Proliferation Of Cancer Cell Lines Research Articles

Serine and one-carbon metabolism sustain non-melanoma skin cancer progression

Non-melanoma skin cancer (NMSC) is a tumor that arises from human keratinocytes, showing abnormal control of cell proliferation and aberrant stratification. Cutaneous basal cell carcinoma (cBCC) and cutaneous squamous cell carcinoma (cSCC) are the most common sub-types of NMSC. From a molecular point of view, we are still far from fully understanding the molecular mechanisms behind the onset and progression of NMSC and to unravel targetable vulnerabilities to leverage for their treatment, which is still essentially based on surgery. Under this assumption, it is still not elucidated how the central cellular metabolism, a potential therapeutical target, is involved in NMSC progression. Therefore, our work is based on the characterization of the serine anabolism/catabolism and/or one-carbon metabolism (OCM) role in NMSC pathogenesis. Expression and protein analysis of normal skin and NMSC samples show the alteration of the expression of two enzymes involved in the serine metabolism and OCM, the Serine Hydroxy-Methyl Transferase 2 (SHMT2) and Methylen-ThetraHydroFolate dehydrogenase/cyclohydrolase 2 (MTHFD2). Tissues analysis shows that these two enzymes are mainly expressed in the proliferative areas of cBCC and in the poorly differentiated areas of cSCC, suggesting their role in tumor proliferation maintenance. Moreover, in vitro silencing of SHMT2 and MTHFD2 impairs the proliferation of epidermoid cancer cell line. Taken together these data allow us to link the central cellular metabolism (serine and/or OCM) and NMSC proliferation and progression, offering the opportunity to modulate pharmacologically the involved enzymes activity against this type of human cancer.

Heracleum persicum Desf. ex Fisch., C.A.Mey. & Avé-Lall. fruit essential oil: content, antimicrobial activity and cytotoxicity against ovarian cancer cell line

BackgroundOne of the most important aromatic species of the Apiaceae family is Heracleum persicum Desf. ex Fisch., C.A.Mey. & Avé-Lall, which used as a spice and condiment in food. It is widely used in traditional Iranian medicine due to its anti-toxic properties. The aim of this study was to evaluate the essential oil of this plant in terms of content and ingredients, cytotoxicity and antimicrobial activity.MethodsThe fruit of H. persicum was collected in June 2019 from Maragheh region of Kashan, Iran. The essential oil was extracted by water distillation using Clevenger for 3 h. Identification analysis of H. persicum fruit essential oil (HPFEO) components was performed using gas chromatography-mass spectrometry (GC–MS). Evaluation of the effect of the HPFEO on the growth and proliferation of ovarian cancer cell line (OVCAR-3) was performed using MTT colorimetric method. Its antimicrobial activity was evaluated by agar diffusion method, minimum inhibitory concentration (MIC) and minimum bactericidal/fungal lethality concentration (MBC/MFC).ResultsThe results of analysis of the HPFEO by GC–MS showed that there were 35 compounds with 99.54% relative content. Hexyl butyrate (35.24%), octyl 2-methylbutyrate (11.65%), octyl isobutyrate (9.23%), and octyl acetate (8.42%) were the predominant compounds. Examination of cell survival showed that the viability of cells decreased depending on the concentration of the HPFEO in 24 h and had value of IC50 ~ 12.08 μg/ml against OVCAR-3 cell line. The strongest inhibitory activity of the HPFEO was against Gram-negative bacteria Pseudomonas aeruginosa and Salmonella paratyphi-A serotype (MIC < 62.50 μg/mL). Also, the strong inhibitory and lethal activity of this essential oil against Candida albicans (MIC and MBC 250 μg/mL was one degree weaker compared to nystatin (MIC = 125 μg/mL).ConclusionsThus, HPFEO, in addition to its traditional use, may have a strong and potential potential for the production of anti-proliferative and antimicrobial drugs.

Pan-Cancer analysis and experimental validation identify the oncogenic nature of ESPL1: Potential therapeutic target in colorectal cancer.

Extra spindle pole bodies like 1 (ESPL1) are required to continue the cell cycle, and its primary role is to initiate the final segregation of sister chromatids. Although prior research has revealed a link between ESPL1 and the development of cancer, no systematic pan-cancer analysis has been conducted. Combining multi-omics data with bioinformatics, we have thoroughly described the function of ESPL1 in cancer. In addition, we examined the impact of ESPL1 on the proliferation of numerous cancer cell lines. In addition, the connection between ESPL1 and medication sensitivity was verified using organoids obtained from colorectal cancer patients. All these results confirm the oncogene nature of ESPL1. Herein, we downloaded raw data from numerous publicly available databases and then applied R software and online tools to explore the association of ESPL1 expression with prognosis, survival, tumor microenvironment, tumor heterogeneity, and mutational profiles. To validate the oncogene nature of ESPL1, we have performed a knockdown of the target gene in various cancer cell lines to verify the effect of ESPL1 on proliferation and migration. In addition, patients' derived organoids were used to verify drug sensitivity. The study found that ESPL1 expression was markedly upregulated in tumorous tissues compared to normal tissues, and high expression of ESPL1 was significantly associated with poor prognosis in a range of cancers. Furthermore, the study revealed that tumors with high ESPL1 expression tended to be more heterogeneous based on various tumor heterogeneity indicators. Enrichment analysis showed that ESPL1 is involved in mediating multiple cancer-related pathways. Notably, the study found that interference with ESPL1 expression significantly inhibited the proliferation of tumor cells. Additionally, the higher the expression of ESPL1 in organoids, the greater the sensitivity to PHA-793887, PAC-1, and AZD7762. Taken together, our study provides evidence that ESPL1 may implicate tumorigenesis and disease progression across multiple cancer types, highlighting its potential utility as both a prognostic indicator and therapeutic target.

Fully human monoclonal antibody targeting activated ADAM10 on colorectal cancer cells

Metastasis and chemoresistance in colorectal cancer are mediated by certain poorly differentiated cancer cells, known as cancer stem cells, that are maintained by Notch downstream signaling initiated upon Notch cleavage by the metalloprotease ADAM10. It has been shown that ADAM10 overexpression correlates with aberrant signaling from Notch, erbBs, and other receptors, as well as a more aggressive metastatic phenotype, in a range of cancers including colon, gastric, prostate, breast, ovarian, uterine, and leukemia. ADAM10 inhibition, therefore, stands out as an important and new approach to deter the progression of advanced CRC. For targeting the ADAM10 substrate-binding region, which is located outside of the catalytic domain of the protease, we generated a human anti-ADAM10 monoclonal antibody named 1H5. Structural and functional characterization of 1H5 reveals that it binds to the substrate-binding cysteine-rich domain and recognizes an activated ADAM10 conformation present on tumor cells. The mAb inhibits Notch cleavage and proliferation of colon cancer cell lines in vitro and in mouse models. Consistent with its binding to activated ADAM10, the mAb augments the catalytic activity of ADAM10 towards small peptide substrates in vitro. Most importantly, in a mouse model of colon cancer, when administered in combination with the therapeutic agent Irinotecan, 1H5 causes highly effective tumor growth inhibition without any discernible toxicity effects. Our singular approach to target the ADAM10 substrate-binding region with therapeutic antibodies could overcome the shortcomings of previous intervention strategies of targeting the protease active site with small molecule inhibitors that exhibit musculoskeletal toxicity.

The Insulin Receptor Substrate 2 Mediates the Action of Insulin on HeLa Cell Migration via the PI3K/Akt Signaling Pathway.

Insulin signaling plays an important role in the development and progression of cancer since it is involved in proliferation and migration processes. It has been shown that the A isoform of the insulin receptor (IR-A) is often overexpressed, and its stimulation induces changes in the expression of the insulin receptor substrates (IRS-1 and IRS-2), which are expressed differently in the different types of cancer. We study the participation of the insulin substrates IRS-1 and IRS-2 in the insulin signaling pathway in response to insulin and their involvement in the proliferation and migration of the cervical cancer cell line. Our results showed that under basal conditions, the IR-A isoform was predominantly expressed. Stimulation of HeLa cells with 50 nM insulin led to the phosphorylation of IR-A, showing a statistically significant increase at 30 min (p ≤ 0.05). Stimulation of HeLa cells with insulin induces PI3K and AKT phosphorylation through the activation of IRS2, but not IRS1. While PI3K reached the highest level at 30 min after treatment (p ≤ 0.05), AKT had the highest levels from 15 min (p ≤ 0.05) and remained constant for 6 h. ERK1 and ERK2 expression was also observed, but only ERK2 was phosphorylated in a time-dependent manner, reaching a maximum peak 5 min after insulin stimulation. Although no effect on cell proliferation was observed, insulin stimulation of HeLa cells markedly promoted cell migration.

PiRNA-18 Inhibition Cell Proliferation, Migration and Invasion in Colorectal Cancer.

Colorectal cancer is one of the most prevalent malignancies worldwide. Evidences indicate that piRNA-18 are closely involved and contributed to tumorigenesis and cancer progression. Therefore, it is very necessary to investigate the effects of piRNA-18 on the proliferation, migration, and invasiveness of colorectal cancer cells, so as to provide theoretical basis for finding new biomarkers and accurate diagnosis and treatment of colorectal cancer. Here, Five pairs of colorectal cancer tissue samples and their corresponding adjacent samples were analyzed by real-time immunofluorescence quantitative PCR and the difference in piRNA-18 expression among colorectal cancer cell lines was further verified. MTT assay were used to study the changes in the proliferation of colorectal cancer cell lines after piRNA-18 overexpression. Wound-healing assay and Transwell assay were used to study the changes in migration and invasion. Flow cytometry were used to study the changes in apoptosis and cycle. SC inoculation of colorectal cancer cell lines into nude mice were used to observe the effect in the proliferation. piRNA-18 was lowlier expressed than adjacent tissues and normal intestinal mucosal epithelial cells in colorectal cancer and colorectal cancer cell line. After overexpression of piRNA-18, cell proliferation and migration as well as invasiveness in SW480 and LOVO cells decreased. The cell lines with piRNA-18 overexpression had obvious G1/S phase arrest in cell cycle, and the weight and volume of subcutaneously transplanted tumors are decreased. Our findings highlighted that piRNA-18 may play an inhibitory role in colorectal cancer.

Comparative Analysis of Volatile Terpenoids Composition in Lavender Leaves in Response to Gamma Irradiation and Anticancer Effect of α-Santalene against Prostate Cancer

Many studies have been reported on the pharmacological effects and extraction methods of lavender essential oil, but little is known about a profiling analysis of terpenoids produced in lavender leaves by ionizing irradiation. Here, we performed the profiling analysis of volatile terpenoids produced by lavender (Lavandula angustifolia L.) leaves in response to gamma irradiation and the anticancer effects of terpenes induced by γ-irradiation. The analyses of volatile terpenoids revealed that lavender leaves biosynthesised 33 species of volatile terpenoids and their relative ratio were significantly changed after exposure to γ-ray. The relative ratio of monoterpene hydrocarbons such as limonene, p-cymene, and camphene (except for δ-3-carene, γ-terpinene, terpinolene, and allo-ocimene) was reduced to less than 60% at 1000 Gy, set to 100% at 0 Gy. On the contrary, the ratio of sesquiterpene hydrocarbons such as α-santalene, (E)-α-bergamotene, and γ-cadinene was up-regulated by more than 1.6-fold at 1000 Gy. Additionally, α-santalene, which was increased the most by γ-irradiation, significantly inhibited the proliferation of the human prostate cancer cell line (PC3) with an IC50 < 12.5 μg mL-1. Our findings indicate that the α-santalene is the most induced terpenoid after exposure to γ-ray in lavender leaves and that it has a pharmacological effect on reducing the cell viability in human prostate cancer cells. We suggest that non-destructive reconstitution of secondary metabolites in target plants (e.g., medicinal plants) can be achieved by using γ-irradiation as a tool.

Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation.

The P2RY1 receptor is known to cause cancer by activating the ERK signal pathway, and its DNA methylation status and corresponding regulatory mechanism remain unknown. This study used the DNA methylation chip to profile the genome-wide DNA methylation level in gastric cancer tissues. The proliferation and apoptosis of the SGC7901 gastric cancer cell line were determined after treatment with a selective P2RY1 receptor agonist, MRS2365. The promoter region of P2RY1 was found to be highly methylated with four hypermethylated sites (|Δβ value| > 0.2) in diffuse gastric cancer and was validated by bioinformatics analysis in the TCGA database. Also, immunohistochemical staining data obtained from the HPA database demonstrated the downregulated expression of proteins encoded by P2RY1 in stomach cancer tissue. The analysis of MRS2365-treated cells by annexin V/propidium iodide staining and caspase-3 activity assays indicated the induction of apoptosis in SGC7901 cells. The P2RY1 receptor activation in human SGC7901 gastric cancer cells via the MRS2365 agonist induced apoptosis and reduced cell growth. High DNA methylation in the promoter region of P2RY1 might have contributed to the reduced expression of P2RY1's mRNA, which was likely responsible for the "aggressive" nature of the diffuse gastric cancer.

Aloe-emodin targets multiple signaling pathways by blocking ubiquitin-mediated degradation of DUSP1 in nasopharyngeal carcinoma cells.

Aloe-emodin (AE) has been shown to inhibit the proliferation of several cancer cell lines, including human nasopharyngeal carcinoma (NPC) cell lines. In this study, we confirmed that AE inhibited malignant biological behaviors, including cell viability, abnormal proliferation, apoptosis, and migration of NPC cells. Western blotting analysis revealed that AE upregulated the expression of DUSP1, an endogenous inhibitor of multiple cancer-associated signaling pathways, resulting in blockage of the extracellular signal-regulated kinase (ERK)-1/2, protein kinase B (AKT), and p38-mitogen activated protein kinase（p38-MAPK） signaling pathways in NPC cell lines. Moreover, the selective inhibitor of DUSP1, BCI-hydrochloride, partially reversed the AE-induced cytotoxicity and blocked the aforementioned signaling pathways in NPC cells. In addition, the binding between AE and DUSP1 was predicted via molecular docking analysis using AutoDock-Vina software and further verified via a microscale thermophoresis assay. The binding amino acid residues were adjacent to the predicted ubiquitination site (Lys192) of DUSP1. Immunoprecipitation with the ubiquitin antibody, ubiquitinated DUSP1 was shown to be upregulated by AE. Our findings revealed that AE can stabilize DUSP1 by blocking its ubiquitin-proteasome-mediated degradation and proposed an underlying mechanism by which AE-upregulated DUSP1 may potentially target multiple pathways in NPC cells.

ER-/PR+ breast cancer is controlled more effectively with an inflammatory inhibitor than hormonal inhibitor.

The anti-estrogen tamoxifen is a highly effective hormonal therapy for hormonal-positive (HR+) breast cancer patients; however, the estrogen receptor-negative, progesterone receptor-positive (ER-/PR+) subtype does not give the benefits of tamoxifen. Therefore ER-/PR+ breast cancer has a poor clinical outcome, and novel drug therapy for ER-/PR+ breast cancer could benefit these patients. 53,805 gene expressions were characterized into HR+ BC and triple-negative breast cancer (TNBC) and analyzed through Breast Cancer Gene Expression Miner in 4319 breast cancer patient samples. The clinical outcomes including overall survival, distant metastasis-free survival, and relapse-free survival were obtained from the PrognoScan database containing 1190 human breast cancer patient samples. To determine the function of ERα and inflammation-related genes such as USP1, CDC20, and CASP1, we used the CRISPR-Cas9 system or gene knockdown (KD) system. To check tumor cell proliferation and migration of ERα KO breast cancer cell line, we used tamoxifen and the inflammation inhibitor Ac-YVAD-CHO. For further confirmation, cancer growth was checked with the inflammation inhibitor in ERα KO breast cancer cell line using a three-dimensional (3D) organoid tissue culture system (ex vivo). We found that gene expression in ER-/PR+ hormonal-positive breast cancer is positively related to ER-/PR- very similar to TNBC, not other HR+ breast cancer using a 4319 breast cancer patient database. Especially, inflammation-related genes, USP1, CDC20, and CASP1, which are highly expressed in TNBC, are also upregulated in ER-/PR+ HR+ breast cancer. Suppression of USP1, CDC20, and CASP1 inhibited tumor cell growth and metastasis in ERα KO (ER-/PR +) cell lines. Interestingly, loss of ERα in HR+ cell lines is not responsive to tamoxifen, but highly sensitive to the inflammation inhibitor, Ac-YVAD-CHO. In in vitro and ex vivo (3D organoid) models, inflammation inhibitor-specific blocks ER-/PR+ tumor proliferation and migration. These findings suggest that an inflammation inhibitor might be a potential option for therapy for ER-/PR+ HR breast cancer patients.

The Extract of Perilla frutescens Seed Residue Attenuated the Progression of Aberrant Crypt Foci in Rat Colon by Reducing Inflammatory Processes and Altered Gut Microbiota.

Perilla frutescens (PF) seed residue is a waste from perilla oil production that still contains nutrients and phytochemicals. This study aimed to investigate the chemoprotective action of PF seed residue crude ethanolic extract (PCE) on the inflammatory-induced promotion stage of rat colon carcinogenesis and cell culture models. PCE 0.1 and 1 g/kg body weight were administered by oral gavage to rats after receiving dimethylhydrazine (DMH) with one week of dextran sulfate sodium (DSS) supplementation. PCE at high dose exhibited a reduction in aberrant crypt foci (ACF) number (66.46%) and decreased pro-inflammatory cytokines compared to the DMH + DSS group (p < 0.01). Additionally, PCE could either modulate the inflammation induced in murine macrophage cells by bacterial toxins or suppress the proliferation of cancer cell lines, which was induced by the inflammatory process. These results demonstrate that the active components in PF seed residue showed a preventive effect on the aberrant colonic epithelial cell progression by modulating inflammatory microenvironments from the infiltrated macrophage or inflammatory response of aberrant cells. Moreover, consumption of PCE could alter rat microbiota, which might be related to health benefits. However, the mechanisms of PCE on the microbiota, which are related to inflammation and inflammatory-induced colon cancer progression, need to be further investigated.

Wogonin induces ferroptosis in pancreatic cancer cells by inhibiting the Nrf2/GPX4 axis.

Pancreatic cancer is a common gastrointestinal tract malignancy. Currently, the therapeutic strategies for pancreatic cancers include surgery, radiotherapy, and chemotherapy; however, the surgical procedure is invasive, and the overall curative outcomes are poor. Furthermore, pancreatic cancers are usually asymptomatic during early stages and have a high degree of malignancy, along with a high rate of recurrence and metastasis, thereby increasing the risk of mortality. Studies have shown that ferroptosis regulates cell proliferation and tumour growth and reduces drug resistance. Hence, ferroptosis could play a role in preventing and treating cancers. Wogonin is a flavonoid with anticancer activity against various cancers, including pancreatic cancer. It is extracted from the root of Scutellaria baicalensis Georgi. In this study, we show that wogonin inhibits the survival and proliferation of human pancreatic cancer cell lines and induces cell death. We performed RNA-sequencing and analysed the differentially expressed gene and potential molecular mechanism to determine if wogonin reduced cell survival via ferroptosis. Our results showed that wogonin upregulates the levels of Fe2+, lipid peroxidation and superoxide and decreases the protein expression levels of ferroptosis suppressor genes, and downregulates level of glutathione in pancreatic cancer cells. In addition, ferroptosis inhibitors rescue the ferroptosis-related events induced by wogonin, thereby confirming the role of ferroptosis. A significant increase in ferroptosis-related events was observed after treatment with both wogonin and ferroptosis inducer. These results show that wogonin could significantly reduces pancreatic cancer cell proliferation and induce ferroptosis via the Nrf2/GPX4 axis. Therefore, wogonin could be potentially used for treating patients with pancreatic cancer.

RBM15 Promates the Proliferation, Migration and Invasion of Pancreatic Cancer Cell Lines.

(1) Background: Pancreatic cancer is increasingly becoming the leading cause of cancer deaths worldwide. In eukaryotic cells, m6A is the most abundant mRNA methylation modification. (2) Methods: We performed a bioinformatic multidimensional analysis using files containing the clinical data of patients and m6A-related gene expression differences downloaded from web-based databases, and performed a statistical analysis and image mapping mainly using R-package. Next, we studied the RBM15 expression in cancer and paracancerous tissues. We then validated these findings in two cell lines by western blot, PCR, Transwell, CCK-8, and EDU animal models. (3) Results: We discovered that RBM15 was highly expressed in pancreatic cancer patients and that it is a significant cause of poor prognosis. Its association with lymphatic T cell family aggregation was established through immune infiltration analysis. A retrospective analysis of data from clinical patient specimens revealed that high expression of RBM15 in patients was closely and positively correlated with preoperative glucose values, gender, and lymphocyte counts. Results from cellular experiments and animal experiments indicated that when the RBM15 gene was silenced, cell proliferation, migration, and metastasis were inhibited. (4) Conclusions: We propose that RBM15 plays a key role in the progression of pancreatic cancer by promoting tumor proliferation, migration and metastasis.

Thimerosal, a competitive thioredoxin reductase 1 (TrxR1) inhibitor discovered via high-throughput screening

Thioredoxin reductase 1 (TrxR1) is considered as an important anti-cancer drug target, inhibition of which can induce reactive oxygen species (ROS)-mediated apoptosis of human cancer cells. Here, we developed and optimized a high-throughput screening (HTS) assay based on enzyme kinetics for the discovery of TrxR1 inhibitors. By utilizing this assay, we performed a HTS for 2500 compounds from an in-house library against TrxR1. We found that a vaccine preservative, thimerosal, strongly inhibited TrxR1 in a competitive and reversible manner with an IC50 of 24.08 ± 0.86 nM. In addition, we determined that thiomersal has an inhibitory effect on the proliferation of A549 lung cancer cell line, with a GI50 of 6.81 ± 0.09 μM, slightly more potent than auranofin (GI50 = 11.85 ± 0.56 μM). Furthermore, we showed by flow cytometer that thimerosal effectively increased the content of ROS in A549 cells. Therefore, our work provided a high-throughput screening assay to quickly and effectively discover TrxR1 inhibitors, identifying thiomersal as a novel TrxR1 inhibitor and chemical probe.

Ocimum sanctum Linn. Ethanolic extract promotes an antiproliferative and apoptosis activity in MCF-7 and T47D breast cancer cell lines mediated by upregulation of ROS/RNS, Caspase 9, and Caspase 3: an in silico and in vitro study

Breast cancer is the most serious disease affecting women worldwide. Recently, breast cancer cases reached 2.2 million people. The treatment method is still developing. In addition, the use of herbal medicine as a palliative therapeutic to chemical and/or synthetic drugs is increasing. Ocimum sanctum Linn. is a popular plant in Indonesia and Southeast Asia countries and is also known as an herbal medicinal plant. The study aimed to prove the ability of ethanolic extract Ocimum sanctum Linn. (EEOS) as an antiproliferative against breast cancer. Cytotoxic assay, adhesion assay, and Reactive Nitrogen Species (RNS) production determined in MCF-7 and T47D breast cancer cell. Furthermore, SEM is applied to visualize cell morphology. In addition, molecular docking is also performed. The result shows EEOS inhibited the proliferation and adhesion of the MCF7 and T47D cells line. Surface morphology showed that MCF7 and T47D tend to be apoptotic (cells turned rougher, gritty, and blebbing). EEOS also increased RNS production. Molecular docking describes the phytochemical compounds on the EEOS (gallic acid, caffeic acid, rosmarinic acid and apigenin) interacted with the caspase-3 and caspase-9. In conclusion, EEOS can inhibit the proliferation of MCF-7 and T47D breast cancer cell lines that correlate with upregulated RNS production, as well as the expression of Caspase 3 and Caspase 9.

Targeted Degradation of PRC1 Components, BMI1 and RING1B, via a Novel Protein Complex Degrader Strategy.

Polycomb repressive complex 1 (PRC1) is an essential epigenetic regulator that mainly controls histone H2A Lys119 mono-ubiquitination (H2AK119ub). B cell-specific Moloney murine leukemia virus Integration site 1 (BMI1) and really interesting new gene 1B (RING1B) are PRC1 core components and play critical roles in the development of various cancers. However, therapeutic agents targeting PRC1 are very limited. In this study, MS147, the first degrader of PRC1 core components, BMI1 and RING1B, is discovered via a novel protein complex degradation strategy that utilizes the target protein's interacting partner protein (embryonic ectoderm development (EED)). MS147, which comprises an EED small-molecule binder linked to a ligand of the E3 ligase von Hippel-Lindau (VHL), degrades BMI1/RING1B in an EED-, VHL-, ubiquitination-, and time-dependent manner. MS147 preferentially degrades BMI1/RING1B over polycomb repressive complex 2 (PRC2) core components. Consequently, MS147 effectively reduces H2AK119ub, but not histone H3 Lys27 tri-methylation (H3K27me3), which is catalyzed by PRC2. Furthermore, MS147 effectively inhibits the proliferation of cancer cell lines that are insensitive to PRC2 inhibitors/degraders. Overall, this study provides a novel BMI1/RING1B degrader, which is a useful chemical tool to further investigate the roles of PRC1 in cancer, and a novel protein complex degradation strategy, which can potentially expand the degradable human proteome.

Drug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21.

We report the discovery of drug-like small molecules that bind specifically to the precursor of the oncogenic and pro-inflammatory microRNA-21 with mid-nanomolar affinity. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA, which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change induced by the small molecules, which is also not observed in other miRNA precursors. The most potent of these compounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds without this specific binding activity are inactive in cells. These molecules are highly ligand-efficient (MW < 330) and display specific biochemical and cellular activity by suppressing the maturation of miR-21, thereby providing an avenue toward therapeutic development in multiple diseases where miR-21 is abnormally expressed.

Effect of apigenin in combination with oxymatrine on non-small cell lung cancer and mechanism

This study explores the effect of apigenin(APG), oxymatrine(OMT), and APG+OMT on the proliferation of non-small cell lung cancer cell lines and the underlying mechanisms. Cell counting kit-8(CCK-8) assay was used to detect the vitality of A549 and NCI-H1975 cells, and colony formation assay to evaluate the colony formation ability of the cells. EdU assay was employed to examine the proliferation of NCI-H1975 cells. RT-qPCR and Western blot were performed to detect the mRNA and protein expression of PLOD2. Molecular docking was carried out to explore the direct action ability and action sites between APG/OMT and PLOD2/EGFR. Western blot was used to study the expression of related proteins in EGFR pathway. The viability of A549 and NCI-H1975 cells was inhibited by APG and APG+OMT at 20, 40, and 80 μmol·L~(-1) in a dose-dependent manner. The colony formation ability of NCI-H1975 cells was significantly suppressed by APG and APG+OMT. The mRNA and protein expression of PLOD2 was significantly inhibited by APG and APG+OMT. In addition, APG and OMT had strong binding activity with PLOD2 and EGFR. In APG and APG+OMT groups, the expression of EGFR and proteins in its downstream signaling pathways was significantly down-regulated. It is concluded that APG in combination with OMT could inhibit non-small lung cancer, and the mechanism may be related to EGFR and its downstream signaling pathways. This study lays a new theoretical basis for the clinical treatment of non-small cell lung cancer with APG in combination with OMT and provides a reference for further research on the anti-tumor mechanism of APG in combination with OMT.

M6A reader HNRNPA2B1 destabilization of ATG4B regulates autophagic activity, proliferation and olaparib sensitivity in breast cancer

N6-methyladenosine RNA (m6A) is the most extensive epigenetic modification in mRNA and influences tumor progression. However, the role of m6A regulators and specific mechanisms in breast cancer still need further study. Here, we investigated the significance of the m6A reader HNRNPA2B1 and explored its influence on autophagy and drug sensitivity in breast cancer. HNRNPA2B1 was selected by bioinformatics analysis, and its high expression level was identified in breast cancer tissues and cell lines. HNRNPA2B1 was related to poor prognosis. Downregulation of HNRNPA2B1 reduced proliferation, enhanced autophagic flux, and partially reversed de novo resistance to olaparib in breast cancer. ATG4B was determined by RIP and MeRIP assays as a downstream gene of HNRNPA2B1, by which recognized the m6A site in the 3′UTR. Overexpression of ATG4B rescued the malignancy driven by HNRNPA2B1 in breast cancer cells and increased the olaparib sensitivity. Our study revealed that the m6A reader HNRNPA2B1 mediated proliferation and autophagy in breast cancer cell lines by facilitating ATG4B mRNA decay and targeting HNRNPA2B1/m6A/ATG4B might enhance the olaparib sensitivity of breast cancer cells.

WXJ-202, a novel Ribociclib derivative, exerts antitumor effects against breast cancer through CDK4/6.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulatory proteins in the cell division and proliferative cycle in humans. They are overactive in many malignant tumors, particularly in triple-negative breast cancer (TNBC). Inhibition of CDK4/6 targets can have anti-tumor effects. Here, we designed and synthesized a novel derivative of Ribociclib that could affect CDK4/6, named WXJ-202. This study aimed to investigate the effects of compound WXJ-202 on proliferation, apoptosis, and cell cycle arrest in human breast cancer cell lines and their molecular mechanisms. We assayed cell viability with methyl thiazolyl tetrazolium (MTT) assay. Clone formation, migration, and invasion ability were assayed by clone formation assay, wound healing assay, and transwell invasion assay. The effect of compound WXJ-202 on apoptosis and cell cycle was detected by flow cytometry analysis. Western blotting was performed to detect the expression of proteins related to the CDK4/6-Rb-E2F pathway. The anti-cancer effects were studied in vivo transplantation tumor models. WXJ-202 was shown to inhibit cell proliferation, colony formation, migration, and invasion, as well as induce apoptosis and cycle arrest in breast cancer cells. The levels of proteins related to the CDK4/6-Rb-E2F pathway, such as CDK4, CDK6, and p-Rb, were decreased. Finally, studies had shown that compound WXJ-202 exhibited significant anti-tumor activity in transplantation tumor models. In this research, the compound WXJ-202 was shown to have better anti-tumor cell proliferative effects and could be used as a potential candidate against TNBC tumors.