Berbamine, a bisbenzylisoquinoline alkaloid (bisBIA), is a promising lead for developing novel therapeutics to treat aggressive cancers such as lymphoma, by targeting the CaMKIIγ:cMyc axis. Herein, we report an aza-Friedel-Crafts method for ortho-aminoalkylation of berbamine's phenolic motif, enabling the semisynthesis of the natural product bersavine and analogs that complement current methods focusing on modifying the phenolic oxygen. Several new analogs synthesized by this method exhibit potent cytotoxicity against lymphoma-associated cell line H9 exceeding the naturally occurring berbamine (1) and bersavine (3a). A molecular docking analysis was used to devise a model that rationalizes the structure-activity relationship between the novel bisBIA analogs and CaMKIIγ inhibition.

The chaperonin tailless complex polypeptide 1 (TCP1) is a key subunit of chaperonin containing TCP1 (CCT) that regulates the folding and stability of proteins during cancer progression. Here, the prognostic significance of TCP1 was explored mainly in patients with hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). We showed that TCP1 expression was significantly greater in clinically malignant tumour tissues than in normal tissues and that high TCP1 expression was associated with poor prognosis. TCP1 suppression not only decreased the proliferation and invasion of cancer cells in vitro but also inhibited tumour growth and metastasis in vivo. The underlying mechanisms were determined by ubiquitination assays and Co-IP (Co-Immunoprecipitation) experiments, and it was found that TCP1 regulated the stability of c-Myc through the RAC-alpha serine/threonine-protein kinase (AKT) /Glycogen synthase kinase 3β (GSK-3β) and extracellular regulated protein kinases (ERK) signalling pathways. Moreover, TCP1 knock-in (TCP1-KI) dramatically promoted the occurrence of diethylnitrosamine (DEN) -induced primary HCC in mice. Our results highlight the critical role of TCP1 in HCC and PDAC and reveal a novel mechanism to suppress HCC and PDAC by targeting c-Myc via the TCP1-induced promotion of the AKT/GSK-3β and ERK signalling pathways. TCP1 is able to modulate the stability of target proteins by multiple pathways, thus promoting the progression of HCC and PDAC. Our study identifies TCP1 as a prognostic novel marker and therapeutic target of HCC and PDAC.

This study aimed to investigate the mechanism and role of MFAP5 in papillary thyroid carcinoma (PTC), laying the foundation for future clinical treatment of PTC. Using WB and RT-qPCR to determine MFAP5 expression in PTC tissues and paracancerous tissues, as well as human normal thyroid cell lines and human PTC cell lines. Viral infection of PTC cells by overexpressing MFAP5 and knocking down EFEMP2. CCK8 and a colony formation assay were used to assess PTC cell proliferation. Kits detect glucose uptake, lactate production, and WB analyses of GLUT1, HK-II, and LDHA expression to evaluate aerobic glycolysis. Nude mice were used as xenograft models for tumor growth assessment. MFAP5. WB detects the expression of EFEMP2, Myc, cyclin D1 and β-catenin. MFAP5 expression is significantly reduced in PTC tissues and cells. MFAP5 overexpression inhibits PTC cell proliferation and aerobic glycolysis. MFAP5 overexpression activates EFEMP2 and suppresses the Wnt/β-catenin pathway. Knockdown of EFEMP2 reverses PTC cell proliferation and aerobic glycolysis. Tumor growth can be inhibited in vivo by MFAP5 overexpression, which regulates the EFEMP2/Wnt/β-catenin pathway. Overexpression of MFAP5 inhibits PTC progression and aerobic glycolysis by regulating the EFEMP2/Wnt/β-catenin pathway.

Cancer cells acquire metabolic advantages over their normal counterparts regarding the use of nutrients for sustained cell proliferation and cell survival in the tumor microenvironment. Notable among the metabolic traits in cancer cells is the Warburg effect, which is a reprogrammed form of glycolysis that favors the rapid generation of ATP from glucose and the production of biological macromolecules by diverting glucose into various metabolic intermediates. Meanwhile, mannose, which is the C-2 epimer of glucose, has the ability to dampen the Warburg effect, resulting in slow-cycling cancer cells that are highly susceptible to chemotherapy. This anticancer effect of mannose appears when its catabolism is compromised in cancer cells. Moreover, de novo synthesis of mannose within cancer cells has also been identified as a potential target for enhancing chemosensitivity through targeting glycosylation pathways. The underlying mechanisms by which alterations in mannose metabolism induce cancer cell vulnerability are just beginning to emerge. This review summarizes the current state of our knowledge of mannose metabolism and provides insights into its manipulation as a potential anticancer strategy.

Tumors arise from uncontrolled cell proliferation driven by mutations in genes that regulate stem cell renewal and differentiation. Intestinal tumors, however, retain some hierarchical organization, maintaining both cancer stem cells (CSCs) and cancer differentiated cells (CDCs). This heterogeneity, coupled with cellular plasticity enabling CDCs to revert to CSCs, contributes to therapy resistance and relapse. Using genetically encoded fluorescent reporters in human tumor organoids, combined with our machine-learning-based cell tracker, CellPhenTracker, we simultaneously traced cell-type specification, metabolic changes, and reconstructed cell lineage trajectories during tumor organoid development. Our findings reveal distinctive metabolic phenotypes in CSCs and CDCs. We find that lactate regulates tumor dynamics, suppressing CSC differentiation and inducing dedifferentiation into a proliferative CSC state. Mechanistically, lactate increases histone acetylation, epigenetically activating MYC. Given that lactate's regulation of MYC depends on the bromodomain-containing protein 4 (BRD4), targeting cancer metabolism and BRD4 inhibitors emerge as a promising strategy to prevent tumor relapse.

This study evaluated the screening of novel possible target proteins of B-AP15 (NSC687852) in silico. Through in vitro investigation, the anticancer activity of B-AP15 was examined with respect to gene expression and cell proliferation of SW620 cells (colon cancer cells). Twenty proteins associated with colon cancer were selected to screen possible target proteins of B-AP15 using molecular docking. The binding position of B-AP15 and the top five candidate proteins were investigated using the Discovery Studio 2021 software program. Cytotoxicity, colonization ability, and cell inhibition were evaluated in SW620 cells for 24, 48, and 72 h via MTT assay, colony formation assay, and trypan blue assay. The gene expression was estimated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) at 48 h. B-AP15 showed higher binding to E2F8 (- 10.88 kcal/mol), Ras (- 10.86 kcal/mol), GSK3B (- 10.77 kcal/mol), CDK6 (- 10.75 kcal/mol), and Raf (- 10.12 kcal/mol) than to USP14 (- 7.83 kcal/mol) as a target protein of B-AP15. Interestingly, Ras, GSK3B, and CDK6 shared the binding position between B-AP15 and known inhibitors. The IC50 values of B-AP15 against SW620 cells for 24, 48, and 72 h were 0.89 ± 0.0019 µM, 1.38 ± 0.16 µM, and 1.77 ± 0.0016 µM, respectively. B-AP15 reduced cell viability and the size and number of colonies and increased cell inhibition in a time- and dose-dependent manner. CDK6, Cyclin A, and VEGF expression were inhibited at B-AP15 concentrations of 0.89 and 1.78 µM after treatment for 48 h. Cyclin E and cMyc expression were suppressed only at 1.78 µM. These results suggest that B-AP15 possesses cytotoxicity, reducing the size and number of colonies and increasing cell inhibition via suppression of CDK6, Cyclin A, Cyclin E c-Myc, and VEGF.

PIM-1 is a type of serine/threonine kinase that plays a crucial role in controlling several vital processes, including proliferation and apoptosis. New synthetic S-amide tetrahydropyrimidinone derivatives were designed and synthesized as PIM-1 inhibitors with potential anticancer activity. Several biochemical assays were performed for anticancer assessment, including PIM-1 inhibitory assays, MTT, apoptosis and cell cycle, gene expression analysis, c-MYC analysis, and ATPase inhibitory assays. Compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibited strong in vitro broad antiproliferative activity against MCF-7, DU-145, and PC-3, with a relatively higher SI index suggesting minimal cytotoxicity to normal cells. Furthermore, these compounds induced mixed late apoptosis and necrosis with cell cycle arrest at the G2/M phase. Moreover, compounds 8b, 8f, 8g, 8k, and 8l showed potent inhibitory action against PIM-1 kinase, with corresponding IC50 values of 660, 909, 373, 518, and 501 nM. In silico prediction studies of physiochemical properties, molecular dynamics, and induced fit docking studies were performed for these compounds to explain their potent biological activity. In conclusion, new pyrimidinone compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibit potential PIM-1 inhibitory activity and can be used as promising scaffolds for further optimization of new leads with selective PIM-inhibitors and anticancer activity.

Chemotherapeutic drugs are commonly used to treat cancers lacking targeted therapy options. However, their low specificity limits their treatment effectiveness. We report here that the cooperative binding of doxorubicin (Dox) with actinomycin D (ActD) enhances the specificity for consecutive GCCG sites in DNA. Using X-ray crystallography, we determined the crystal structure of ActD and Dox bound to d(AGCCGT)2 DNA. ActD intercalation at the GpC site induces a novel Dox binding mode at the adjacent CpG step. This ensures a snug fit, avoids steric clashes, and enhances the specificity. Transcriptome analysis revealed that combining Dox with ActD synergistically down-regulates EGFR in TNBC cells. Additionally, it reduces EGFR promoter activity. In vivo, the combination significantly suppresses tumor growth and outperforms the standard Dox and cyclophosphamide regimen in inhibiting metastasis. This study highlights targeting the activated EGFR pathway with sequence-specific DNA-targeting drug combinations as a potential TNBC treatment.

i-Motifs, cytosine-tetrads, or C-quadruplexes are intercalated structures formed by base pairing between cytosine and protonated cytosine. These structures demonstrate increased stability in acidic environments due to the presence of the latter cytosinium group (i.e., the protonated cytosine). Research has shown that i-motifs are typically disrupted or destabilized at physiological pH levels (7.0-7.4), which makes their potential formation in the nucleus and their biological relevance uncertain. However, in 2018, it was demonstrated that i-motifs exist within the nucleus under physiological conditions, with various intracellular factors contributing to their stability. Identification of i-motifs in the nucleus and their association with gene promoters-particularly with those of proto-oncogenes-has generated significant interest in their potential regulatory functions. Additionally, recent studies suggest that i-motifs may function as switches for gene expression, influencing gene regulation through their folding and stabilization or unfolding and destabilization. This review aims to delve into these mechanisms to improve our understanding of the physiological significance of i-motifs.

RNA-binding motif 22 (RBM22) is an RNA-binding protein involved in gene regulation, with the capacity to bind DNA and function as a transcription factor for various target genes. Recent studies demonstrated that RBM22 depletion affects cell viability and proliferation of glioblastoma and breast cancer cells. However, the role of RBM22 in colon cancer and the molecular mechanisms underlying its tumor-suppressive function remain largely unclear. In this study, we demonstrate that RBM22 induces apoptosis and suppresses colon cancer cell viability and proliferation by modulating c-Myc expression. Furthermore, RBM22 knockdown reduces c-Myc stability. Therefore, our findings suggest that RBM22 depletion regulates cancer cell proliferation and induces apoptosis via the c-Myc pathway.

Glioma is a prevalent form of primary malignant central nervous system tumor, characterized by its cellular invasiveness, rapid growth, and the presence of the blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB). Current therapeutic approaches, such as chemotherapy and radiotherapy, have shown limited efficacy in achieving significant antitumor effects. Therefore, there is an urgent demand for new treatments. Therapeutic peptides represent an innovative class of pharmaceutical agents with lower immunogenicity and toxicity. They are easily modifiable via chemical means and possess deep tissue penetration capabilities which reduce side effects and drug resistance. These unique pharmacokinetic characteristics make peptides a rapidly growing class of new therapeutics that have demonstrated significant progress in glioma treatment. This review outlines the efforts and accomplishments in peptide-based therapeutic strategies for glioma. These therapeutic peptides can be classified into four types based on their anti-tumor function: tumor-homing peptides, inhibitor/antagonist peptides targeting cell surface receptors, interference peptides, and peptide vaccines. Furthermore, we briefly summarize the results from clinical trials of therapeutic peptides in glioma, which shows that peptide-based therapeutic strategies exhibit great potential as multifunctional players in glioma therapy.

Cancer is among the leading causes of death worldwide. The effectiveness of conventional chemotherapy has some drawbacks, therefore, there is an urgency to develop novel strategies to fight this disease. Ornithine decarboxylase (ODC) is the most finely tuned enzyme of the polyamine (PA) biosynthesis pathway as it is regulated at different levels: transcriptional, translational, post-translational, and by feedback inhibition. In cancer, this enzyme is overexpressed due to its regulation by the protooncogene c-Myc, thus it has been proposed as a drug target against this disease. This review describes information regarding the biochemistry and regulation of the ODC at different levels and its role in cancer. Moreover, we discuss the molecules aiming on the inhibition of the ODC activity that have been tested as therapeutic options. ODC remains as a therapeutic opportunity that needs to be more explored.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide and the most common form of liver cancer. Despite global efforts toward early diagnosis and effective treatments, HCC is often diagnosed at advanced stages, where conventional therapies frequently lead to resistance and/or high recurrence rates. Therefore, novel biomarkers and promising medications are urgently required. Epi-drugs, or epigenetic-based medicines, have recently emerged as a promising therapeutic modality. Since the epigenome of the cancer cells is always dysregulated and this is followed by apoptosis-resistance, reprogramming the epigenome of cancer cells by epi-drugs (such as HDAC inhibitors (HDACis), and DNMT inhibitors (DNMTis)) could be an alternative approach to use in concert with established treatment protocols. C-FLIP, an anti-apoptotic protein, and Ku70, a member of the DNA repair system, bind together and make a cytoplasmic complex in certain cancers and induce resistance to apoptosis. Many epi-drugs, such as HDACis, can dissociate this complex through Ku70 acetylation and activate cellular apoptosis. The novel compounds for dissociating this complex could provide an innovative insight into molecular targeted HCC treatments. In this review, we address the innovative therapeutic potential of targeting c-FLIP/Ku70 complex by epi-drugs, particularly HDACis, to overcome apoptosis resistance of HCC cells. This review will cover the mechanisms by which the c-FLIP/Ku70 complex facilitates cancer cell survival, the impact of epigenetic alterations on the complex dissociation, and highlight HDACis potential in combination therapies, biomarker developments and mechanistic overviews. This review highlights c-FLIP ubiquitination and Ku70 acetylation levels as diagnostic and prognostic tools in HCC management.

Adult T cell leukemia (ATL) is a highly aggressive T cell malignancy characterized by human T cell leukemia virus type 1 (HTLV-1) infection. ATL has a very poor prognosis and lacks satisfactory treatments; therefore, it is critical to identify potential targets in ATL cells in order to develop effective targeted therapeutics. Here, we report the identification of two oncogenes, AK4 and RHOC, as target genes of miR-455-3p, a tumor-suppressive microRNA in ATL patients. Importantly, AK4 and RHOC are highly expressed in ATL and exhibit oncogenic potentials in vitro and in vivo. Interestingly, transcriptome and metabolome analyses reveal a functional overlap of AK4 and RHOC, including activating oncogenic pathways such as Myc targets and deregulating lipid metabolism such as enhancing the production of sphingomyelin, a tumor-promoting lipid. In particular, compared to other types of T cell malignancy such as T cell acute lymphoblastic leukemia (T-ALL) and cutaneous T cell lymphoma (CTCL), ATL is sensitive to sphingomyelin inhibition and AK4 or RHOC depletion. Altogether, we report a distinct dependency of ATL on AK4 and RHOC oncogenes and an oncometabolite sphingomyelin, which together represent targetable vulnerabilities of ATL that could be exploited for developing effective therapeutics.

MYC plays a pivotal role in the biology of various sarcoma subtypes, acting as a key regulator of tumor growth, proliferation, and metabolic reprogramming. This oncogene is frequently dysregulated across different sarcomas, where its expression is closely intertwined with the molecular features unique to each subtype. MYC interacts with critical pathways such as cell cycle regulation, apoptosis, and angiogenesis, amplifying tumor aggressiveness and resistance to standard therapies. Furthermore, MYC influences the tumor microenvironment by modulating cell-extracellular matrix interactions and immune evasion mechanisms, further complicating therapeutic management. Despite its well-established centrality in sarcoma pathogenesis, targeting MYC directly remains challenging due to its "undruggable" protein structure. However, emerging therapeutic strategies, including indirect MYC inhibition via epigenetic modulators, transcriptional machinery disruptors, and metabolic pathway inhibitors, offer new hope for sarcoma treatment. This review underscores the importance of understanding the intricate roles of MYC across sarcoma subtypes to guide the development of effective targeted therapies. Given MYC's central role in tumorigenesis and progression, innovative approaches aiming at MYC inhibition could transform the therapeutic landscape for sarcoma patients, providing a much-needed avenue to overcome therapeutic resistance and improve clinical outcomes.

The hematopoietic stem cell (HSC) continues their functional integrity and return to quiescence quickly even after inflammatory and other proliferative stress. The mechanism which is responsible for this highly regulatory process is not understood clearly. Previous results have shown that CD53 is noticeably upregulated in HSCs in response to a variety of stimuli. Gene expression profile using RNASeq data of HSCs from the bone marrow and spleen of CD53 knock out and their wild-type littermate had been deposited by Greenberg and co-authors, in GEO database, "GSE219050". They reported that knockout of CD53 promotes continued cell cycle. To identify key genes and specific processes are affected in absence of CD53, we applied weighted gene co-expression analysis. The results show that cyan module is correlated and dark red and light cyan are anti-correlated with CD53 loss. CDK1 is identified as more connected gene or hub gene in cyan module and it is upregulated in the absence of CD53. Likewise, hub genes from dark-red module are EP300, EGF, MCL1, LPL and IGF1R. The gene enrichment analysis depicts, two biological processes, MAPK cascade and Delta Notch signalling were suppressed. Similarly, the biological processes involved in light-cyan module are chromatin organisation and hub genes are Ehmt2, Ezh2, Kdm1a, Rbbp4, Esr1 and Mysm1. It uncovers the roles of CD53 in chromatin organisation, and MAPK cascade and Delta Notch signalling are the major contributors in quiescence mechanism. These findings might provide a new avenue in quiescence research.

Ovarian cancer (OC) is the most lethal gynecological malignancy and a major global health concern, often diagnosed at advanced stages with poor survival rates. Despite advancements in treatment, resistance to standard chemotherapy remains a critical challenge with limited treatment options available. In recent years, the role of metabolic reprogramming in OC has emerged as a key factor driving tumor progression, therapy resistance, and poor clinical outcomes.

This review explores the intricate connections between metabolic syndrome, enhanced glycolysis, and altered lipid metabolism within OC cells, which fuel the aggressive nature of the disease. We discuss how metabolic pathways are rewired in OC to support uncontrolled cell proliferation, survival under hypoxic conditions, and evasion of cell death mechanisms, positioning metabolic alterations as central to disease progression. The review also highlights the potential of repurposed metabolic-targeting drugs, such as metformin and statins, which have shown promise in preclinical studies for their ability to disrupt these altered metabolic pathways.

Drug repurposing offers a promising strategy to overcome chemoresistance and improve patient outcomes. Future research should focus on unraveling the complex metabolic networks in OC to develop innovative, targeted therapies that can enhance treatment efficacy and patient survival.

Brain plasticity is at the basis of many cognitive functions, including learning and memory. It includes several mechanisms of synaptic and extrasynaptic changes, neurogenesis, and the formation and elimination of synapses. The plasticity of synaptic transmission involves the expression of immediate early genes (IEGs) that regulate neuronal activity, thereby supporting learning and memory. In addition, IEGs are involved in the regulation of brain cells' metabolism, proliferation, and survival, in the establishment of multicellular ensembles, and, presumably, in cell competition in the tissue. In this review, we analyze the current understanding of the role of IEGs (c-Fos, c-Myc, Arg3.1/Arc) in controlling brain plasticity in physiological and pathological conditions, including brain aging and neurodegeneration. This work might inspire new gene therapy strategies targeting IEGs to regulate synaptic plasticity, and potentially prevent or mitigate neurodegenerative diseases.

Caffeic acid phenethyl ester (CAPE) is the main bioactive component of poplar type propolis. We previously reported that treatment with caffeic acid phenethyl ester (CAPE) suppressed the cell proliferation, tumor growth, as well as migration and invasion of prostate cancer (PCa) cells via inhibition of signaling pathways of AKT, c-Myc, Wnt and EGFR. We also demonstrated that combined treatment of CAPE and docetaxel altered the genes involved in glycolysis and tricarboxylic acid (TCA) cycle. We therefore suspect that CAPE treatment may interfere glucose metabolism in PCa cells.

Seahorse Bioenergetics platform was applied to analyzed the extra cellular acidification rate (ECAR) and oxygen consumption rate (OCR) of PCa cells under CAPE treatment. UPLC-MSMS with Multiple Reaction Monitoring (MRM), PCR, and western blot were used to analyze the effects of CAPE on metabolites, genes, and proteins involved in glycolysis, TCA cycle and pentose phosphate pathway in PCa cells. Flow cytometry and ELISA were used to determine the level of reactive oxygen species in PCa cells being treated with CAPE.

Seahorse Bioenergetics analysis revealed that ECAR, glycolysis, OCR, and ATP production were elevated in C4-2B cells under CAPE treatment. Protein levels of glucose-6-phosphate dehydrogenase (G6PD), phosphogluconate dehydrogenase (PGD), glutaminase (GLS), phospho-AMPK Thr172 as well as abundance of pyruvate, lactate, ribulose-5-phosphate, and sedoheptulose-7-phosphate were increased in CAPE-treated C4-2B cells. ROS level decreased 48 h after treatment with CAPE. Co-treatment of AMPK inhibitor with CAPE exhibited additive growth inhibition on PCa cells.

Our study indicated that PCa cells attempted to overcome the CAPE-induced stress by upregulation of glycolysis and G6PD but failed to impede the growth inhibition caused by CAPE. Concurrent treatment of CAPE and inhibitors targeting glycolysis may be effective therapy for advanced PCa.

The molecular link between stress and carcinogenesis and the positive outcomes of stress intervention in cancer therapy have recently been well documented. Cancer stem cells (CSCs) facilitate cancer malignancy, drug resistance, and relapse and, hence, have emerged as a new therapeutic target. Here, we aimed to investigate the effect of three previously described antistress compounds (triethylene glycol, TEG; Withanone, Wi-N, and Withaferin A, Wi-A) on the stemness and differentiation characteristics of cancer cells. Breast carcinoma, glioblastoma, and neuroblastoma cells were treated with a non-toxic concentration of TEG (0.1%), Wi-N (5 µM), and Wi-A (0.1 µM) in 2D and 3D cultures. The results demonstrated that TEG, Wi-N, and Wi-A suppressed the stemness properties, which was linked with their inhibition of epithelial-mesenchymal transition (EMT) signaling. In particular, Wi-N and TEG caused a stronger reduction in the self-renewal capability of CSCs than Wi-A, as evidenced by a tumor spheroid formation assay and analyses of stemness-related genes (ALDH1, CD44, NANOG, CD133, SOX2). Furthermore, TEG and Wi-N caused the differentiation of cancer cells. Each of these was supported by (i) the upregulation of KRT18, KRT19, E-cadherin, and downregulation of vimentin in breast carcinoma; (ii) increased levels of GFAP, MAP2, and PSD-95 in astrocytoma; and (iii) increased NeuN, GAP-43, and NF200 levels in neuroblastoma. Furthermore, a reduction in cancer progression-related proteins (PI3K, N-myc) was recorded in treated cells. Our results suggest that TEG and Wi-N may be recruited to target cancer cell stemness and differentiation therapy.

Alzheimer's disease (AD) is the most common form of dementia, affecting approximately 47 M people worldwide. Histological features and genetic risk factors, among other evidence, supported the amyloid hypothesis of the disease. This neuronocentric paradigm is currently undergoing a shift, considering evidence of the role of other cell types, such as microglia and astrocytes, in disease progression. Previously, we described a particular astrocyte subtype obtained from the 3xTg-AD murine model that displays neurotoxic properties in vitro. We continue here our exploratory analysis through the lens of metabolomics to identify potentially altered metabolites and biological pathways. Cell extracts from neurotoxic and control astrocytes were compared using high-resolution mass spectrometry-based metabolomics. Around 12 % of metabolic features demonstrated significant differences between neurotoxic and control astrocytes, including alterations in the key metabolite glutamate. Consistent with our previous transcriptomic study, the present results illustrate many homeostatic and regulatory functions of metabolites, suggesting that neurotoxic 3xTg-AD astrocytes exhibit alterations in the Krebs cycle as well as the prostaglandin pathway. This is the first metabolomic study performed in 3xTg-AD neurotoxic astrocytes. These results provide insight into metabolic alterations potentially associated with neurotoxicity and pathology progression in the 3xTg-AD mouse model and strengthen the therapeutic potential of astrocytes in AD. BIOLOGICAL SIGNIFICANCE: Our study is the first high-resolution metabolomic characterization of the novel neurotoxic 3xTg-AD astrocytes. We propose key metabolites and pathway alterations, as well as possible associations with gene expression alterations in the model. Our results are in line with recent hypotheses beyond the amyloid cascade, considering the involvement of several stress response cascades during the development of Alzheimer's disease. This work could inspire other researchers to initiate similar studies in related models. Furthermore, this work illustrates a powerful workflow for metabolite annotation and selection that can be implemented in other studies.

Dysregulated energy metabolism has emerged as a defining hallmark of cancer, particularly evident in triple-negative breast cancer (TNBC). Distinct from other breast cancer subtypes, TNBC exhibits heightened glycolysis and aggressiveness. However, the transcriptional mechanisms of aerobic glycolysis in TNBC remains poorly understood.

The Cancer Genome Atlas (TCGA) cohort was utilized to identify genes associated with glycolysis. The role of FOSL1 in glycolysis and tumor growth in TNBC cells was confirmed through both loss-of-function and gain-of-function experiments. The subcutaneous xenograft model was established to evaluate the therapeutic potential of targeting FOSL1 in TNBC. Additionally, chromatin immunoprecipitation and luciferase reporter assays were employed to investigate the transcriptional regulation of glycolytic genes mediated by FOSL1.

FOSL1 is identified as a pivotal glycolysis-related transcription factor in TNBC. Functional verification shows that FOSL1 enhances the glycolytic metabolism of TNBC cells, as evidenced by glucose uptake, lactate production, and extracellular acidification rates. Notably, FOSL1 promotes tumor growth in TNBC in a glycolysis-dependent manner, as inhibiting glycolysis with 2-Deoxy-D-glucose markedly diminishes the oncogenic effects of FOSL1 in TNBC. Mechanistically, FOSL1 transcriptionally activates the expression of genes such as SLC2A1, ENO1, and LDHA, which further accelerate the glycolytic flux. Moreover, FOSL1 is highly expressed in doxorubicin (DOX)-resistant TNBC cells and clinical samples from cases of progressive disease following neoadjuvant chemotherapy. Targeting FOSL1 proves effective in overcoming chemoresistance in DOX-resistant MDA-MB-231 cells.

In summary, FOSL1 establishes a robust link between aerobic glycolysis and carcinogenesis, positioning it as a promising therapeutic target, especially in the context of TNBC chemotherapy.

Lung cancer is the leading cause of cancer death globally, with non-small cell lung cancer accounting for the majority (85%) of cases. Standard treatments including chemotherapy and radiotherapy present multiple adverse effects. Medicinal plants, used for centuries, are traditionally processed by methods such as boiling and oral ingestion, However, water solubility, absorption, and hepatic metabolism reduce phytoceutical bioavailability. More recently, isolated molecular compounds from these plants can be extracted with these phytoceuticals administered either individually or as an adjunct with standard therapy. Phytoceuticals have been shown to alleviate symptoms, may reduce dosage of chemotherapy and, in some cases, enhance pharmaceutical mechanisms. Research has identified many phytoceuticals' actions on cancer-associated pathways, such as oncogenesis, the tumour microenvironment, tumour cell proliferation, metastasis, and apoptosis. The development of novel nanoparticle delivery systems such as solid lipid nanoparticles, liquid crystalline nanoparticles, and liposomes has enhanced the bioavailability and targeted delivery of pharmaceuticals and phytoceuticals. This review explores the biological pathways associated with non-small cell lung cancer, a diverse range of phytoceuticals, the cancer pathways they act upon, and the pros and cons of several nanoparticle delivery systems.

Hepatocellular carcinoma (HCC) is influenced by several factors, among which genetic polymorphisms play a key role. Polymorphisms in various genes affect key pathways involved in HCC development, including metabolism, expression of inflammatory cytokines, cell proliferation, and apoptosis regulation. These polymorphisms induce differential effects on susceptibility to HCC, disease progression, and treatment outcomes. Understanding the effect of genetic variations on HCC pathogenesis is essential to elucidate underlying mechanisms and identify potential therapeutic targets. This review explores the diverse roles of genetic polymorphisms in HCC, providing insights into the complex interplay between genetic factors and disease development.

While mitotic spindle inhibitors specifically kill proliferating tumor cells without the toxicities of microtubule poisons, resistance has limited their clinical utility. Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of activated STAT3. Furthermore, these senescent cells expand the repertoire of cells resistant to these drugs by secreting an array of factors, including TGFβ, which induce proliferating cells to exit mitosis and become quiescent-a state that also resists spindle inhibitors. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. These results support a therapeutic strategy of targeting STAT3-dependent therapy-induced senescence to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma.

Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered to be undruggable targets have become increasingly feasible due to the progress that has been made over the last two decades and the rapid technological advances. This work explores the influence of technological innovations on PPI research and development. Additionally, the diverse strategies for discovering, modulating, and characterizing PPIs and their corresponding modulators are examined with the aim of presenting a streamlined pipeline for advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in PPI modulator discovery and development, we aim to illustrate the efficacy of various strategies for identifying, optimizing, and overcoming challenges associated with PPI modulator design. The valuable lessons and insights gained from the identification, optimization, and approval of PPI modulators are discussed with the aim of demonstrating that PPI modulators have transitioned beyond early-stage drug discovery and now represent a prime opportunity with significant potential. The selected examples of PPI modulators encompass those developed for cancer, inflammation and immunomodulation, as well as antiviral applications. This perspective aims to establish a foundation for the effective targeting and modulation of PPIs using PPI modulators and pave the way for future drug development.

Boron neutron capture therapy (BNCT) is a highly targeted, selective and effective technique to cure various types of cancers, with less harm to the healthy cells. In principle, BNCT treatment needs to distribute the 10boron (10B) atoms inside the tumor tissues, selectively and homogeneously, as well as to initiate a nuclear fission reaction by capturing sufficient neutrons which releases high linear energy particles to kill the tumor cells. In BNCT, it is crucial to have high quality boron agents with acceptable bio-selectivity, homogeneous distribution and deliver in required quantity, similar to chemotherapy and other radiotherapy for tumor treatment. Nevertheless, boron drugs currently used in clinical trials yet to meet the full requirements. On the other hand, BNCT processing has opened up the era of renaissance due to the advanced development of the high-quality neutron source and the global construction of new BNCT centers. Consequently, there is an urgent need to use boron agents that have increased biocapacity. Artificial intelligence (AI) tools such as molecular docking and molecular dynamic simulation technologies have been utilized to develop new medicines. In this work, the in silico assessments including bioinformatics assessments of BNCT related tumoral receptor proteins, computational assessments of optimized small molecules of boron agents, are employed to speed up the screening process for boron drugs. The outcomes will be applicable to pave the way for future BNCT that utilizes artificial intelligence. The in silico molecular docking and dynamic simulation results of the optimized small boron agents, such as 4-borono-l-phenylalanine (BPA) with optimized proteins like the L-type amino acid transporter 1 (LTA1, also known as SLC7A5) will be examined. The in silico assessments results will certainly be helpful to researchers in optimizing druggable boron agents for the BNCT application. The clinical status of the optimized proteins, which are highly relevant to cancers that may be treated with BNCT, has been assessed using bioinformatics technology and discussed accordingly. Furthermore, the evaluations of cytotoxicity (IC50), boron uptake and tissue distribution of the optimized ligands 1 and 7 have been presented.

By delivering the environmental inputs to transport nutrients and growth factors, Mechanistic Target of Rapamycin (mTOR) plays a significant role in the growth and metabolism of eukaryotic cells through the regulation of numerous elementary cellular processes such as autophagy, protein synthesis, via translation of mitochondrial protein transcription factor A mitochondrial, mitochondrial ribosomal proteins, and mitochondrial respiratory complexes I &V that are encoded in the nucleus with the help of translation initiation factor 4E-BP. These mitochondrial proteins are involved in cell signaling to regulate proper cell growth, proliferation, and death which are essential for tumor growth and proliferation. This suggests that tumor cells are dependent on mTORC1 for various metabolic pathways. However, this crucial regulator is activated and regulated by calcium homeostasis. Mounting evidence suggests the role of calcium ions in regulating mitochondrial enzymes and proteins. Hence, disrupting calcium homeostasis leads to calcium-dependent cell death called "Oxytosis" through hampering the expression of various mitochondrial proteins. "Oxytosis" is a novel non-apoptotic cell death characterized by glutamate cytotoxicity and ferritin degradation. The present review focuses on the crosstalk between mTORC1 and mitochondrial proteins in the cancer pathophysiology and the impact of calcium ions on disrupting mTORC1 leading to the induction of "Oxytosis."

Cancer is one of the most prevalent diseases and the leading cause of death worldwide. Despite the improved survival rates of cancer in recent years, the current available treatments often face resistance and side effects. Drug repurposing represents a cost‑effective and efficient alternative to cancer treatment. Recent studies revealed that penfluridol (PF), an antipsychotic drug, is a promising anticancer agent. In the present study, a scoping review was conducted to ascertain the anticancer properties of PF. For this, a literature search was performed using the Scopus, PubMed and Web of Science databases with the search string 'penfluridol' AND 'cancer'. A total of 23 original articles with in vivo and/or in vitro studies on the effect of PF on cancer were included in the scoping review. The outcome of the analysis demonstrated the anticancer potential of PF. PF significantly inhibited cell proliferation, metastasis and invasion while inducing apoptosis and autophagy in vivo and across a spectrum of cancer cell lines, including breast, lung, pancreatic, glioblastoma, gallbladder, bladder, oesophageal, leukaemia and renal cancers. However, research on PF derivatives with high anticancer activities and reduced neurological side effects may be necessary.

Hepatocellular carcinoma (HCC) is one of the most aggressive types of liver cancer, and it is frequently associated with upregulated c-Myc expression. Sorafenib (Sor) is commonly used to treat HCC, but many patients experienced mild to severe side effects due to prolonged Sor treatment during therapy. It has been known that Pentagamavunone-1 (PGV-1) exhibits a remarkable antiproliferative effect on several cancer cells, yet limited studies have reported its cellular activities in HCC. The current study aims to evaluate the anticancer effects of Sor in combination with PGV-1 on the progression of HCC proliferation. c-Myc expressing cells, JHH-7 and Huh-7, were used for this study, then Sor and PGV-1 were tested for their effect on the cellular physiology phenomena including cytotoxicity combination assay and colony formation assay, cell cycle profile and reactive oxygen species (ROS) level by flow cytometry, senescence induction by beta-galactosidase (SA-β-gal) assay, and migration inhibition by wound healing assay. The c-Myc expression was evaluated through Western blot. PGV-1 was more effective than Sor at inhibiting cell growth, and it showed greater selectivity for HCC over fibroblast cells. The combination of Sor with PGV-1 exhibited synergistic-additive cytotoxicity with an irreversible effect in HCC cell lines. The combination induced senescence similarly with Sor alone in JHH-7 cells, while PGV-1 enhanced the cellular senescence when combined with Sor in Huh-7 cells. Furthermore, the combination increased ROS level in the same way as PGV-1 did in HCC. The combination with PGV-1 acted better than Sor alone to inhibit JHH-7 cell migration. In addition, the combination treatment led to the suppression of c-Myc, particularly in JHH-7 cells. Taken together, combining Sor with PGV-1 promotes better efficacy than Sor alone to inhibit HCC cell proliferation, and further evaluation of the efficacy and safety of adding PGV-1 to Sor in HCC therapy is worthwhile as a potential combination treatment option.

Endometrial cancer (EC) is a common gynecological malignancy, and its metastasis is one of the primary causes of treatment failure. Immunoglobulin superfamily member 1 (IGSF1), a membrane protein, has been associated with the aggressiveness and metastatic capability of various cancers. However, the role and mechanism of this protein in EC remains unclear. Therefore, this study aimed to explore the role of IGSF1 in EC and its possible mechanism.

In this study, IGSF1 expression was knocked down through small interfering RNA and short hairpin RNA techniques, and its levels were controlled through overexpression experiments to observe its effects on Ishikawa cells. Wound healing assays, Transwell migration and invasion assays, quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence double labeling were performed to evaluate the ability of cells to migrate, invade, and express markers of the epithelium mesenchymal transition (EMT). In addition, we investigated the regulatory role of IGSF1 in Myc proto-oncogene (c-Myc) expression and its function in lung metastasis through animal models of lung metastasis.

The results indicate that IGSF1 knockdown inhibited EMT and greatly reduced the invasion ability of Ishikawa cells (P < 0.01). Animal experiments demonstrated that IGSF1 knockdown reduced the number of pulmonary metastatic foci (P < 0.001). On the other hand, IGSF1 overexpression increased Ishikawa cells' ability to migrate and invade (P < 0.01). IGSF1 overexpression also inhibited E-cadherin expression and promoted that of vimentin (P < 0.001). The expression of c-Myc decreased following IGSF1 knockdown and increased after its overexpression. Silencing of c-Myc reversed the oncogenic effects of IGSF1 (P < 0.01).

IGSF1 promotes EMT and metastasis in EC through the upregulation of the c-Myc expression. IGSF1 may serve as a potential therapeutic target for EC, and its inhibition can offer new strategies for mitigating the aggressiveness and metastatic potential of this malignancy.

Diffuse large B-cell lymphoma (DLBL) and systemic lupus erythematosus (SLE) are complex autoimmune disorders that present unique clinical challenges. These conditions may share underlying genetic and signaling pathways despite their distinct manifestations. Uncovering these commonalities could offer invaluable insights into disease pathogenesis, paving the way for more targeted and effective therapeutic interventions. This study embarks on a comprehensive investigation of the common genes and signaling pathways between SLE and DLBL.

The researchers scoured the Gene Expression Omnibus database, meticulously gathering microarray datasets for SLE (GSE61635) and DLBL (GSE56315). Differential expression analysis was performed, allowing the team to identify the genes that were commonly dysregulated across these 2 autoimmune conditions. To delve deeper into the biological significance of these shared genes, the researchers conducted functional enrichment analysis, network analysis, and core gene identification. Notably, the diagnostic potential of the identified hub genes was assessed using a cutting-edge neural network model.

The data analysis revealed a remarkable 146 genes that were shared between SLE and DLBL, of which 111 were upregulated and 45 downregulated. Functional enrichment analysis unveiled the involvement of these shared genes in vital immune system-related processes-such as defense response to viruses, interferon signaling, and broader immune system pathways. Network analysis pinpointed 5 hub genes (IFIT3, IFIT1, DDX58, CCL2, and OASL) that emerged as central players, exhibiting a high degree of centrality and predicted to hold crucial roles in the underlying molecular mechanisms. Remarkably, the neural network model demonstrated exceptional diagnostic accuracy in distinguishing between the disease states (DLBL and SLE) based solely on the expression patterns of these hub genes.

The identified hub genes and their associated pathways hold immense potential as diagnostic biomarkers and may serve as valuable targets for future therapeutic explorations.

Colorectal cancer (CRC) is a common cancer worldwide with an increasing annual incidence. Cancer stem cells (CSCs) play important roles in the occurrence, development, recurrence, and metastasis of CRC. The molecular mechanism regulating the development of colorectal CSCs remains unclear. The discovery of human induced pluripotent stem cells (hiPSCs) through somatic cell reprogramming has revolutionized the fields of stem cell biology and translational medicine. In the present study, we converted hiPSCs into cancer stem-like cells by culture with conditioned medium (CM) from CRC cells. These transformed cells, termed hiPSC-CSCs, displayed cancer stem-like properties, including a spheroid morphology and the expression of both pluripotency and CSC markers. HiPSC-CSCs showed tumorigenic and metastatic abilities in mouse models. The epithelial-mesenchymal transition phenotype was observed in hiPSC-CSCs, which promoted their migration and angiogenesis. Interestingly, upregulation of C-MYC was observed during the differentiation of hiPSC-CSCs. Mechanistically, CREB binding protein (CBP) bound to the C-MYC promoter, while histone deacetylase 1 and 3 (HDAC1/3) dissociated from the promoter, ultimately leading to an increase in histone acetylation and C-MYC transcriptional activation during the differentiation of hiPSC-CSCs. Pharmacological treatment with a CBP inhibitor or abrogation of CBP expression with a CRISPR/Cas9-based strategy reduced the stemness of hiPSC-CSCs. This study demonstrates for the first time that colorectal CSCs can be generated from hiPSCs. The upregulation of C-MYC via histone acetylation plays a crucial role during the conversion process. Inhibition of CBP is a potential strategy for attenuating the stemness of colorectal CSCs.

Tumor fatty acid (FA) metabolic plasticity plays a pivotal role in resistance to therapy and poses limitations to anticancer strategies. In this study, our aim is to uncover the role of acetate metabolism in neurodifferentiation (NED)-mediated castration-resistant prostate cancer (CRPC).

We conducted analyses using LC-MS/MS on clinical prostate cancer tissue before and after hormone therapy. We established tumor xenograft mouse models, primary tumor cells, and human-derived organoids to detect the novel mechanism of NED and to identify potential therapies.

The hormone therapy-induced upregulation of acetate metabolism was mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2), which increased c-MYC expression for NED induction. Notably, combined treatment with an ACSS2 inhibitor and enzalutamide significantly reduced the xenograft tumor volume.

Our findings uncovered the critical role of acetate metabolism in NED-mediated CRPC and suggest that ACSS2 inhibitors may represent a novel, low-toxicity strategy when combined with hormone therapy for treating patients with NED-mediated CRPC.

Mass spectrometry (MS)-based single-cell proteomics, while highly challenging, offers unique potential for a wide range of applications to interrogate cellular heterogeneity, trajectories, and phenotypes at a functional level. We report here the development of the spectral library-based multiplex segmented selected ion monitoring (SLB-msSIM) method, a conceptually unique approach with significantly enhanced sensitivity and robustness for single-cell analysis. The single-cell MS data is acquired by msSIM technique, which sequentially applies multiple isolation cycles with the quadrupole using a wide isolation window in each cycle to accumulate and store precursor ions in the C-trap for a single scan in the Orbitrap. Proteomic identification is achieved through spectral matching using a well-defined spectral library. We applied the SLB-msSIM method to interrogate cellular heterogeneity among multiple cell lines and to analyze cellular trajectories during epithelial-mesenchymal transition. Our results demonstrate that SLB-msSIM is a highly sensitive and robust platform applicable to a wide range of single-cell proteomic studies.

Breast cancer (BC) is the most common and malignant tumor diagnosed in women, with 2.9 million cases in 2023 and the fifth highest cancer-causing mortality worldwide. Recent developments in targeted therapy options for BC have demonstrated the promising potential of small interfering RNA (siRNA)-based cancer therapeutic approaches. As BC continues to be a global burden, siRNA therapy emerges as a potential treatment strategy to regulate disease-related genes in other types of cancers, including BC. siRNAs are tiny RNA molecules that, by preventing their expression, can specifically silence genes linked to the development of cancer. In order to increase the stability and effectiveness of siRNA delivery to BC cells, minimize off-target effects, and improve treatment efficacy, advanced delivery technologies such as lipid nanoparticles and nanocarriers have been created. Additionally, combination therapies, such as siRNAs that target multiple pathways are used in conjunction with conventional chemotherapy agents, have shown synergistic effects in various preclinical studies, opening up new treatment options for breast cancer that are personalized and precision medicine-oriented. Targeting important genes linked to BC growth, metastasis, and chemo-resistance has been reported in BC research using siRNA-based therapies. This study reviews recent reports on therapeutic approaches to siRNA for advanced treatment of BC. Furthermore, this review evaluates the role and mechanisms of siRNA in BC and demonstrates the potential of exploiting siRNA as a novel target for BC therapy.

Reprogrammed glucose metabolism is considered as the hallmark of cancer with therapeutic implications. Phytocompounds have potential to inhibit cancer metabolism. Here, we tested the ability of Withaferin A (WA), a withanolide derived from Withania somnifera, in modulating cancer metabolism. The assessed effect of WA on aerobic glycolysis in breast cancer cell lines showed that WA decreases the glucose uptake, lactate production and ATP generation by inhibiting the expression of key glycolytic enzymes i.e., GLUT1, HK2 and PKM2. We also identified that WA induced inhibition of cancer glycolysis by targeting c-myc as validated by silencing experiments followed by metabolic readouts. Decreased glycolysis resulted in reduced cell viability, biomass and colony forming ability of breast cancer cells. To further validate our in vitro findings in breast cancer patients, we analyzed 90 metabolic pathways in ~ 2000 breast tumors and observed that glycolysis is the most deregulated pathway in breast tumors. Deregulated glycolysis also predicted poor prognosis in breast cancer patients. In addition, patient data showed correlation between c-myc expression and glycolytic deregulation in breast cancer. Taken together, our results highlight the role of WA in inhibiting breast cancer metabolism via c-myc/glycolysis axis.

During the aging process, elastin is degraded and the level of elastin-derived peptides (EDPs) successively increases. The main peptide released from elastin during its degradation is a peptide with the VGVAPG sequence. To date, several papers have described that EDPs or elastin-like peptides (ELPs) affect human mesenchymal stem cells (hMSCs) derived from different tissues. Unfortunately, despite the described effect of EDPs or ELPs on the hMSC differentiation process, the mechanism of action of these peptides has not been elucidated. Therefore, the aim of the present study was to evaluate the impact of the VGVAPG and VVGPGA peptides on the hMSC stemness marker and elucidation of the mechanism of action of these peptides. Our data show that both studied peptides (VGVAPG and VVGPGA) act with the involvement of ERK1/2 and c-SRC kinases. However, their mechanism of activation is probably different in hMSCs derived from adipose tissue. Both studied peptides increase the KI67 protein level in hMSCs, but this is not accompanied with cell proliferation. Moreover, the changes in the NANOG and c-MYC protein expression and in the SOX2 and POU5F1 mRNA expression suggest that EDPs reduced the hMSC stemness properties and could initiate cell differentiation. The initiation of differentiation was evidenced by changes in the expression of AhR and PPARγ protein as well as specific genes (ACTB, TUBB3) and proteins (β-actin, RhoA) involved in cytoskeleton remodeling. Our data suggest that the presence of EDPs in tissue can initiate hMSC differentiation into more tissue-specific cells.

Disturbances in lipid metabolism are one of the hallmarks of cancer cells. Fatty acid synthesis and oxidation play a crucial role in the proliferation, growth, and survival of cancer cells. Several enzymes are involved in lipid metabolism. MYC is an oncogene and plays various regulatory roles in lipid metabolism. This study aimed to evaluate MYC expression and its association with the expressions of Lipin-1, ACSL4 (enzymes involved in lipid metabolism), in pairs of breast cancer (BC) and adjacent normal tissues to further understand the MYC influence on metabolic regulation.

Fifty-five pairs of samples of BC and noncancerous adjacent tissues were utilized in the present study to analyze MYC, Lipin-1, and ACSL4 by quantitative real-time polymerase chain reaction. Further, the expression of Lipin-1 and ACSL4 proteins and a number of other clinicopathologically relevant variables were studied employing immunohistochemistry staining.

MYC expression was substantially higher in BC tissues than in adjacent normal tissues, according to our findings. This upregulation was positively correlated with tumor size and stage. Although MYC expression was not correlated with that of ACSL4 and Lipin-1 expression, this may result from the complex metabolic changes that occur when cells become malignant.

Although further research is required to assess MYC's impact on tumor metabolic regulation, the correlations seen here between MYC, the pathological stage, and tumor size may indicate its prognostic significance in BC. Hence, it may be considered as a potential therapeutic target for further studies.