Inhibit Tumor Cell Research Articles

Unveiling the therapeutic potential: KBU2046 halts triple-negative breast cancer cell migration by constricting TGF-β1 activation in vitro.

Triple-negative breast cancer (TNBC) is a heterogeneous, recurring cancer characterized by a high rate of metastasis, poor prognosis, and lack of efficient therapies. KBU2046, a small molecule inhibitor, can inhibit cell motility in malignant tumors, including breast cancer. However, the specific targets and the corresponding mechanism of its function remain unclear. In this study, we employed (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium) (MTS) assay and transwell assay to investigate the impact of KBU2046 on the proliferation and migration of TNBC cells in vitro. RNA-Seq was used to explore the targets of KBU2046 that inhibit the motility of TNBC. Finally, confirmed the predicted important signaling pathways through RT-qPCR and western blotting. In this study, we found that KBU2046 functioned as a novel transforming growth factor-β (TGF-β1) inhibitor, effectively suppressing tumor cell motility in vitro. Mechanistically, it directly down-regulated leucine-rich repeat-containing 8 family, member E (LRRC8E), latent TGFβ-binding protein 3 (LTBP3), dynein light chain 1 (DNAL1), and MAF family of bZIP transcription factors (MAFF) genes, along with reduced protein expression of the integrin family. Additionally, KBU2046 decreased phosphorylation levels of Raf and ERK. This deactivation of the ERK signaling pathway impeded cancer invasion and metastasis. In summary, these findings advocate for the utilization of TGF-β1 as a diagnostic and prognostic biomarker and as a therapeutic target in TNBC. Furthermore, our data underscore the potential of KBU2046 as a novel therapeutic strategy for combating cancer metastasis.

ULK2 suppresses ovarian cancer cell migration and invasion by elevating IGFBP3.

Ovarian cancer is an aggressive malignancy with high mortality known for its considerable metastatic potential. This study aimed to explore the expression and functional role of Unc-51 like autophagy activating kinase 2 (ULK2) in the progression of ovarian cancer. ULK2 expression patterns in ovarian cancer tissues as well as benign tumor control samples obtained from our institution were evaluated using immunohistochemistry. Cell counting kit 8 and Transwell assays were applied to assess the effects of ULK2 overexpression on cell proliferation, migration and invasion, respectively. RNA sequencing was performed to explore potential mechanisms of action of ULK2 beyond its classical autophagy modulation. Our experiments showed significant downregulation of ULK2 in ovarian cancer tissues. Importantly, low expression of ULK2 was markedly correlated with decreased overall survival. In vitro functional studies further demonstrated that overexpression of ULK2 significantly suppressed tumor cell proliferation, migration, and invasion. RNA sequencing analysis revealed a potential regulatory role of ULK2 in the insulin signaling pathway through upregulation of insulin-like growth factor binding protein-3 (IGFBP3) in ovarian cancer cells. In summary, the collective data indicated that ULK2 acted as a tumor suppressor in ovarian cancer by upregulating the expression of IGFBP3. Our study underscores the potential utility of ULK2 as a valuable prognostic marker for ovarian cancer.

Precise design of dual active-site catalysts for synergistic catalytic therapy of tumors.

A proven and promising method to improve the catalytic performance of single-atom catalysts through the interaction between bimetallic atoms to change the active surface sites or adjust the catalytic sites of reactants is reported. In this work, we used an iron-platinum bimetallic reagent as the metal source to precisely synthesise covalent organic framework-derived diatomic catalysts (FePt-DAC/NC). Benefiting from the coordination between the two metal atoms, the presence of Pt single atoms can successfully regulate Fe-N3 activity. FePt-DAC/NC exhibited a stronger ability to catalyze H2O2 to produce toxic hydroxyl radicals than Fe single-atom catalysts (Fe-SA/NC) to achieve chemodynamic therapy of tumors (the catalytic efficiency improved by 186.4%). At the same time, under the irradiation of an 808 nm laser, FePt-DAC/NC exhibited efficient photothermal conversion efficiency to achieve photothermal therapy of tumors. Both in vitro and in vivo results indicate that FePt-DAC/NC can efficiently suppress tumor cell growth by a synergistic therapeutic effect with photothermally augmented nanocatalytic therapy. This novel bimetallic dual active-site monodisperse catalyst provides an important example for the application of single-atom catalysts in the biomedical field, highlighting its promising clinical potential.

Iron-Based Nanoplatforms Achieve Hepatocellular Carcinoma Regression Through a Cascade of Effects.

Ferroptosis is a regulated form of cell death characterized by iron-dependent accumulation of associated lipid peroxides (LPO), which can induce cell death when a certain level is reached. However, the extremely complex tumor microenvironment (TME) has the characteristics of antioxidant, even if it induces ferroptosis of tumor cells, its killing effect on tumor cells is still very limited. To solve this problem, we constructed a novel nanomaterials (GOx/EC@Fe3O4@CCM). We evaluated the anticancer effect of this nanomaterial in inhibiting tumor growth through comprehensive in vitro and in vivo experiments. We successfully synthesized GOx/EC@Fe3O4 by one-pan synthesis method, then coated the Hepatocellular carcinoma cell membrane on its surface by co-extrusion technology, and finally synthesized the GOx/EC@Fe3O4@CCM nanoplatforms. We characterized the compounds in terms of morphology, particle size, and Zeta potential. In addition, we also studied the anti-tumor effect of GOx/EC@Fe3O4@CCM nanoplatforms from the following aspects, including the performance test of the nanoplatform, the intracellular effect of the nanoplatform, the anti-tumor effect in vitro, the intracellular ROS analysis, the intracellular effect of EC, and the anti-tumor effect in vivo. The iron-based carriers in GOx/EC@Fe3O4@CCM nanoplatforms are released and produce ferrous ions (Fe2+) in an acidic environment. Due to the limitation of the endogenous level of hydrogen peroxide (H2O2), we introduced GOx into the TME or tumor cells. Under the catalysis of GOx, glucose reacted rapidly to produce a large amount of H2O2, which then combined with Fe2+ to produce a large number of Hydroxyl radical (·OH). Its toxicity leads to dysfunction of cell membrane and organelles, and then causes cell damage. EC inhibits Nuclear factor erythroid 2-related factor 2 (Nrf2) in cancer cells, which effectively down-regulates downstream gene products, including NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HMOX1). A series of chain reactions reduce the escape effect of oxidative stress (OS) and effectively maintain a high level of intracellular oxidation. Furthermore, it induces sustained and intense ferroptosis in tumor cells. Finally, the use of cancer cell membrane modified nanoplatforms due to the homology of membrane protein components improves the tumor cell targeting of the nanoplatforms, showing significant tumor cell inhibition and killing effect in vivo. The results showed that the GOx/EC@Fe3O4@CCM nanoplatforms successfully induced significant ferroptosis of Hepatocellular carcinoma cells through a cascade effect, and finally effectively promoted cancer cell regression.

Comparative study of linear polyglycidol acylhydrazones and curcumin conjugates: Surface activity and targeted antitumor drug delivery

Linear polyglycidol (LPG) has emerged as a polyethylene glycol (PEG) alternative in novel surfactant development due to its unique advantages, such as high bioavailability and multiple functionalization sites. In this study, a series of LPG based acylhydrazones, including copolymers CLPG1–3 with different length (n = 7–11) of alkyl chains and a curcumin (CUR) drug conjugate CLPG4 were synthesized for the first time. CLPG1-4 exhibited a decreasing trend in their surface-active properties as the molecular hydrophobicity increased. Among them, CLPG1 revealed the most powerful foaming ability, emulsion stability than the other analogs and tested commercial references, attributing to its optimal hydrophilic/hydrophobic balance. On the other hand, the drug conjugate CLPG4 revealed significantly enhanced selective tumor cell inhibition and cellular uptake than free CUR in the in vitro experiments. The established structure-property profile in this study provides a useful reference for their practical applications in the chemical and pharmaceutical fields.

Filamentous-Actin-Mimicking Nanoplatform for Enhanced Cytosolic Protein Delivery.

Despite the potential of protein therapeutics, the cytosolic delivery of proteins with high efficiency and bioactivity remains a significant challenge owing to exocytosis and lysosomal degradation after endocytosis. Therefore, it is important to develop a safe and efficient strategy to bypass endocytosis. Inspired by the extraordinary capability of filamentous-actin (F-actin) to promote cell membrane fusion, a cyanine dye assembly-containing nanoplatform mimicking the structure of natural F-actin is developed. The nanoplatform exhibits fast membrane fusion to cell membrane mimics and thus enters live cells through membrane fusion and bypasses endocytosis. Moreover, it is found to efficiently deliver protein cargos into live cells and quickly release them into the cytosol, leading to high protein cargo transfection efficiency and bioactivity. The nanoplatform also results in the superior inhibition of tumor cells when loaded with anti-tumor proteins. These results demonstrate that this fusogenic nanoplatform can be valuable for cytosolic protein delivery and tumor treatment.

Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon (IFN) response uniformly across models. The induction of an IFN response is partially due to the inhibition of Sox4 translation by zotatifin. A similar induction of IFN-stimulated genes was observed in breast cancer patient biopsies following zotatifin treatment. Surprisingly, zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened IFN response, resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for zotatifin, and provide a rationale for new combination regimens consisting of zotatifin and chemotherapy or immunotherapy as treatments for TNBC.

Fabrication of GSH‐Responsive Poly(Tertiary Amine‐Oxide)‐Based Nanomedicines for Enhanced Anticancer Drug Release

AbstractPoly(tertiary amine‐oxide)‐based polymeric nanocarriers have showed more functionalities than stealthy PEG‐based analogs due to the structure of phospholipid affinitive N‐oxides groups, which has attracted considerable attention to the synthesis of various zwitterionic copolymers with tertiary amine‐oxide grafts for enhanced anticancer drug delivery. However, poly(tertiary amine‐oxide)‐based amphiphilic copolymers with tumor intracellular microenvironment sensitivities, to the knowledge, have been rarely reported likely due to the lack of a controlled synthetic strategy. Herein, a reducible zwitterionic copolymer, poly(ε‐caprolactone)25‐SS‐poly(2‐(N‐oxide‐N,N‐diethylamino)ethyl methacrylate)30 (PCL25‐SS‐OPDEA30) is designed and synthesized successfully via combination of controlled polymerization techniques and post polymerization modification. Specifically, postoxidation of poly(tertiary amine) is confirmed to be a better synthetic strategy toward a well‐defined polymer structure relative to direct polymerization of N,N‐diethylaminoethyl methacrylate (ODEA). The effect of disulfide bridges on the self‐assembly behaviors, in vitro drug loading and drug release properties is investigated in detail. Notablely, the resulting micelles self‐assembled from PCL25‐SS‐OPDEA30 show much greater colloidal stability, higher drug loading content (DLC), and better in vitro tumor cell inhibition than the reduction‐insensitive counterparts. Overall, this study reports a robust strategy toward zwitterionic nanomedicines for on‐demand anticancer drug delivery.

P38 Mitogen-Activated Protein Kinase Inhibition of Mesenchymal Transdifferentiated Tumor Cells in Head and Neck Squamous Cell Carcinoma.

High mortality in head and neck squamous cell carcinoma (HNSCC) is due to recurrence, metastasis, and radiochemotherapy (RCT) resistance. These phenomena are related to the tumor cell subpopulation undergoing partial epithelial to mesenchymal transition (pEMT). Repeated transforming growth factor-beta (TGF-beta-1) treatment via the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway induces pEMT in SCC-25 HNSCC cells, and activates and stabilizes the pro-EMT transcription factor Slug. We investigated the growth inhibitory, cisplatin-sensitizing, and pro-apoptotic effects of p38 MAPK inhibition in cisplatin-resistant (SCC-25) and -sensitive (UPCI-SCC090) HNSCC cell lines, using two specific p38 MAPK inhibitors, SB202190 and ralimetinib. Cell viability was measured by MTT assay; cell cycle distribution and cell death were evaluated by flow cytometry; p38 MAPK phosphorylation, Slug protein stabilization, and p38 MAPK downstream targets were investigated by Western blot. p-p38 inhibitors achieved sustained phosphorylation of p38 MAPK (Thr180/Tyr182) and inhibition of its function, which resulted in decreased phosphorylation (Thr69/71) of the downstream target pATF2 in pEMT cells. Subsequently, the p-p38 inhibition resulted in reduced Slug protein levels. In accordance, p-p38 inhibition led to sensitization of pEMT cells to cisplatin-induced cell death; moreover, p-p38 inhibitor treatment cycles significantly decreased the viability of cisplatin-surviving cells. In conclusion, clinically relevant p38 inhibitors might be effective for RCT-resistant pEMT cells in HNSCC patients.

The Emerging Roles of the Metabolic Regulator G6PD in Human Cancers.

Metabolic reprogramming, especially reprogrammed glucose metabolism, is a well-known cancer hallmark related to various characteristics of tumor cells, including proliferation, survival, metastasis, and drug resistance. Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), a branch of glycolysis, that converts glucose-6-phosphate (G6P) into 6-phosphogluconolactone (6PGL). Furthermore, PPP produces ribose-5-phosphate (R5P), which provides sugar-phosphate backbones for nucleotide synthesis as well as nicotinamide adenine dinucleotide phosphate (NADPH), an important cellular reductant. Several studies have shown enhanced G6PD expression and PPP flux in various tumor cells, as well as their correlation with tumor progression through cancer hallmark regulation, especially reprogramming cellular metabolism, sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Inhibiting G6PD could suppress tumor cell proliferation, promote cell death, reverse chemoresistance, and inhibit metastasis, suggesting the potential of G6PD as a target for anti-tumor therapeutic strategies. Indeed, while challenges-including side effects-still remain, small-molecule G6PD inhibitors showing potential anti-tumor effect either when used alone or in combination with other anti-tumor drugs have been developed. This review provides an overview of the structural significance of G6PD, its role in and regulation of tumor development and progression, and the strategies explored in relation to G6PD-targeted therapy.

Relief of tumor hypoxia using a nanoenzyme amplifies NIR-II photoacoustic-guided photothermal therapy.

Hypoxia is a critical tumor microenvironment (TME) component. It significantly impacts tumor growth and metastasis and is known to be a major obstacle for cancer therapy. Integrating hypoxia modulation with imaging-based monitoring represents a promising strategy that holds the potential for enhancing tumor theranostics. Herein, a kind of nanoenzyme Prussian blue (PB) is synthesized as a metal-organic framework (MOF) to load the second near-infrared (NIR-II) small molecule dye IR1061, which could catalyze hydrogen peroxide to produce oxygen and provide a photothermal conversion element for photoacoustic imaging (PAI) and photothermal therapy (PTT). To enhance stability and biocompatibility, silica was used as a coating for an integrated nanoplatform (SPI). SPI was found to relieve the hypoxic nature of the TME effectively, thus suppressing tumor cell migration and downregulating the expression of heat shock protein 70 (HSP70), both of which led to an amplified NIR-II PTT effect in vitro and in vivo, guided by the NIR-II PAI. Furthermore, label-free multi-spectral PAI permitted the real-time evaluation of SPI as a putative tumor treatment. A clinical histological analysis confirmed the amplified treatment effect. Hence, SPI combined with PAI could offer a new approach for tumor diagnosing, treating, and monitoring.

How can Fullerenes Help in the Treatment of Diseases? A Review Article on Pharmaceutical Usage of Fullerenes as Carriers.

Drug degradation is a process that can render pharmaceuticals inactive without causing any visible distortion. This can disrupt the therapeutic process, and on occasion, when the process produces toxic metabolites, it can have much more fatal consequences. Light is one of the most significant components that might cause deterioration, and several attempts have been made to improve and increase the practical photosensitizing of nano-scaled pharmaceuticals. Considering this, the insolubility and aggregating qualities of fullerenes have received significant attention. Fullerene is considered to have a unique carbon structure. In order to gain improved water solubility and biocompatible properties, fullerenes have been combined with water-soluble, biodegradable, and adjustable polymers. More specifically, these linkers exhibit increased tumor cell identification and greater tumor cell suppression when linked to therapeutic ligands (tumor-targeting) or stimuliresponsive polymers. According to scientific studies, fullerene-drug combinations can be used in certain complex diseases, like infectious and viral types. Several studies have combined fullerenes into nano-emulsions or liposomes for various pharmacological objectives. In the current work, fullerene/polymer nanomaterials are discussed for potential therapeutic techniques for the treatment of various diseases, particularly cancer and AIDS. According to the research studies, fullerene is a suitable element with outstanding physical and chemical properties that has a wide range of potential applications in the pharmaceutical industry, including drug delivery system design, photodynamic cancer therapy, and antioxidant therapy.

Radiofrequency ablation induces tumor cell dissemination in a mouse model of hepatocellular carcinoma

BackgroundWe tested the hypothesis that radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) promotes tumor cell release and explored a method for reducing these effects.MethodsA green fluorescent protein-transfected orthotopic HCC model was established in 99 nude mice. In vivo flow cytometry was used to monitor circulating tumor cell (CTC) dynamics. Pulmonary fluorescence imaging and pathology were performed to investigate lung metastases. First, the kinetics of CTCs during the periablation period and the survival rate of CTCs released during RFA were investigated. Next, mice were allocated to controls, sham ablation, or RFA with/without hepatic vessel blocking (ligation of the portal triads) for evaluating the postablation CTC level, lung metastases, and survival over time. Moreover, the kinetics of CTCs, lung metastases, and mice survival were evaluated for RFA with/without ethanol injection. Pathological changes in tumors and surrounding parenchyma after ethanol injection were noted. Statistical analysis included t-test, ANOVA, and Kaplan-Meier survival curves.ResultsCTC counts were 12.3-fold increased during RFA, and 73.7% of RFA-induced CTCs were viable. Pre-RFA hepatic vessel blocking prevented the increase of peripheral CTCs, reduced the number of lung metastases, and prolonged survival (all p ≤ 0.05). Similarly, pre-RFA ethanol injection remarkably decreased CTC release during RFA and further decreased lung metastases with extended survival (all p ≤ 0.05). Histopathology revealed thrombus formation in blood vessels after ethanol injection, which may clog tumor cell dissemination during RFA.ConclusionRFA induces viable tumor cell dissemination, and pre-RFA ethanol injection may provide a prophylactic strategy to reduce this underestimated effect.Relevance statementRFA for HCC promotes viable tumor cell release during ablation, while ethanol injection can prevent RFA induced tumor cell release.Key points• RFA induced the release of viable tumor cells during the ablation procedure in an animal model.• Hepatic vessel blocking can suppress tumor cells dissemination during RFA.• Ethanol injection can prevent RFA-induced tumor cell release, presumably because of the formation of thrombosis.Graphical

Selinexor in Combination with Salvage Regimen for Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Patients with TP53 Alterations

Background TP53 has been identified as one of the most frequently altered gene in diffuse large B-cell lymphoma (DLBCL). The prognosis of DLBCL patients with TP53 mutations ( TP53mut) was poor prognosis in R-CHOP era, even with treatments like autologous stem-cell transplantation (ASCT) or anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy. Moreover, TP53 mutations are more prevalent at relapse and are associated with therapeutic resistance. Selinexor is a selective inhibitor of nuclear export with promising anti-cancer properties and preclinical studies have shown its potential to suppress tumor cells with TP53 mutations. Several clinical studies proved selinexor in combination with R-GDP/R-ICE/R-Gemox was effective in relapsed/refractory DLBCL. Method The study enrolled relapsed/refractory DLBCL patients with TP53 alterations (including TP53 mutation and/or deletion) for treatment with selinexor in combination with salvage regimens (R-GDP/R-ICE/R-Gemox) since November 2021 in our center. The treatment was administered orally as 40 mg of selinexor on days 1, 8, and 15, combined with one of the following regimens: R-GDP (R 375mg/m2 d0, gemcitabine 1g/m2*d1, cisplatin 25mg/m2 d1-d3, dexamethasone 40mg d1-d4). R-ICE (R 375mg/m2 d0, ifosfamide 1.5g/m2*3d, carboplatin (AUC 5) and etoposide 100mg/m2*3d). R-Gemox ((R 375mg/m2 d0, gemcitabine 1g/m2*d1, oxaliplatin 100mg/m2*d1) every 3 weeks as per physician's choice. Objective response rate (ORR) was evaluated every 3 cycles based on Lugano 2014 criteria and Adverse events (AE) were rated according to the NCI CTCAE 5.0. Results 20 patients were treated with selinexor plus salvage regimen in this study and received at least two cycles of treatment, making them eligible for analysis. The median age of the 20 patients was 54 years (range 15 to 77), of this patients, 12 (60%) were male, 12 (60%) patients had disease stage III-IV at screening, and 45% with IPI>2. The median number of prior regimen was 1 (range, 1-4) with 2 patients (2 L) and 1 patient (3L). ALL patients were refractory to the last line of treatment. The patients received a median of three cycles (range, 2-6) of selinexor 40mg once a week combined with salvage regimen (13 patients received selinexor plus R-GDP, 6 with selinexor plus R-ICE and 1 with selinexor plus R-Gemox). The mutational profile of patients was presented in Figure A (14 patients with TP53 mutation, 5 patients with TP53 mutation and deletion, 1 with TP53 deletion). The best overall and complete response rates were 75% and 25%, respectively. Among them, 6 patients in PR and 1 patient in SD received CART treatment, and 5 achieved PR and 2 with CR after CART treatment (Figure B). One patient experienced PD after selinexor+R-GDP and died of disease progression within one month after CART transfusion. 1 SD patient transferred to CD3/CD20 bispecific antibody clinical trial and still progressed during the bispecific treatment. Taken together, selinexor-based salvage regimen had promising response rate in refractory DLBCL with TP53 alterations, and could be a potential bridging approach before CART therapy. Patients responded to selinexor-based regimen tended to have better outcome after CART or bispecific antibody treatment. Conclusions TP53 alterations are associated with poor outcomes in DLBCL. We identified an effective dosing schedule of selinexor (40mg QW) in combination with R-GDP/R-ICE/R-Gemox for TP53-altered refractory DLBCL patients. Further research is warranted to investigate the mechanism of action behind this treatment approach

Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein 3 (TACC3) is a component of the centrosome axis and a member of the TACC family, which affect mitosis and regulate chromosome stability and are involved in tumor development and progression. However, the role of TACC3 in PDAC remains elusive. In this study, by exploiting the TCGA database, we found that high TACC3 expression in PDAC is associated with poor prognosis. shRNA-mediated TACC3 knockdown caused S phase arrest of the cell cycle and inhibited proliferation in PDAC cell lines. Through RNA sequencing and protein co-immunoprecipitation combined with mass spectrometry, KIF11 was identified as a protein that interacts with TACC3. TACC3 stabilizes and regulates KIF11 protein expression levels in PDAC cells through physical interaction. Knockdown of TACC3 or KIF11 resulted in abnormal spindle formation during cell division both in vitro and in vivo. Pharmacological inhibition of TACC3 or KIF11 can suppress tumor cell proliferation and promote apoptosis. Our studies further demonstrated that high expression of TACC3 and KIF11 mediated the resistance of PDAC to gemcitabine, and deficiency of TACC3 or KIF11 increased the sensitivity of PDAC cells to chemotherapy. In conclusion, our study reveals the fundamental role of TACC3 expression in PDAC cell proliferation and chemoresistance, suggesting that TACC3 can be used as a molecular marker to evaluate the prognosis of PDAC.

Boosting chemotherapy of bladder cancer cells by ferroptosis using intelligent magnetic targeting nanoparticles

A versatile nano-delivery platform was reported to enhance the tumor suppression effect of chemotherapy by augmenting tumor cells' ferroptosis. The platform consists of pomegranate-like magnetic nanoparticles (rPAE@SPIONs) fabricated by encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) within a reduced poly(β-amino ester)s-PEG amphiphilic copolymer (rPAE). The resulting platform exhibits several functionalities. Firstly, it promotes the doxorubicin (DOX) release by leveraging the mild hyperthermia generated by NIR irradiation. Secondly, it triggers ferroptosis in tumor cells, inducing their demise. Thirdly, it induces polarization of macrophages towards an anti-tumor M1 phenotype, contributing to ferroptosis of tumor cells and enhanced tumor cell suppression. This study effectively capitalizes on the versatility of SPIONs and offers a simple yet powerful strategy for developing a new nanosized ferroptosis-inducing agent, ultimately improving the inhibition of bladder cancer cells.

ESCO2 promotes hypopharyngeal carcinoma progression in a STAT1-dependent manner

BackgroundThe establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) is involved in the development of multiple malignancies. However, its role in hypopharyngeal carcinoma (HPC) progression remains uncharacterized.MethodsThis study employed bioinformatics to determine the ESCO2 expression in head and neck squamous cell carcinoma (HNSC) and normal tissues. In vitro cell proliferation, migration, apoptosis, and/or cell cycle distribution assays were used to determine the function of ESCO2 and its relationship with STAT1. Xenograft models were established in nude mice to determine ESCO2 in HPC growth in vivo. Co-immunoprecipitation/mass spectrometry (Co-IP/MS) was conducted to identify the potential ESCO2 binding partners.ResultsWe found that ESCO2 expression was elevated in HNSC tissues, and ESCO2 depletion suppressed tumor cell migration in vitro and inhibited tumor growth in vitro and in vivo. Co-IP/MS and immunoblotting assays revealed the interaction between ESCO2 and STAT1 in HPC cells. STAT1-overexpression compromised ESCO2-mediated suppressive effects on HPC cell proliferation, viability, and migration.ConclusionsThese findings suggest that ESCO2 is crucial in promoting HPC malignant progression through the STAT1 pathway and provides novel therapeutic targets for HPC treatment.

A novel CPT1A covalent inhibitor modulates fatty acid oxidation and CPT1A-VDAC1 axis with therapeutic potential for colorectal cancer

Colorectal cancer (CRC) is a common and deadly disease of the digestive system, but its targeted therapy is hampered by the lack of reliable and specific biomarkers. Hence, discovering new therapeutic targets and agents for CRC is an urgent and challenging task. Here we report that carnitine palmitoyltransferase 1A (CPT1A), a mitochondrial enzyme that catalyzes fatty acid oxidation (FAO), is a potential target for CRC treatment. We show that CPT1A is overexpressed in CRC cells and that its inhibition by a secolignan-type compound, 2,6-dihydroxypeperomin B (DHP-B), isolated from the plant Peperomia dindygulensis, suppresses tumor cell growth and induces apoptosis. We demonstrate that DHP-B covalently binds to Cys96 of CPT1A, blocks FAO, and disrupts the mitochondrial CPT1A-VDAC1 interaction, leading to increased mitochondrial permeability and reduced oxygen consumption and energy metabolism in CRC cells. We also reveal that CPT1A expression correlates with the survival of tumor-bearing animals and that DHP-B exhibits anti-CRC activity in vitro and in vivo. Our study uncovers the molecular mechanism of DHP-B as a novel CPT1A inhibitor and provides a rationale for its preclinical development as well as a new strategy for CRC targeted therapy.

IMMU-28. TREM2 INHIBITION REPROGRAMS MYELOID CELLS TO STIMULATE ANTI-TUMOR IMMUNITY THROUGH BOTH DIRECT AND INDIRECT MECHANISMS

Abstract The prevailing view is that myeloid cells—macrophages and microglia—in the tumor microenvironment (TME) are immunosuppressive and promote glioblastoma (GBM) progression. However, myeloid cells have the functional plasticity to restrict or support tumor cell growth. TREM2 plays important roles in brain microglial function in neurodegenerative diseases, but the functional role of TREM2 in the GBM TME and whether TREM2 represents a meaningful therapeutic target remain largely unknown. To address these questions, we investigated the immune and tumor cell consequences of TREM2 inhibition by multiple orthogonal approaches—transgenic mice, antisense oligonucleotides, and blocking antibodies—in immunocompetent preclinical models (SB28, NPA C54B) and human GBM samples through bulk and single cell RNA-sequencing, flow cytometry, biochemistry, and functional assays. We found TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors, and that high TREM2 expression correlates with poor prognosis in GBM patients. TREM2 loss of function in human macrophages and mouse myeloid cells increased IFNγ-induced immunoactivation and proinflammatory polarization. Conditioned media from TREM2 deficient human macrophages directly killed patient-derived GBM tumor cells, and biochemical analysis identified TNF and other putative tumoricidal proteins in this conditioned media. In mouse GBM models, mice with chronic and acute Trem2 loss of function demonstrated increased tumor cell death and increased animal survival. Trem2 inhibition reprogrammed myeloid cell phenotypes and increased PD-1+CD8+ T cells in the TME. Remarkably, Trem2 deficiency enhanced the effectiveness of anti-PD-1 treatment in vivo. Trem2 inhibition suppresses tumor cell growth through direct and indirect immune cell mechanisms--by reshaping myeloid subset and T cell functions. Thus, Trem2 inhibitory strategies, in combination with immune checkpoint blockade, may represent an attractive new approach for GBM therapy.

Effect of paclitaxel octreotide conjugate on human ovarian paclitaxel-resistant cell xenograft tumor model and the mechanism underlying reversal of paclitaxel resistance

Purpose: To determine the effect of paclitaxel octreotide conjugate (POC) on human ovarian paclitaxelresistant cell xenograft tumor model and the mechanism underlying reversal of paclitaxel resistance.
 Methods: Forty female BALB/c-nu/nu mice were subcutaneously inoculated with 106 paclitaxel-resistant cells (a2780/taxol) per mouse during the logarithmic growth phase of ovarian cancer. They were randomly divided into four groups (control, octreotide, paclitaxel and POC). Immunohistochemical streptavidin-peroxidase (SP) method was used to determine expression of nuclear proliferation antigen (PCNA) while TUNEL method was used to assess apoptosis of human ovarian cancer metastasis. Realtime polymerase chain reaction (PCR) was used to assay mRNA expression levels of somatostatin receptor 2 (SSTR2), multidrug-resistant gene (MDR1), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and acetylated tubulin (α-tubulin and β-III-tubulin), while the corresponding protein expressions were assayed using western blotting.
 Results: Immunohistochemical SP showed significantly lower PCNA levels in octreotide, paclitaxel and POC groups than in control mice, but that of POC mice was significantly reduced, relative to those of octreotide and paclitaxel groups (p < 0.05). There were significantly higher expression levels of SSTR2 mRNA and protein in octreotide, paclitaxel and POC groups than in control mice, but they were significantly higher in POC group than in octreotide and paclitaxel groups (p < 0.05). The mRNA and protein expressions of other factors in POC mice were significantly lower than those in both octreotide and paclitaxel groups (p < 0.05).
 Conclusion: Paclitaxel-octreotide conjugate effectively inhibits the growth of a2780/taxol xenografts in nude mice, induces tumor cell apoptosis, and suppresses tumor cell growth via mechanism involving enhancement of SSTR2 expression, and decreases in levels of acetylated tubulin, matrix metalloproteinase-9, and vascular endothelial growth factor.