is effective in several malignancies; however, the success has always been limited by drug resistance and/or side effects. Anticancer with multi-targeted actions simultaneously modulates multiple cancer cell signaling pathways and, therefore, may ease the chance of effective anticancer drug development. In this research, a series of 7-deazapurine incorporating isatin hybrid compounds was designed and successfully synthesized. Among those hybrids, compound 5 demonstrated a very potent cytotoxic effect compared to the reference anticancer drug against four cancer cell lines. Likewise, compound 5 inhibited the activity of four protein kinase enzymes in nanomolar ranges. Further analysis of the biological evaluation of compound 5 revealed the capability of compound 5 to arrest cell cycle progression and induce programmed cell death. Moreover, molecular simulation studies were performed to investigate the possible types of interactions between compound 5 and the investigated protein kinases. Finally, taking into consideration all the abovementioned findings, compound 5 could be a good candidate for further investigations.

New Insights on Dietary Polyphenols for the Management of Oxidative Stress and Neuroinflammation in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a neurodegenerative and vascular pathology that is considered one of the leading causes of blindness worldwide, resulting from complications of advanced diabetes mellitus (DM). Current therapies consist of protocols aiming to alleviate the existing clinical signs associated with microvascular alterations limited to the advanced disease stages. In response to the low resolution and limitations of the DR treatment, there is an urgent need to develop more effective alternative therapies to optimize glycemic, vascular, and neuronal parameters, including the reduction in the cellular damage promoted by inflammation and oxidative stress. Recent evidence has shown that dietary polyphenols reduce oxidative and inflammatory parameters of various diseases by modulating multiple cell signaling pathways and gene expression, contributing to the improvement of several chronic diseases, including metabolic and neurodegenerative diseases. However, despite the growing evidence for the bioactivities of phenolic compounds, there is still a lack of data, especially from human studies, on the therapeutic potential of these substances. This review aims to comprehensively describe and clarify the effects of dietary phenolic compounds on the pathophysiological mechanisms involved in DR, especially those of oxidative and inflammatory nature, through evidence from experimental studies. Finally, the review highlights the potential of dietary phenolic compounds as a prophylactic and therapeutic strategy and the need for further clinical studies approaching the efficacy of these substances in DR management.

Sequence-based machine learning method for predicting the effects of phosphorylation on protein-protein interactions

Protein phosphorylation, catalyzed by kinases, is an important biochemical process, which plays an essential role in multiple cell signaling pathways. Meanwhile, protein-protein interactions (PPI) constitute the signaling pathways. Abnormal phosphorylation status on protein can regulate protein functions through PPI to evoke severe diseases, such as Cancer and Alzheimer's disease. Due to the limited experimental evidence and high costs to experimentally identify novel evidence of phosphorylation regulation on PPI, it is necessary to develop a high-accuracy and user-friendly artificial intelligence method to predict phosphorylation effect on PPI. Here, we proposed a novel sequence-based machine learning method named PhosPPI, which achieved better identification performance (Accuracy and AUC) than other competing predictive methods of Betts, HawkDock and FoldX. PhosPPI is now freely available in web server (https://phosppi.sjtu.edu.cn/). This tool can help the user to identify functional phosphorylation sites affecting PPI and explore phosphorylation-associated disease mechanism and drug development.

Boron stress signal is transmitted through the TOR pathway

Although boron is an essential element for many organisms, an excess amount of it can cause toxicity, and the mechanism behind this toxicity is not yet fully understood. The Gcn4 transcription factor plays a crucial role in the boron stress response by directly activating the expression of the boron efflux pump Atr1. More than a dozen transcription factors and multiple cell signaling pathways have roles in regulating the Gcn4 transcription factor under various circumstances. However, it is unknown which pathways or factors mediate boron signaling to Gcn4. Using the yeast Saccharomyces cerevisiae as a model, we analyzed the factors that converge on the Gcn4 transcription factor to assess their possible roles in boron stress signaling. Our findings show that the GCN system is activated by uncharged tRNA stress in response to boron treatment and that GCN1, which plays a role in transferring uncharged tRNAs to Gcn2, is necessary for the kinase activity of Gcn2. The SNF and PKA pathways were not involved in mediating boron stress, even though they interact with Gcn4. Mutations in TOR pathway genes, such as GLN3 and TOR1, abolished Gcn4 and ATR1 activation in response to boric acid treatment. Therefore, our study suggests that the TOR pathway must be functional to form a proper response against boric acid stress.

S100A8 and S100A9 in Cancer.

S100A8 and S100A9 are Ca2+ binding proteins that belong to the S100 family. Primarily expressed in neutrophils and monocytes, S100A8 and S100A9 play critical roles in modulating various inflammatory responses and inflammation-associated diseases. Forming a common heterodimer structure S100A8/A9, S100A8 and S100A9 are widely reported to participate in multiple signaling pathways in tumor cells. Meanwhile, S100A8/A9, S100A8, and S100A9, mainly as promoters, contribute to tumor development, growth and metastasis by interfering with tumor metabolism and the microenvironment. In recent years, the potential of S100A8/A9, S100A9, and S100A8 as tumor diagnostic or prognostic biomarkers has also been demonstrated. In addition, an increasing number of potential therapies targeting S100A8/A9 and related signaling pathways have emerged. In this review, we will first expound on the characteristics of S100A8/A9, S100A9, and S100A8 in-depth, focus on their interactions with tumor cells and microenvironments, and then discuss their clinical applications as biomarkers and therapeutic targets. We also highlight current limitations and look into the future of S100A8/A9 targeted anti-cancer therapy.

The roles of FHL2 in cancer.

LIM domain protein 2, also known as LIM protein FHL2, is a member of the LIM-only family. Due to its LIM domain protein characteristics, FHL2 is capable of interacting with various proteins and plays a crucial role in regulating gene expression, cell growth, and signal transduction in muscle and cardiac tissue. In recent years, mounting evidence has indicated that the FHLs protein family is closely associated with the development and occurrence of human tumors. On the one hand, FHL2 acts as a tumor suppressor by down-regulating in tumor tissue and effectively inhibiting tumor development by limiting cell proliferation. On the other hand, FHL2 serves as an oncoprotein by up-regulating in tumor tissue and binding to multiple transcription factors to suppress cell apoptosis, stimulate cell proliferation and migration, and promote tumor progression. Therefore, FHL2 is considered a double-edged sword in tumors with independent and complex functions. This article reviews the role of FHL2 in tumor occurrence and development, discusses FHL2 interaction with other proteins and transcription factors, and its involvement in multiple cell signaling pathways. Finally, the clinical significance of FHL2 as a potential target in tumor therapy is examined.

Abstract 306: Alternatively activated macrophages induce bystander effects via arginase 1

Abstract Colorectal cancer is a leading cause of cancer mortality and arises from genetic and epigenetic changes in colon epithelial cells. One of the mechanisms driving colon epithelial cell transformation is the bystander effect (BSE). BSE primarily arises from polarized macrophages (MØs) in stromal tissue. Herein, we report that alternatively activated (M2) MØs, as generated by interleukin (IL)-4, induce double-strand DNA breaks in target cells through BSE. Unlike M1 MØs that are activated by intestinal microbiota, BSE and DNA damage due to M2-like MØs occur through a distinct mechanism that differs from M1 MØs and does not involve pro-inflammatory mediators (e.g., cyclooxygenase-2 or tumor necrosis factor-α). Murine MØs (RAW264.7 cells) treated with IL-4 were polarized to an M2-like phenotype and found to strongly express arginase 1 (ARG1), a prototypical enzyme that converts L-arginine to L-ornithine and urea. L-Ornithine is a precursor in polyamine synthesis with H2O2 being a key oxidizing byproduct of polyamine catabolism. In a dual-chamber system using Young Adult Mouse Colon (YAMC) cells as targets for BSE generated by M2-like MØs, inhibition of ARG1 by N-hydroxy-nor-L-arginine abolished DNA damage (as measured by γH2AX). Direct treatment of YAMC cells with L-ornithine resulted in similar levels of DNA damage as M2-like MØs. YAMC cells exposed to M2-like MØs had increased intracellular H2O2. MDL-72527, an inhibitor polyamine oxidase and polyamine catabolism, reduced intracellular H2O2 to background levels and decreased DNA damage. YAMC cells sustaining DNA damage due to BSE from M2-like MØs showed specific phosphorylation of p53(ser15) and NF-κB(ser536) with no evidence for active caspase-3. These data along with an increased expression of cyclinD1 in YAMC cells indicated that DNA damage caused by M2-like MØs occurred via polyamine catabolism and was not due to cellular toxicity or apoptosis. Pathway analysis of RNAseq data for YAMC cells exposed to M2-like MØs identified multiple activated pathways including DNA repair, ubiquitination, Nrf2-mediated stress responses, endoplasmic reticulum overload responses, and lipid biosynthesis. These results provide additional evidence for global cellular responses to BSE generated by M2-like MØs. In conclusion, our findings show that M2-like MØs can generate BSE via a novel mechanism involving ARG1. Induction of BSE by M2-like MØs results in acute DNA damage in colon epithelial cells and activates multiple signaling pathways in target epithelial cells. These data imply a role for alternatively activated M2-like MØs in the malignant transformation of epithelial cells. Citation Format: Ram B. Undi, Hunter L. Porter, Jonathan D. Wren, Naushad Ali, Mark M. Huycke. Alternatively activated macrophages induce bystander effects via arginase 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 306.

A STUDY ON EXPRESSION OF LATENT MEMBRANE PROTEIN 1 OF EPSTEIN BARR VIRUS IN NASOPHARYNGEAL CARCINOMA IN SOUTH INDIA

Background- Nasopharyngeal carcinoma arises from the nasopharynx epithelial lining and is caused by Epstein Barr virus. Latent Membrane Protein 1(LMP 1) expressed on cytoplasmic portion of cell surface of Epstein Barr virus is an oncoprotein which triggers multiple cell signalling pathways and facilitates the expression of virus infected cell population at an early stage of development of nasopharyngeal carcinoma. Aims and Objectives- To study the age,sex distribution, clinical presentation, histologic spectrum and expression of LMP1 in the histologic types of nasopharyngeal carcinoma. The present study is a cross sectional study done over a Material And Methods- period of two years at a tertiary care hospital.Histologic typing of nasopharyngeal carcinoma done on light microscopy followed by expression of Latent Membrane Protein 1 by Immunohistochemistry. The present study showed a male predominance (75%), bimodal age Results- distribution in second and fth decades of life, presented most commonly as nasal obstruction (82.5%), non keratinising undifferentiated type being the commonest histologic type (80%) and LMP 1 expression in 45% of cases. The detection of Latent Membrane Protei Conclusion- n 1 by immunohistochemistry helps in early diagnosis of nasopharyngeal carcinoma and may aid in treatment as a therapeutic target

Deciphering the modulatory role of apigenin targeting oncogenic pathways in human cancers.

Cancer is a complicated malignancy controlled by numerous intrinsic and extrinsic pathways. There has been a significant increase in interest in recent years in the elucidation of cancer treatments based on natural extracts that have fewer side effects. Numerous natural product-derived chemicals have been investigated for their anticancer effects in the search for an efficient chemotherapeutic method. Therefore, the rationale behind this review is to provide a detailed insights about the anticancerous potential of apigenin via modulating numerous cell signaling pathways. An ingestible plant-derived flavonoid called apigenin has been linked to numerous anticancerous potential in numerous experimental and biological studies. Apigenin has been reported to induce cell growth arrest and apoptotic induction by modulating multiple cell signaling pathways in a wider range of human tumors including those of the breast, lung, liver, skin, blood, colon, prostate, pancreatic, cervical, oral, and stomach. Oncogenic protein networks, abnormal cell signaling, and modulation of the apoptotic machinery are only a few examples of diverse molecular interactions and processes that have not yet been thoroughly addressed by scientific research. Thus, keeping this fact in mind, we tried to focus our review towards summarizing the apigenin-mediated modulation of oncogenic pathways in various malignancies that can be further utilized to develop a potent therapeutic alternative for the treatment of various cancers.