Inhibits Tumor Invasion Research Articles

Tumor Receptor-Mediated Morphological Transformation and In Situ Polymerization of Diacetylene-Containing Lipidated Peptide Amphiphile on Cell Membranes for Tumor Suppression.

In situ polymerization on cell membranes can decrease cell mobility, which may inhibit tumor growth and invasion. However, the initiation of radical polymerization traditionally requires exogenous catalysts or free radical initiators, which might cause side effects in normal tissues. Herein, we synthesized a Y-type diacetylene-containing lipidated peptide amphiphile (TCDA-KFFFFK(GRGDS)-YIGSR, Y-DLPA) targeting integrins and laminin receptors on murine mammary carcinoma 4T1 cells, which underwent nanoparticle-to-nanofiber morphological transformation and in situ polymerization on cell membranes. Specifically, the polymerized Y-DLPA induced 4T1 cell apoptosis and disturbed the substance exchange and metabolism. In vitro assays demonstrated that the polymerized Y-DLPA nanofibers decreased the migration capacity of 4T1 cells, potentially suppressing tumor invasion and metastasis. When administered locally to 4T1 tumor-bearing mice, the Y-DLPA nanoparticles formed a biomimetic extracellular matrix that effectively suppressed tumor growth. This study provides an in situ polymerization strategy that can serve as an effective drug-free biomaterial with low side effects for antitumor therapy.

Potential Antitumor Mechanism of Propolis Against Skin Squamous Cell Carcinoma A431 Cells Based on Untargeted Metabolomics.

Propolis is a sticky substance produced by honeybees (Apis mellifera) through the collection of plant resins, which they mix with secretions from their palate and wax glands. Propolis can inhibit tumor invasion and metastasis, thereby reducing the proliferation of tumor cells and inducing cell apoptosis. Previous research has shown that propolis has an inhibitory effect on skin squamous cell carcinoma A431 cells. Nevertheless, its inhibitory mechanism is unclear because of many significantly different Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between the ethanol extract of the propolis (EEP) group and the control group of cells. In this study, the main components of EEP and the antitumor mechanism at an IC50 of 29.04 μg/mL EEP were determined via untargeted metabolomics determined using ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC‒MS/MS), respectively. The results revealed 43 polyphenolic components in the EEP and 1052 metabolites, with 160 significantly upregulated and 143 significantly downregulated metabolites between cells treated with EEP and solvent. The KEGG enrichment results revealed that EEP significantly inhibited A431 cell proliferation via the steroid hormone biosynthesis and linoleic acid metabolism pathways. These findings may provide valuable insights for the development of targeted therapies for the treatment of cutaneous squamous cell carcinoma.

Downregulation of chemokine (C‑C motif) ligand 5 induced by a novel 8‑hydroxyquinoline derivative (91b1) suppresses tumor invasiveness in esophageal carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a particularly aggressive form of cancer with high mortality. In the present study, a novel 8‑hydroxyquinoline derivative (91b1) was investigated for its anticancer activities in ESCC along with its associated mechanisms. The in vitro cytotoxic effect of 91b1 were evaluated across five ESCC cell lines using MTS assay, with cisplatin serving as a comparative standard. Changes in gene expression profile were identified by cDNA microarray and further validated by qualitative PCR and immunostaining. Additionally, protein levels of the most notably downregulated target in archival ESCC samples were also studied. 91b1 demonstrated comparable anticancer effect with cisplatin. Notably, chemokine ligand 5 (Ccl5) was identified as the most substantially downregulated gene, with its suppression at both mRNA and protein expression in ESCC cells, exhibiting a dose‑dependent manner. The recombinant human protein of CCL5 enhanced the invasion of ESCC cells using the Transwell assay. The upregulation of CCL5 protein was also detected in 50% of ESCC cell lines. CCL5 was also overexpressed in 76.9% of ESCC specimens. The overall results indicated that 91b1 could effectively induce anticancer effect on ESCC cells through downregulating CCL5 expression with suppression of tumor invasion. Overall, these findings suggested that 91b1 effectively inhibited ESCC cell proliferation and tumor invasion by downregulating CCL5 expression, highlighting its potential as a therapeutic agent for ESCC treatment.

A self-targeting MOFs nanoplatform for treating metastatic triple-negative breast cancer through tumor microenvironment remodeling and chemotherapy potentiation

Triple-negative breast cancer (TNBC) is the most aggressive and fatal subtype of breast cancer with disappointing treatment and high mortality. Tumor microenvironment (TME) plays an important role in the invasion and metastasis of TNBC through multiple complex processes. Most anti-metastatic therapies only focus on cancer cells themselves or interfering with single factors of the metastasis process, which is often related to poor outcomes. Thus, effective TNBC treatment relies on regulating multiple key metastasis-related aspects of the TME. Herein, a self-targeting Metal-Organic Frameworks (MOFs) nanoplatform (named as MTX-PEG@TPL@ZIF-8) was designed to improve treatment of TNBC through tumor microenvironment remodeling and chemotherapy potentiation. The self-targeting MOF nanoplatform is consist of ZIF-8 nanoparticles loaded triptolide (TPL) and followed by the coating with methotrexate-polyethylene glycol conjugates (MTX-PEG). Due to MTX’s affinity for the overexpressed folate receptor on tumor cell surfaces, MTX-PEG@TPL@ZIF-8 enables effective accumulation and deep penetration in the tumor area by an MTX-mediated self-targeting strategy. This MOF nanoplatform could promptly release the medication after penetrating the tumor cell, due to pH-triggered degradation. Its anti-metastasis mechanism is to inhibit tumor invasion and metastasis by down-regulating the expression of Vimentin, MMP-2 and MMP-9 and increasing the expression of E-cadherin, upregulation of cleaved caspase-3 and cleaved caspase-9 protein expression promote the apoptosis of tumor cells, thereby reducing their migration. It also downregulated the expression of VEGF and CD31 protein to inhibit the generation of neovascularization. Overall, these findings suggest the self-targeting MOF nanoplatform offers new insights into the treatment of metastatic TNBC by TME remodeling and potentiating chemotherapy.

Design, synthesis and biological evaluation of novel naphthoquinothiazole derivatives as potent antitumor agents through inhibiting STAT3

The signal transducer and activator of transcription 3 (STAT3) has been established as a crucial drug target in the development of antitumor agents. In this study, a series of 21 derivatives of the STAT3 inhibitor napabucasin were designed and synthesized. Through preliminary screening against tumor cell lines, SZ6 emerged as the most potent compound with half maximal inhibitory concentration (IC50) values of 46.3 nM, 66.4 nM, and 53.8 nM against HCT116, HepG2, and Hela cells respectively. Furthermore, SZ6 effectively suppressed tumor invasion and migration in HCT116 cell assays by inducing S-phase arrest and apoptosis through inhibition of Protein Kinase B (PKB/AKT) activity and induction of reactive oxygen species (ROS). The mechanism underlying SZ6′s action involves inhibition of STAT3 phosphorylation, which was confirmed by western blotting analysis. Additionally, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) demonstrated direct binding between SZ6 and STAT3. Notably, in vivo studies revealed that SZ6 significantly inhibited tumor growth without any observed organ toxicity. Collectively, these findings identify SZ6 as a promising STAT3 inhibitor for colorectal cancer treatment.

Atorvastatin can inhibit ovarian cancer by decreasing VEGF, TGF-β1 and increasing cytochrome-c and caspase-3 expressions

Objective: Atorvastatin (ATV), being widely utilized in clinical practice, is recognized as a prevalent cancer drug with established safety profiles. The objective of this study was to examine the potential anti-tumor effects of ATV in ovarian cancer (OC), as well as explore its underlying mechanism. Methods: The CCK-8 method was employed to assess the efficacy of ATV on both OC cells and normal ovarian epithelial cells. Furthermore, the anti-proliferative impact of ATV on OC cells was determined through CCK-8 and colony formation techniques. Additionally, flow cytometry was employed to detect apoptosis in SKOV3 cells, while Transwell assays were utilized to assess cell migration and invasion. Western Blot analysis was conducted to evaluate EMT-related proteins (E-cadherin, Vimentin, and N-cadherin), as well as VEGF, TGF-β1, cytochrome-c, and caspase-3. Result: ATV had dose-dependent and time-dependent anti-tumor activity on SKOV3 cells, which promoted apoptosis of tumor cells, significantly up-regulated E-cadherin, cytochrome-c, and caspase3, and downregulated Vimentin, N-cadherin, VEGF, and TGF-β1. Conclusion: ATV exhibits anti-tumor properties on SKOV3 cells by modulating various cellular factors, including reducing VEGF and TGF-β1 levels, enhancing cytochrome-c and caspase-3 expression, and inhibiting tumor invasion and metastasis. The findings of this study contribute to the establishment of a scientific foundation for the potential clinical utilization of ATV in the management of OC.

TRIM21-mediated ubiquitylation of TAT suppresses liver metastasis in gallbladder cancer

Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.

Taurine Inhibits Lung Metastasis in Triple-Negative Breast Cancer by Modulating Macrophage Polarization Through PTEN-PI3K/Akt/mTOR Pathway.

Taurine (Tau) has been found to inhibit triple-negative breast cancer (TNBC) invasion and metastasis. However, its effect on tumor-promoting macrophages and tumor suppressor macrophages in breast cancer progression remains unknown. In this study, we investigated the effects of Tau on macrophage polarization and its role in TNBC cell growth, invasion, and metastasis. We induced human THP-1 monocytes to differentiate into M2 macrophages through exogenous addition of interleukin-4. We used the TNBC cell lines MDA-MB-231 and BT-549 cultured in a conditioned medium from M2 macrophages to investigate the effect of Tau on tumor growth and invasion. We analyzed macrophage subset distribution, M1 and M2 macrophage-associated markers, and mRNA expression by quantitative polymerase chain reaction. We also detected the PTEN-PI3K/Akt/mTOR signaling pathway that mediates M1 macrophage to suppress tumor invasion using western blotting. Our results showed that Tau inhibits breast cancer metastasis to the lungs in vivo and cell invasion by altering the polarization of tumor-associated macrophage in vitro. In addition, Tau can up-regulate PTEN expression, suppress the PI3K-Akt signaling pathway, and promote the M1 polarization of macrophages, which ultimately inhibits the metastasis of TNBC cells. Our findings suggest that Tau inhibits the activation of the PI3K-Akt-mTOR signaling pathway by up-regulating PTEN , promotes the proportion of M1 macrophages in tumor-associated macrophage, and suppresses the invasion and metastasis of TNBC. This provides a potential therapeutic approach to influence cancer progression and metastasis.

Assessment of Inhibition of the Growth of Breast and Colon Tumors when Blocking VEGFR-1 with Monoclonal Antibodies

Vascular endothelial growth factor receptor-1 (VEGFR-1) plays a critical role in tumor-associated angiogenesis. VEGFR-1 is found on the surface of tumor cells and cells in the tumor microenvironment. Blocking this receptor leads to the suppression of proliferation and increased apoptosis of tumor cells, reduction of tumor vascularization, inhibition of the production of immunosuppressive cytokines by tumor-associated macrophages, and the suppression of tumor invasion and metastasis. The creation of monoclonal antibody drugs that block VEGFR-1 is an urgent task in the development of potential antitumor therapeutic drugs. Target molecules created on the basis of antibodies that bind to VEGFR-1 are a promising basis for the creation of theranostic radiopharmaceuticals for the diagnosis and treatment of malignant neoplasms. To study the therapeutic potential of VEGFR-1 inhibition in breast and colon cancers using antibodies, monoclonal antibodies against recombinant human VEGFR-1 protein are developed. The resulting monoclonal antibodies bind to the VEGFR-1 receptor on the cell surface and effectively inhibit the proliferation of breast and colon cancer cells in vitro, reduce the growth rate of the tumor node in vivo, and prolong the survival of tumor-inoculated mice.

Abstract 192: Orchestrating CDC42 turnover to regulate membrane protrusion and tumor metastasis

Abstract F-actin cytoskeleton remodeling is essential for cell migration, organ development, and immune responses. CDC42, a factor orchestrating F-actin remodeling for membrane dynamics, switches between its inactive GDP- and active GTP-bound forms. However, the biological and clinical significance of the mechanisms regulating CDC42 protein turnover remains unclear. Here we show that KLHL23-mediated CDC42·GTP polyubiquitylation for degradation and RhoGDI-mediated CDC42·GDP sequestration away from the plasma membrane co-inactivate CDC42 in a spatiotemporal context, influencing membrane dynamics and homeostasis during migration. Via a functional genomic screen, we identified KLHL23 as a suppressor of tumor invasion. Decreased KLHL23 level was associated with tumor metastasis and poor clinical outcomes in patients with liver and pancreas cancers. KLHL23 functions as the E3 ligase responsible for CDC42 polyubiquitylation and degradation. KLHL23 shares with RhoGDI the switch II region of CDC42 for binding, enhancing selective targeting of CDC42·GTP and CDC42·GDP, respectively. KLHL23 depletion in cells leads to F-actin and membrane over-protrusion, as well as epithelial-mesenchymal transition and tumor metastasis. Fluorescence resonance energy transfer assays reveal that the KLHL23—CDC42·GTP interaction plays a primary role in quenching CDC42 activity during membrane protrusion-retraction, while the RhoGDI—CDC42·GDP interaction occurs lately. Our results demonstrate the spatiotemporal interplay between RhoGDI and KLHL23 in regulating CDC42 turnover for membrane dynamics. As KLHL23/RhoGDI—CDC42 axis dysregulation causes tumor metastasis, our findings open avenues for exploring novel therapeutics. Citation Format: Sen-Yung Hsieh. Orchestrating CDC42 turnover to regulate membrane protrusion and tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 192.

Abstract 2991: Global analysis of miR-210 and miR-21 dysregulation and direct targeting in thyroid cancer during hypoxia

Abstract Introduction: Hypoxia is frequent in solid tumors and stabilizes Hypoxia Inducible Factor-1 (HIF-1). HIF-1, in turn, activates several cellular pathways that promote tumor growth and resistance to chemotherapy. MicroRNA (miRNA) miR-210 is a direct HIF-1 target. HIF-1 binds to a Hypoxia-Response Element (HRE) in the miR-210 promoter, up-regulating its expression. miR-21 is the most widely reported oncogenic miRNA in cancer. miRNAs complexed with Argonaute-2 (AGO2) bind target mRNAs to inhibit translation. Given that a single miRNA can have hundreds of predicted mRNA targets, we sought to identify mRNA targets of miR-210 and miR-21. Identifying dysregulated target genes of miR-210 and miR-21 may highlight new therapeutic targets. Methods: The SW1736 (anaplastic thyroid cancer) cell line was cultured at 2% (hypoxic) or atmospheric (normoxic) O2 for 24 or 48hrs. HIF-1α accumulation relative to normoxia was analyzed by Western blot. miR-210-3p expression was measured relative to normoxia by RT-qPCR. Small and total RNA-sequencing was performed to identify additional differentially expressed miRNAs and mRNAs in hypoxia after 48hrs. To identify direct miRNA targets, SW1736 cells were cross-linked by UV irradiation after 48hrs of normoxic or hypoxic conditions. AGO2 covalently cross-linked to miRNA and target mRNAs were purified by immunoprecipitation after DNA and RNA digestion. miRNA and target mRNAs protected by AGO2 were ligated to generate chimeric miRNA:mRNA molecules followed by sequencing. miRNA:mRNA chimeras were analyzed using the SCRAP bioinformatic pipeline. Results: miR-210-3p expression was up-regulated by ~11-fold at 24hrs and ~19-fold at 48hrs, which was consistent with increased HIF-1α protein levels assessed by Western blot. miR-210-3p and HIF-1α levels were highest after 48hr of hypoxia relative to normoxia. Small RNA-seq showed that miR-210-3p was the only miRNA significantly up-regulated (>2-fold) in hypoxia (48hr) in SW1736. Further, miRNA:mRNA chimeric sequencing results confirmed that miRNAs primarily interacted with the 3’UTRs and coding sequences of mRNA. miR-210-3p was most abundant in hypoxia and found in chimeras with HIF-1α mRNA as well as some oncogenic and tumor suppressor transcripts involved in metabolism and mRNA processing. miR-21-5p was the most abundant chimera miRNA in both normoxia and hypoxia and was primarily bound to tumor suppressor mRNAs associated with cell cycle arrest, TGFB signaling, and inhibition of tumor invasion and migration. Conclusions: miR-210-3p and miR-21-5p elevated levels and interactions indicate hypoxia and malignancy in solid tumors including breast, thyroid, prostate, and lung. Further analysis of other miRNA:mRNA interactions and functional validation may aid in identifying novel therapies for solid tumors. Citation Format: Bonita H. Powell, William T. Mills, Andrey Turchinovich, Yongchun Wang, Martha A. Zeiger, Christopher B. Umbricht, Mollie K. Meffert, Kenneth W. Witwer. Global analysis of miR-210 and miR-21 dysregulation and direct targeting in thyroid cancer during hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2991.

Abstract 4141: Quantitative measurement of 3D tumor spheroid invasion using live cell time-lapse imaging

Abstract 90% of the death of cancer individuals is related to cancer metastasis1. The invasion and migration of cancer cells into surrounding tissues and chambers is the first step of metastasis2. To have a better and more in-depth understanding of the pathophysiological activities involved in metastatic cancer, accurate and reliable methods for evaluating cell invasion are urgently needed. Compared to the 2D cell model, the 3D system mimics the natural physiological properties and conditions, such as structure, physiology, biological signals of living tissues, cell-matrix interactions4. In this study, we followed the commonly used protocol for 3D tumor invasion assay3 to generate spheroids in Ultra-Low-attachment (ULA) round bottom 96-well plate and subsequently embedded them in Matrigel® (5 mg/mL). After polymerization, the Matrigel that contains tumor spheroid was submerged in 100 μL cell culture media. The invasion of the 3D spheroid in the presence or absence of drug treatment was monitored and quantified using the brightfield and fluorescence live cell time-lapse image acquisition and image analysis functions of the Agilent xCELLigence RTCA eSight. The progress of spheroid invasion and the drug-inhibitory effects on tumor invasion were quantified by tracking and calculating the area of invasive protrusion from the spheroid. Our data show that 1) different types of cancer cells had different metastatic potentials demonstrated by the level of invadopodium extending into the Matrigel at desired time points; 2) the invasion of 3D HT1080 spheroid was inhibited by cytochalasin D (Cyto D), an inhibitor of actin polymerization, and GM6001, a potent broad-spectrum inhibitor of matrix metalloproteinases (MMP), in a dose-dependent manner; 3) Cyto D exhibited higher efficacy of inhibiting tumor invasion than GM6001. In summary, our approach by combining the 3D tumor spheroid invasion model with the RTCA eSight’s capability of live cell imaging and automatic quantification of the area of invasive protrusion can facilitate and enhance the development of new treatments at the preclinical stage in the future. Citation Format: Grace Yang, Tian Wang, Peifang Ye, Xiaoyu Zhang. Quantitative measurement of 3D tumor spheroid invasion using live cell time-lapse imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4141.

Brusatol's anticancer activity and its molecular mechanism: a research update.

Brusatol (BT) is a quassinoid compound extracted from Brucea javanica that is a traditional Chinese herbal medicine. Brusatol possesses biological and medical activity, including antitumor, antileukemia, anti-inflammatory, antitrypanosomal, antimalarial, and antitobacco mosaic virus activity. To summarize and discuss the antitumor effects of BT and its mechanisms of actions, we compiled this review by combining the extensive relevant literature and our previous studies. We searched and retrieved the papers that reported the pharmacological effects of BT and the mechanism of BT antitumor activity from PubMed until July 2023. Numerous studies have shown that BT is a unique nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor that acts on various signaling pathways and has good antitumor properties. Brusatol shows great potential in cancer therapy by inhibiting cell proliferation, blocking the cell cycle, promoting tumor cell differentiation, accelerating tumor cell apoptosis, inducing autophagy, suppressing angiogenesis, inhibiting tumor invasion and metastasis, and reversing multidrug resistance. This review summarizes recent updates on the antitumor activity and molecular mechanisms of BT and provides references for future development and clinical translation of BT and its derivatives as antitumor drugs.

A Therapeutic Pretargeting Strategy for Triple‐Negative Breast Cancer Based on a Bioorthogonal Reaction and a Self‐Assembled Peptide

AbstractTriple‐negative breast cancer (TNBC), a disease with a poor prognosis and high mortality, is difficult to targeted therapy, due to the metastatic nature of TNBC cells and their lack of estrogen, progesterone, and Her‐2/Neu receptor targets. Here, a novel pretargeting strategy involving self‐assembled peptides and a bioorthogonal reaction are described. This process generates nanofibers on TNBC cell surface that prevent them migration and invasion and deliver untargeted anticancer drugs (e.g., doxorubicin) that synergistically eliminates TNBC cells. The self‐assembled peptide contains four modules: i) an aromatic group‐rich tetraphenylethylene (TPE) unit for promoting self‐assembly and nanofiber formation, ii) a GFFY peptide motif that supports self‐assembly of nanofibers into peptide scaffolds, iii) a targeting RGD motif that binding with the abundant integrin molecules present on TNBC cell surface, and iv) an azide group acting as the bioorthogonal reaction site that reacts with drugs or probes containing the dibenzocyclooctyne (DBCO) group. Results of in vitro and in vivo experiments indicate that the self‐assembled peptide inhibits tumor invasion and metastasis, while also pretargeting and killing TNBC cells with superior effectiveness and lower toxicity to that of current chemotherapies. In conclusion, this novel bioorthogonal pretargeting strategy holds promise as an effective anticancer therapeutic approach.

Mechanism of inhibition of growth and metastasis of colon cancer by celecoxib analog OSU-03013 via wnt signaling pathway

OSU-03013 is a structurally modified analog of celecoxib. This study probed the antitumor activity of OSU-03013 on colon cancer (CC) and explored its possible mechanism. CCK-8 method was used to evaluate the activity of OSU-03013 on CC cell SW480 and normal colon epithelial cell FHC, and the anti-proliferation effect of OSU-03013 was detected by CCK-8 and colony formation assay. In addition, flow cytometry and Annexin V-FITC/PI were applied to detect apoptosis of SW480 cells, and Transwell was to detect cell migration and invasion. β-catenin, c-myc, and Wnt1 genes were assessed by RT-qPCR, and E-cadherin, N-cadherin, and β-catenin, c-myc, mTOR, p-mTOR, and Wnt1 proteins were detected by Western Blot. OSU-03013 had dose-dependent and time-dependent antitumor activity on SW480 cells, which can promote tumor cell apoptosis, up-regulate E-cadherin, and down-regulate β-catenin, c-myc, Wnt1, and N-cadherin. OSU-03013 has anti-tumor activity on CC cells. The anti-cancer mechanism of OSU-03013 is achieved by inhibiting the activation of Wnt pathway genes and inhibiting tumor invasion and metastasis. This study provides a scientific basis for the clinical application of OSU-03013 in the treatment of CC.

Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis

HMGA2, a pivotal transcription factor, functions as a versatile regulator implicated in the progression of diverse aggressive malignancies. In this study, mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2, and USP48 was identified as a deubiquitinating enzyme of HMGA2. The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation, while the deprivation of USP48 promoted HMGA2 degradation, thereby suppressing tumor invasion and metastasis. We discovered that USP48 undergoes SUMOylation at lysine 258, which enhances its binding affinity to HMGA2. Through subsequent phenotypic screening of small molecules, we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48. Interestingly, the small-molecule inhibitor targeting USP48 induces destabilization of HMGA2. Clinically, upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer (CRC). Collectively, our study not only elucidates the regulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC, but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.

Retraction to: miR-206 is an independent prognostic factor and inhibits tumor invasion and migration in colorectal cancer.

Retraction to: miR-206 is an independent prognostic factor and inhibits tumor invasion and migration in colorectal cancer.

Research progress in Astragali Radix and its active ingredients in treatment of lung cancer

Lung cancer is the leading cause of cancer death, and its effective treatment is a difficult medical problem. Lung cancer belongs to the traditional Chinese medicine(TCM) disease categories of lung accumulation, lung amassment, and overstrain cough. Rich theoretical basis and practical experience have been accumulated in the TCM treatment of lung cancer. Astragali Radix is one of the representatives of Qi-tonifying drugs. It mainly treat the lung cancer with the syndrome of Qi deficiency and pathogen stagnation, following the principle of reinforcing healthy Qi and eliminating patgogenic Qi. Astragali Radix exerts a variety of pharmacological activities in the treatment of lung cancer, including inhibiting tumor cell proliferation and promoting tumor cell apoptosis, inhibiting tumor invasion and migration, regulating the tumor microenvironment, suppressing tumor angiogenesis, modulating autophagy, inducing macrophage polarization, enhancing immunity, inhibiting immune escape, and reversing cisplatin resistance. The active ingredients of Astragali Radix in treating lung cancer include polysaccharides, saponins, and flavonoids. This study reviewed the pharmacological activities and active ingredients of Astragali Radix in the treatment of lung cancer, providing a basis for the development and utilization of Astragali Radix resources and active ingredients and the research and development of anti-tumor drugs.

IKIP downregulates THBS1/FAK signaling to suppress migration and invasion by glioblastoma cells.

Inhibitor of NF-κB kinase-interacting protein (IKIP) is known to promote proliferation of glioblastoma (GBM) cells, but how it affects migration and invasion by those cells is unclear. We compared levels of IKIP between glioma tissues and normal brain tissue in clinical samples and public databases. We examined the effects of IKIP overexpression and knockdown on the migration and invasion of GBM using transwell and wound healing assays, and we compared the transcriptomes under these different conditions to identify the molecular mechanisms involved. Based on data from our clinical samples and from public databases, IKIP was overexpressed in GBM tumors, and its expression level correlated inversely with survival. IKIP overexpression in GBM cells inhibited migration and invasion in transwell and wound healing assays, whereas IKIP knockdown exerted the opposite effects. IKIP overexpression in GBM cells that were injected into mouse brain promoted tumor growth but inhibited tumor invasion of surrounding tissue. The effects of IKIP were associated with downregulation of THBS1 mRNA and concomitant inhibition of THBS1/FAK signaling. IKIP inhibits THBS1/FAK signaling to suppress migration and invasion of GBM cells.

TS-2021, a third-generation oncolytic adenovirus that carried Ki67 promoter, TGF-β2 5'UTR, and IL-15 against experimental glioblastoma.

Oncolytic virotherapy is a promising therapeutic approach for glioblastoma (GBM) treatment, although the outcomes are partially satisfactory. Hence, more effective strategies are needed urgently to modify therapeutic viruses to enhance their efficiency and safety in killing tumor cells and improve the survival rate of GBM patients. This study generated a new-generation oncolytic adenovirus Ad5 KT-E1A-IL-15 (TS-2021) and evaluated its antitumor efficacy. Ex vivo analyses revealed Ki67 and TGF-β2 co-localized in GBM cells. In addition, TS-2021 selectively replicated in GBM cells, which was dependent on the expression of Ki67 and TGF-β2. The immunocompetent mice model of GBM demonstrated the in vivo efficacy of TS-2021 by inhibiting tumor growth and improving survival proficiently. Notably, TS-2021 effectively reduced MMP3 expression by inactivating the MKK4/JNK pathway, thereby reducing tumor invasiveness. Altogether, the findings of the present study highlight that TS-2021 can effectively target GBM cells expressing high levels of Ki67 and TGF-β2, exerting potent antitumor effects. Additionally, it can improve efficacy and suppress tumor invasiveness by inhibiting the MKK4/JNK/MMP3 pathway. Thus our study demonstrates the efficiency of the novel TS-2021 in the mouse model and provides a potential therapeutic option for patients with GBM.