Inhibit Cancer Cell Proliferation Research Articles

Reactivated thyroid hormone receptor β attenuates anaplastic thyroid cancer (ATC) stem cell activity.

Anaplastic thyroid cancer (ATC) is one of the most aggressive solid cancers in humans, with limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity contributes to therapeutic resistance and recurrence of ATC. We show that the expression of the endogenous thyroid hormone receptor β gene (THRB) is silenced in ATC and demonstrate that the exogenously expressed TRβ suppresses CSC activity. Decitabine is one of the demethylation agents to treat myelodysplastic syndrome and acute myeloid leukemia patients and is currently in clinical trials for hematopoietic malignancies and solid tumors. We aim to show that the re-expression of the endogenous THRB gene by decitabine can attenuate CSC activity to block ATC tumor growth. We treated ATC cell lines derived from human ATC tumors (11T and 16T cells) with decitabine and evaluated the effects of the reactivated endogenous TRβ on CSC activity in vitro and in vivo xenograft models. We found that treatment of 11T and 16T cells with decitabine reactivated the expression of endogenous TRβ, as evidenced by western blot and immunohistochemical analyses. The expressed TRβ inhibited cell proliferation by arresting cells at the S phase, increased apoptotic cell death by upregulation of cleaved caspase-3, and markedly suppressed the expression of CSC regulators, including cMYC, ALDH, SOX2, CD44, and β-catenin. Decitabine also inhibited xenograft tumor growth by suppressing CSC activity, inhibiting cancer cell proliferation, and increasing apoptosis. Our findings suggest that re-expression of the endogenous TRβ is a novel therapeutic approach for ATC via suppression of CSC activity.

Semi-Synthesis and Biological Evaluation of 25(R)-26-Acetoxy-3β,5α-Dihydroxycholest-6-One

Previously, we identified a series of steroids (1-6) that showed potent anti-virus activities against respiratory syncytial virus (RSV), with IC50 values ranging from 3.23 to 0.19 µM. In this work, we first semi-synthesized and characterized the single isomer of 5, 25(R)-26-acetoxy-3β,5α-dihydroxycholest-6-one, named as (25R)-5, in seven steps from a commercially available compound diosgenin (7), with a total yield of 2.8%. Unfortunately, compound (25R)-5 and the intermediates only showed slight inhibitions against RSV replication at the concentration of 10 µM, but they possessed potent cytotoxicity activities against human bladder cancer 5637 (HTB-9) and hepatic cancer HepG2, with IC50 values ranging from 3.0 to 15.5 µM without any impression of normal liver cell proliferation at 20 µM. Among them, the target compound (25R)-5 possessed cytotoxicity activities against 5637 (HTB-9) and HepG2 with IC50 values of 4.8 µM and 15.5 µM, respectively. Further studies indicated that compound (25R)-5 inhibited cancer cell proliferation through inducing early and late-stage apoptosis. Collectively, we have semi-synthesized, characterized and biologically evaluated the 25R-isomer of compound 5; the biological results suggested that compound (25R)-5 could be a good lead for further anti-cancer studies, especially for anti-human liver cancer.

ALKBH5 Inhibits Cancer Cell Proliferation in Prostate Cancer through KLF4/TERT Signaling

N6-methyladenosine (m6A), as a reversible chemical modification of RNA, is a new type of posttranscriptional gene regulation, which plays an important role in cell differentiation and tumorigenesis, and is also a research hotspot in epigenetic transcriptomics in recent years. The purpose of this study was to discuss the action mechanism of m6A demethylase ALKBH5 in the occurrence of prostate cancer (PCa). We found that ALKBH5 was lowly expressed in PCa, and the decreased expression of ALKBH5 was responsible for the poor prognosis of prostate carcinomas. Moreover, ALKBH5 downregulated the expression of Krüppel-like factor 4 (KLF4) by reducing its mRNA stability, which reduced the transcriptional activity of KLF4 on the downstream target telomerase reverse transcriptase (TERT) and decreased TERT expression and telomerase activity, eventually inhibiting PCa cell growth. The findings of this study reveal the action mechanism of ALKBH5 in PCa from the perspective of epitranscriptomics, which would provide new ideas for the prevention of PCa.

Propolis: A Detailed Insight of Its Anticancer Molecular Mechanisms.

Cancer is the second most life-threatening disease and has become a global health and economic problem worldwide. Due to the multifactorial nature of cancer, its pathophysiology is not completely understood so far, which makes it hard to treat. The current therapeutic strategies for cancer lack the efficacy due to the emergence of drug resistance and the toxic side effects associated with the treatment. Therefore, the search for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Propolis is a mixture of resinous compounds containing beeswax and partially digested exudates from plants leaves and buds. Its chemical composition varies widely depending on the bee species, geographic location, plant species, and weather conditions. Since ancient times, propolis has been used in many conditions and aliments for its healing properties. Propolis has well-known therapeutic actions including antioxidative, antimicrobial, anti-inflammatory, and anticancer properties. In recent years, extensive in vitro and in vivo studies have suggested that propolis possesses properties against several types of cancers. The present review highlights the recent progress made on the molecular targets and signaling pathways involved in the anticancer activities of propolis. Propolis exerts anticancer effects primarily by inhibiting cancer cell proliferation, inducing apoptosis through regulating various signaling pathways and arresting the tumor cell cycle, inducing autophagy, epigenetic modulations, and further inhibiting the invasion and metastasis of tumors. Propolis targets numerous signaling pathways associated with cancer therapy, including pathways mediated by p53, β-catenin, ERK1/2, MAPK, and NF-κB. Possible synergistic actions of a combination therapy of propolis with existing chemotherapies are also discussed in this review. Overall, propolis, by acting on diverse mechanisms simultaneously, can be considered to be a promising, multi-targeting, multi-pathways anticancer agent for the treatment of various types of cancers.

Co-delivery of gemcitabine and Triapine by calcium carbonate nanoparticles against chemoresistant pancreatic cancer

Pancreatic cancer is a malignant disease with high mortality, and its systemic treatment strategy mainly focuses on chemotherapy. Yet, the overall prognosis of pancreatic cancer patients is still extremely poor with a low survival rate. Gemcitabine (GEM) is a widely used chemotherapeutic agent for the treatment of pancreatic cancer. However, GEM chemoresistance remains the major challenge. In this study, we prepared calcium carbonate nanoparticles (CaCO3 NPs) loaded with a nucleotide reductase inhibitor (Triapine) and GEM to suppress the GEM resistance of pancreatic cancer cells (PANC-1/GEM) and solve the problem of poor solubility of Triapine. CaCO3-GEM-Triapine NPs nano-formulations enhanced the therapeutic effect of GEM-based chemotherapy by inhibiting cancer cell proliferation, migration, and resistance to GEM using both 2D PANC-1/GEM cells and 3D tumor spheroids. The study indicated that CaCO3 NPs loaded with GEM and Triapine could provide an effective treatment option to overcome drug resistance in pancreatic cancer.

A264 ORAL IRON SUPPLEMENTATION SHAPES THE RECOVERY OF GUT THE MICROBIOTA AND PROMOTES CARCINOGENESIS IN THE APCMIN/+ MOUSE MODEL

Abstract Background Colorectal cancer (CRC) induces anemia in a large proportion of patients and is usually treated with oral iron supplementation. Surgery, the main treatment for CRC, is routinely accompanied by prophylactic antibiotics to avoid infection. Moreover, the concomitance of oral iron supplementation and antibiotics treatment is highly prevalent in general population. However, the combined effect of antibiotics and high luminal iron concentration in the gut on the microbiota and intestinal homeostasis remains unknown. Purpose This study sought to identify possible deleterious effects of the recovery from antibiotics exposure of the gut microbiota under oral iron supplementation. Method In order to assess the effects of luminal iron on the recovery of the gut microbiota, WT mice were subjected to antibiotic treatment with different concentrations of dietary iron. Then, to explore potential deleterious effects of this setup on CRC promotion and progression mediated by the human CRC gut microbiota, CRC model ApcMin/+ mice were subjected to antibiotics prior to gavage with fecal samples from anemic CRC patients, then fed different concentrations of dietary iron. The composition of the gut microbiota and its recovery after these interventions were assessed in stool samples by 16S rRNA. Gut microbiota functions were inferred by using the PICRUSt2, and short chain fatty acid (SCFA) concentration in feces were assessed by liquid-chromatography mass spectrometry. CRC progression and promotion were assessed by tumour counts and immunohistochemistry. Result(s) Recovery from antibiotics under high luminal iron concentration shifted the gut microbiota toward a Bacteroidetes phylum-dominant composition. Three bacterial species characterized as CRC initiators were significantly more abundant. Nitrogen, pentose phosphate, cyanoamino acid metabolisms were higher after recovery under oral iron supplementation. Antibiotic exposure induced a long-term increase in SCFAs linked to gut inflammation, propionate and succinate. For mice under high luminal iron concentration, they showed a lack of recovery in baseline levels of butyrate, a SCFA that inhibits cancer cell proliferation in the gut. In addition, an increase in CRC burden and progression were found in ApcMin/+ mice receiving fecal sample from patients and oral iron supplementation. Conclusion(s) Gut microbiota recovery from antibiotic exposure under oral iron supplementation is frequent in CRC patients, but is also common in the general population. This study identifies possible deleterious effects of the concomitance of these two disruptive agents of the gut microbiota on the CRC progression. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; NSERC, ICM Disclosure of Interest None Declared

Formosanin C suppresses cancer cell proliferation and migration by impeding autophagy machinery.

Formosanin C (FC) is a natural compound extracted from Paris formosana Hayata with anticancer activity. FC induces both autophagy and apoptosis in human lung cancer cells. FC-induced depolarization of mitochondrial membrane potential (MMP) may trigger mitophagy. In this study, we clarified the effect of FC on autophagy, mitophagy, and the role of autophagy in FC-related cell death and motility. We found FC caused the continuous increase of LC3 II (representing autophagosomes) from 24 to 72 h without degradation after treatment of lung and colon cancer cells, indicating that FC blocks autophagic progression. In addition, we confirmed that FC also induces early stage autophagic activity. Altogether, FC is not only an inducer but also a blocker of autophagy progression. Moreover, FC increased MMP accompanied by overexpression of COX IV (mitochondria marker) and phosphorylated Parkin (p-Parkin, mitophagy marker) in lung cancer cells, but no colocalization of LC3 with COX IV or p-Parkin was detected under confocal microscopy. Moreover, FC could not block CCCP (mitophagy inducer)-induced mitophagy. These results imply that FC disrupts mitochondria dynamics in the treated cells, and the underlying mechanism deserves further exploration. Functional analysis reveals that FC suppresses cell proliferation and motility through apoptosis and EMT-related pathway, respectively. In conclusion, FC acts as an inducer as well as a blocker of autophagy that results in cancer cell apoptosis and decreased motility. Our findings shed the light on the development of combined therapy with FC and clinical anticancer drugs for cancer treatment.

Quercetin downregulates the expression of IL15 in cancer cells through DNA methylation.

This study aimed to investigate the effect of quercetin on cellular immunity (via IL15 expression) against cancer and to elucidate its regulatory mechanism. HeLa cells and A549 cells were cultured in vitro and were divided into control (DMSO treated) and experimental groups (treated with different concentrations of quercetin). Transcript levels of IL15 and DNA methyltransferase (DNMTS) were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Genomic DNA was extracted, treated with bisulfite, and the promoter region of IL15 was cloned. Finally, Sanger sequencing was used to detect the degree of promoter methylation. Following quercetin treatment, the expression of IL15 was significantly downregulated in HeLa and A549 cells. The methylation level of IL15 promoter in HeLa cells was about twice that of the control group, and the methylation level of IL15 promoter in A549 cells was about three times that of the control group. Quercetin inhibits cancer cell proliferation while downregulating IL15 expression, and this regulation is achieved by increasing the methylation of the IL15 promoter.

MicroRNA-122 mimic/microRNA-221 inhibitor combination as a novel therapeutic tool against hepatocellular carcinoma.

Therapeutic microRNAs (miRNAs) delivery holds a lot of promise for treating human malignancies. So, this study was carried out to examine the potential of miR-122 mimic and/or miR-221 inhibitor as an innovative therapeutic strategy for HCC in an animal model. Mice were categorized into five groups comprising: (1) a normal control group, (2) an HCC group subjected to diethylnitrosamine (DEN) injection for 12 weeks, (3) a miR-122 mimic-treated HCC group, (4) a miR-221 inhibitor-treated HCC group, and (5) a miR-122 mimic/miR-221 inhibitor-treated HCC group. After 16 weeks, all animals were sacrificed and underwent biochemical, miRNAs and genes expression, histopathological, and immunohistochemical examinations. The miR-122 mimic/miR-221 inhibitor combination dramatically reduced the levels of pro-inflammatory, liver cancer, angiogenesis, and cell proliferation markers when compared to either treatment alone. It also down-regulated the expression of cyclin D1, TGF-β, and β-catenin genes, which are involved in promoting cell cycle progression and cancer cell proliferation. Furthermore, it caused the resolution of nearly all the histological malignant features as well as the reduction of malignant cellular markers, including α-smooth muscle actin, arginase-1, and tropomyosin-1. The co-treatment with miR-122 mimic and miR-221 inhibitor amplifies the benefits of either treatment on HCC through targeting the SENP1 and ARF4 genes, respectively. This combination can inhibit cancer cell proliferation and angiogenesis while inducing tumor apoptosis and necrosis. This study demonstrates the therapeutic potential of reversing a dysregulated miRNAs expression pattern in HCC. As a result, future research should concentrate on turning miRNA understanding into therapeutic applications.

Abstract P6-10-17: Pharmacological Strategies to Target Circadian Clock Genes in TNBC

Abstract Pharmacological Strategies to Target Circadian Clock Genes in TNBC Yuanzhong Pan, Priya Jayachandran, Evanthia T. Roussos Torres, Steve A. Kay Background: Triple-negative breast cancer (TNBC) remains the most aggressive form of breast cancer and more targeted treatment options remain challenging. Our recent analysis of clinical data showed that circadian clock genes (including positive regulators BMAL1 and CLOCK, and negative regulators CRYs, PERs, and REV-ERBs) play important roles in breast cancer, and most prominently in TNBC. We have also shown in other cancer types that cells with a mesenchymal signature and stem-cell like state rely on BMAL1/CLOCK activity to support proliferation. BMAL1 and CLOCK are transcription factors that have remained “undruggable” to date. Alternatively, our lab developed small molecule compounds that target the negative regulators CRY, REV-ERB and CK2. We are therefore prompted to study if the clock genes can serve as a therapeutic target in TNBC using our small molecules that target clock regulators in TNBC. In addition, BMAL1 and CLOCK require ubiquitin E3 ligases and proteasomes for their transcriptional function, thus we hypothesize proteosome inhibitors may provide synergy to improve response to our novel clock-based therapeutics. Methods: We first used shRNA-mediated gene knockdown (KD) to disrupt the core circadian clock regulator BMAL1 and CLOCK in a panel of TNBC cell lines across different molecular subtypes (MDA-MB-231, MDA-MB-157 and MDA-MB-436, MDA-MB-453, HCC70, HCC1143, BT549, Hs578T). After KD, cell proliferation was quantified using CellTiter-Glo. We then tested our small molecule compounds SHP656—that stabilizes CRY, SR29065 and derivatives—that agonizes REV-ERB, and GO289—an inhibitor of CK2 that stabilizes PER. Based on our knowledge of the clock regulators, we tested drug synergy between SHP1705 and proteasome inhibitors MG132 and Carfilzomib across a range of concentrations. RNA-seq of cells treated with either single drug or drug combination were performed to study the mechanism of the synergistic effect. Results: A subset of the tested TNBC cell lines showed significantly impaired proliferation after BMAL1 or CLOCK KD. All cells in the mesenchymal-like molecular subtype responded to BMAL1/CLOCK KD, which is consistent with our previous data in other cancer types. It also confirmed BMAL1 and CLOCK have the potential to serve as therapeutic targets for mesenchymal-like TNBC. We then tested the clock compounds in our TNBC panel. We found SR29065 and GO289 both inhibit cancer cell proliferation at a clinically relevant EC50. Combination of our novel small molecule SHP1705 with the proteosome inhibitor MG132 and carfilzomib, demonstrated significant synergistic effects in vitro. In order to understand the mechanism of the synergistic effect between clock compounds and proteasome inhibitors, we performed RNA-seq on single drug and combo-treated cells. Differential expression analysis revealed that over two-thousand genes are specifically changed in the combo group. GO analysis showed that these genes are enriched in MYC target genes. Because MYC is also, like BMAL1 and CLOCK, a E-box binding transcription factor, this result implies that the mechanism driving synergy may be due to a disruption of E-box-dependent transcription. Conclusions: Here we showed that the core circadian clock regulator BMAL1 and CLOCK are potential therapeutic targets in mesenchymal-like TNBCs. Using REV-ERB agonists and CK2 inhibitors to target BMAL1/CLOCK transcription activity, we can achieve compound EC50s in single-micromolar range. In vivo experiments in murine models of TNBC are underway to determine the efficacy of single agent and combination therapy with proteosome inhibitors. Given the recently established safety of CRY stabilizers there is great potential for translation of these findings to clinical trials in patients with TNBC. Citation Format: Yuanzhong Pan, Priya Jayachandran, Evanthia T. Roussos Torres, Steve A. Kay. Pharmacological Strategies to Target Circadian Clock Genes in TNBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-17.

Epigallocatechin Gallate Inhibits Cell Growth and Hedgehog Signalling in Human Rhabdomyosarcoma Cell Lines.

Epigallocatechin gallate (EGCG), a major polyphenol of green tea, has been shown to inhibit cancer cell proliferation. In this study the effect of EGCG on cell metabolism and the human hedgehog signalling pathway (HH) in human rhabdomyosarcoma (RMS) cells was investigated. Two human RMS cell lines (RD and RH30) were incubated with EGCG. To evaluate the effects of EGCG on RMS cells, cell viability, colony formation, cell migration, and alteration of genes related to the HH signalling pathway were investigated. EGCG showed cytostatic effects on RMS cells in a dose-dependent manner. Incubation with 25 μM EGCG resulted in a significant reduction of cell migration by 70% and downregulation of the HH pathway transcription factor GLI1. EGCG inhibits RMS cells in vitro by reducing cell proliferation and downregulating the HH signalling pathway. It may therefore be a promising agent in chemoresistant or advanced RMS in children.

RUNX3 Meets the Ubiquitin-Proteasome System in Cancer

RUNX3 is a transcription factor with regulatory roles in cell proliferation and development. While largely characterized as a tumor suppressor, RUNX3 can also be oncogenic in certain cancers. Many factors account for the tumor suppressor function of RUNX3, which is reflected by its ability to suppress cancer cell proliferation after expression-restoration, and its inactivation in cancer cells. Ubiquitination and proteasomal degradation represent a major mechanism for the inactivation of RUNX3 and the suppression of cancer cell proliferation. On the one hand, RUNX3 has been shown to facilitate the ubiquitination and proteasomal degradation of oncogenic proteins. On the other hand, RUNX3 can be inactivated through the ubiquitin-proteasome system. This review encapsulates two facets of RUNX3 in cancer: how RUNX3 suppresses cell proliferation by facilitating the ubiquitination and proteasomal degradation of oncogenic proteins, and how RUNX3 is degraded itself through interacting RNA-, protein-, and pathogen-mediated ubiquitination and proteasomal degradation.

Nanoscale Two-Dimensional FeII- and CoII-Based Metal-Organic Frameworks of Porphyrin Ligand for the Photodynamic Therapy of Breast Cancer.

The delivery of biocompatible reagents into cancer cells can elicit an anticancer effect by taking advantage of the unique characteristics of the tumor microenvironment (TME). In this work, we report that nanoscale two-dimensional FeII- and CoII-based metal-organic frameworks (NMOFs) of porphyrin ligand meso-tetrakis (6-(hydroxymethyl) pyridin-3-yl) porphyrin (THPP) can catalyze the generation of hydroxyl radicals (•OH) and O2 in the presence of H2O2 that is overexpressed in the TME. Photodynamic therapy consumes the generated O2 to produce a singlet oxygen (1O2). Both •OH and 1O2 are reactive oxygen species (ROS) that inhibit cancer cell proliferation. The FeII- and CoII-based NMOFs were non-toxic in the dark but cytotoxic when irradiated with 660 nm light. This preliminary work points to the potential of porphyrin-based ligands of transition metals as anticancer drugs by synergizing different therapeutic modalities.

A Natural Glucan from Black Bean Inhibits Cancer Cell Proliferation via PI3K-Akt and MAPK Pathway.

A natural α-1,6-glucan named BBWPW was identified from black beans. Cell viability assay showed that BBWPW inhibited the proliferation of different cancer cells, especially HeLa cells. Flow cytometry analysis indicated that BBWPW suppressed the HeLa cell cycle in the G2/M phase. Consistently, RT-PCR experiments displayed that BBWPW significantly impacts the expression of four marker genes related to the G2/M phase, including p21, CDK1, Cyclin B1, and Survivin. To explore the molecular mechanism of BBWPW to induce cell cycle arrest, a transcriptome-based target inference approach was utilized to predict the potential upstream pathways of BBWPW and it was found that the PI3K-Akt and MAPK signal pathways had the potential to mediate the effects of BBWPW on the cell cycle. Further experimental tests confirmed that BBWPW increased the expression of BAD and AKT and decreased the expression of mTOR and MKK3. These results suggested that BBWPW could regulate the PI3K-Akt and MAPK pathways to induce cell cycle arrest and ultimately inhibit the proliferation of HeLa cells, providing the potential of the black bean glucan to be a natural anticancer drug.

Astragaloside IV, as a potential anticancer agent.

Cancer is a global intractable disease, and its morbidity and mortality are increasing year by year in developing countries. Surgery and chemotherapy are often used to treat cancer, but they result in unsatisfactory outcomes, such as severe side effects and drug resistance. With the accelerated modernization of traditional Chinese medicine (TCM), an increasing body of evidence has shown that several TCM components have significant anticancer activities. Astragaloside IV (AS-IV) is considered the main active ingredient of the dried root of Astragalus membranaceus. AS-IV exhibits various pharmacological effects, such as anti-inflammatory, hypoglycemic, antifibrotic, and anticancer activities. AS-IV possesses a wide range of activities, such as the modulation of reactive oxygen species-scavenging enzyme activities, participation in cell cycle arrest, induction of apoptosis and autophagy, and suppression of cancer cell proliferation, invasiveness, and metastasis. These effects are involved in the inhibition of different malignant tumors, such as lung, liver, breast, and gastric cancers. This article reviews the bioavailability, anticancer activity, and mechanism of AS-IV and provides suggestions for further research of this TCM.

Engineering J-aggregates for NIR-induced meso-CF3-BODIPY nanoparticles by activated apoptosis mechanism in photothermal therapy

Forming J-aggregates by organic monomer is a fascinating strategy to urge spectroscopic redshift with respect to that of the monomer. Herein, we designed 1,7-diphenyl-substituted meso‑CF3-BDP monomer confirmed by X-ray crystallographic analysis. The low-barrier rotation of the –CF3 group in meso‑CF3-BDP 1 significantly enhances the non-radiative efficiency, and the photothermal conversion efficiency (PCE) of the self-assembled nanoparticles (1-NPs: λabs = 746 nm) by J-aggregates was 82%. 1-NPs could effectively block cell cycle progression, inhibit cancer cell proliferation and trigger cell apoptosis under low power laser irradiation (0.2 W/cm2). This study proposes an alternate molecular design platform by J-aggregates to promote PCE through the insertion of rotating segment and trigger the cancer cells apoptosis in photothermal therapy at low power laser density.

LncRNA GABPB1-IT1 inhibits the tumorigenesis of renal cancer via the miR-21/PTEN axis.

Long noncoding RNA (lncRNA) (GABPB1-IT1) has been reported to be downregulated in lung cancer, while its expression and function in other cancers are unknown. In this study, the expression levels of GABPB1-IT1 in tissue samples from 62 ccRCC patients were measured by performing RT-qPCR. Potential base pairing formed between GABPB1-IT1 and miR-21 was explored using the online program IntaRNA 2.0 and further confirmed by Dual-luciferase activity assay and RNA pulldown assay. The role of GABPB1-IT1 and miR-21 in regulating the expression of PTEN was evaluated by RT-qPCR and Western blot. The role of GABPB1-IT1, miR-21, and PTEN in regulating the proliferation of Caki-2 cells was explored by CCK-8 assay. It was observed that GABPB1-IT1 was downregulated in ccRCC and predicted poor survival. GABPB1-IT1 directly interacted with miR-21, while it did not regulate the expression of each other. Moreover, upregulation of PTEN, which is a target of miR-21, was observed in ccRCC cells with overexpression of GABPB1-IT1. Overexpression of GABPB1-IT1 and PTEN decreased the proliferation rates of ccRCC cells. In addition, overexpression of GABPB1-IT1 reduced the enhancing effects of miR-21 on cell proliferation. Therefore, GABPB1-IT1 may upregulate PTEN by sponging miR-21 in ccRCC to inhibit cancer cell proliferation. Our study characterized a novel GABPB1-IT1/miR-21/PTEN axis in ccRCC.

The Potential of Senescence as a Target for Developing Anticancer Therapy.

Senescence occurs in response to various stimuli. Senescence has attracted attention because of its potential use in anticancer therapy as it plays a tumor-suppressive role. It also promotes tumorigeneses and therapeutic resistance. Since senescence can induce therapeutic resistance, targeting senescence may help to overcome therapeutic resistance. This review provides the mechanisms of senescence induction and the roles of the senescence-associated secretory phenotype (SASP) in various life processes, including therapeutic resistance and tumorigenesis. The SASP exerts pro-tumorigenic or antitumorigenic effects in a context-dependent manner. This review also discusses the roles of autophagy, histone deacetylases (HDACs), and microRNAs in senescence. Many reports have suggested that targeting HDACs or miRNAs could induce senescence, which, in turn, could enhance the effects of current anticancer drugs. This review presents the view that senescence induction is a powerful method of inhibiting cancer cell proliferation.

“Anti-cancer” effect of ketamine in comparison with MK801 on neuroglioma and lung cancer cells

Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, is commonly used to induce anaesthesia during cancer surgery and relieve neuropathic and cancer pain. This study was conducted to assess whether ketamine has any inhibiting effects on neuroglioma (H4) and lung cancer cells (A549) in vitro.The cultured H4 and A549 cells were treated with ketamine and MK801 (0.1, 1, 10, 100, or 1000 μM) for 24 h. The expressions of glutamate receptors on both types of cancer cells were assessed with qRT-PCR. In addition, cell proliferation and migration were assessed with cell counting Kit-8 and wound healing assays. Cyclin D1, matrix metalloproteinase 9 (MMP9), phosphorylation of extracellular signal-regulated kinase (pERK), and cleaved-caspase-3 expression together with reactive oxygen species (ROS) were also assessed with Western blot, immunostaining, and/or flowcytometry.NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors were expressed on both H4 and A549 cells. Ketamine inhibited cancer cell proliferation and migration in a dose-dependent manner by suppressing the cell cycle and inducing apoptosis. Ketamine decreased cyclin D1, pERK, and MMP9 expression. In addition, ketamine increased ROS and cleaved caspase-3 expression and induced apoptosis. The anti-cancer effect of ketamine was more pronounced in A549 cells when compared with H4 cells. MK801 showed similar effects to those of ketamine.Ketamine suppressed cell proliferation and migration in both neuroglioma and lung cancer cells, likely through the antagonization of NMDA receptors.

Role of LGMN in tumor development and its progression and connection with the tumor microenvironment.

Legumain (LGMN) has been demonstrated to be overexpressed not just in breast, prostatic, and liver tumor cells, but also in the macrophages that compose the tumor microenvironment. This supports the idea that LGMN is a pivotal protein in regulating tumor development, invasion, and dissemination. Targeting LGMN with siRNA or chemotherapeutic medicines and peptides can suppress cancer cell proliferation in culture and reduce tumor growth in vivo. Furthermore, legumain can be used as a marker for cancer detection and targeting due to its expression being significantly lower in normal cells compared to tumors or tumor-associated macrophages (TAMs). Tumor formation is influenced by aberrant expression of proteins and alterations in cellular architecture, but the tumor microenvironment is a crucial deciding factor. Legumain (LGMN) is an in vivo-active cysteine protease that catalyzes the degradation of numerous proteins. Its precise biological mechanism encompasses a number of routes, including effects on tumor-associated macrophage and neovascular endothelium in the tumor microenvironment. The purpose of this work is to establish a rationale for thoroughly investigating the function of LGMN in the tumor microenvironment and discovering novel tumor early diagnosis markers and therapeutic targets by reviewing the function of LGMN in tumor genesis and progression and its relationship with tumor milieu.