Sensitivity Of Cells Research Articles

2-methoxyestradiol sensitizes tamoxifen-resistant MCF-7 breast cancer cells via downregulating HIF-1α

The clinical studies for breast cancer (BC) are now assessing the efficacy of 2-Methoxyestradiol (2-ME), a naturally occurring derivative of estradiol. Our study aimed to explore the potential of combining the 2-ME and tamoxifen (TAM) on sensitization of TAM-resistant cells using LCC2 the TAM-resistant cells as a model and comparing the results to the sensitive cells MCF-7. Sulphorhodamine-B (SRB) assay is used to examine the 2-ME chemo-sensitizing impact on the cytotoxicity of TAM on LCC2 cells. Colorimetric assay kits were used to assess the level of the apoptosis-related markers caspases 3, Bcl2, and Bax in cell lysate. Hypoxia-inducible factor 1 alpha (HIF-1α) expression was measured using western blotting. Total cholesterol and triglyceride (TG) levels were examined colorimetrically, using the BIOLABO kit. The use of 2-ME enhanced the cytotoxic effects of TAM and effectively reversed TAM resistance. This was achieved by inhibiting the expression of HIF-1α, while concurrently increasing the levels of apoptotic marker caspase-3, as well as the pro-apoptotic protein Bax. Additionally, there was a reduction in the levels of Bcl2, an anti-apoptotic protein. Furthermore, a reduction in TG and cholesterol levels was noted. Our findings show that HIF-1α plays an important role in TAM resistance and that suppression of HIF-1α by 2-ME-mediated sensitization of BC-resistant cells to TAM. Therefore, the concurrent administration of TAM/2-ME might potentially serve as a viable therapeutic approach to address TAM resistance and enhance the overall therapy efficacy for patients with BC.

Mitochondrial Deoxyguanosine Kinase Induces 5-Fluorouracil Chemotherapy Sensitivity through Autophagy.

The purpose of this study was to investigate the role of DGUOK in the pro-gression of colorectal cancer (CRC) and its impact on the sensitivity of CRC cells to 5-FU treatment. We conducted bioinformatics analysis and qRT-PCR to evaluate DGUOK expression in CRC tissues/cells. Cell viability of CRC cells treated with 5-FU was assessed using CCK-8 and colony formation assays. Autophagy levels were determined through immunofluorescence assays and Western blot analysis. Additionally, the influence of p-p38 on autophagy was inves-tigated via Western blotting. A rescue assay was performed to confirm whether DGUOK/p38 affects 5-FU sensitivity in CRC cells through autophagy. Our findings indicate that DGUOK is upregulated in CRC tissues compared to normal tissues, correlating with increased cell proliferation and migration. Functionally, inhibition of DGUOK enhances autophagy, thereby decreasing the sensitivity of CRC cells to 5-FU. This ef-fect is partly mediated by DGUOK's impact on the mitogen-activated protein kinase (MAPK) pathway, specifically promoting the phosphorylation of p38 MAPK, a crucial regulator in au-tophagy pathways. These results suggest that DGUOK could serve as a novel marker for predicting the efficacy of 5-FU in CRC treatment.

The role of dendritic cells in the instruction of helper T cells in the allergic march.

Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by barrier defects and immune dysregulation, sometimes leading to asthma and food allergies because of the atopic march. During atopic skin inflammation, Langerhans cells and dendritic cells (DCs) in the skin capture and deliver allergen information to local lymph nodes. DCs are essential immune sensors coordinating immune reactions by capturing and presenting antigens to T cells. In the context of allergic responses, DCs play a crucial role in instructing two types of helper T cells - type 2 helper T (Th2) cells and follicular helper T (TFH) cells - in allergic responses and IgE antibody responses. In skin sensitization, the differentiation and function of Th2 cells and TFH cells are influenced by skin-derived factors, including epithelial cytokines, chemokines, and signaling pathways to modify the function of migratory DCs and conventional DCs. In this review, we aim to understand the specific mechanisms involving DCs in allergic responses to provide insights into the pathogenesis of allergic diseases and potential therapeutic strategies.

BP1003 Decreases STAT3 Expression and Its Pro-Tumorigenic Functions in Solid Tumors and the Tumor Microenvironment.

Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2+, triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in vivo patient-derived models of pancreatic ductal adenocarcinoma (PDAC) show reduced tissue viability and tumor volume with BP1003 and gemcitabine combination treatments. In addition to directly affecting tumor cells, BP1003 can modulate the tumor microenvironment. Unlike M1 differentiation, monocyte differentiation into anti-inflammatory M2 macrophages is suppressed by BP1003, indicating its potential contribution to immunotherapy. The broad anti-tumor effect of BP1003 in numerous preclinical solid tumor models, such as breast, ovarian, and pancreatic cancer models shown in this work, makes it a promising cancer therapeutic.

Novel D–π–A dye as a co-sensitizer of indoline and benzothiadiazole dyes to enhance photovoltaic performance of dye-sensitized solar cells

A novel D–π–A type of dye (BIM33) comprising diphenylamine as electron donor, diphenylacridine as a π-bridge and cyanoacrylic acid as an anchoring unit has been synthesized and used as sensitizer and co-sensitizer in dye-sensitized solar cells (DSSCs). The DSSC based on BIM33 achieved a power conversion efficiency (PCE) of 3.19 % under one sun (AM 1.5G). To improve the photovoltaic performance of the DSSCs, this orange dye was also co-sensitized with red benzothiadiazole (C1) and purple indoline (D205) organic dyes. The DSSCs based on co-sensitizers BIM33/D205 and BIM33/C1 showed superior PCEs of 6.57 % (JSC = 13.69 mA cm−2, VOC = 0.766 V, and FF = 0.63) and 6.82 % (JSC = 14.47 mA cm−2, VOC = 0.722 V, and FF = 0.65), respectively, exhibiting significant improvements of 28 % and 36 % compared to the DSSCs based on D205 and C1, respectively. The high photovoltaic performance of the co-sensitized DSSCs may be explained by the broader visible light absorption and a denser packing of the dyes on the TiO2 surface.

In Vivo Tracking and 3D Mapping of Cell Death in Regeneration and Cancer Using Trypan Blue.

Tracking cell death in vivo can enable a better understanding of the biological mechanisms underlying tissue homeostasis and disease. Unfortunately, existing cell death labeling methods lack compatibility with in vivo applications or suffer from low sensitivity, poor tissue penetration, and limited temporal resolution. Here, we fluorescently labeled dead cells in vivo with Trypan Blue (TBlue) to detect single scattered dead cells or to generate whole-mount three-dimensional maps of large areas of necrotic tissue during organ regeneration. TBlue effectively marked different types of cell death, including necrosis induced by CCl4 intoxication in the liver, necrosis caused by ischemia-reperfusion in the skin, and apoptosis triggered by BAX overexpression in hepatocytes. Moreover, due to its short circulating lifespan in blood, TBlue labeling allowed in vivo "pulse and chase" tracking of two temporally spaced populations of dying hepatocytes in regenerating mouse livers. Additionally, upon treatment with cisplatin, TBlue labeled dead cancer cells in livers with cholangiocarcinoma and dead thymocytes due to chemotherapy-induced toxicity, showcasing its utility in assessing anticancer therapies in preclinical models. Thus, TBlue is a sensitive and selective cell death marker for in vivo applications, facilitating the understanding of the fundamental role of cell death in normal biological processes and its implications in disease.

NUAK1-Mediated Phosphorylation of NADK Mitigates ROS Accumulation to Promote Osimertinib Resistance in Non-Small Cell Lung Carcinoma.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is approved as a first-line therapy in advanced non-small cell lung carcinoma (NSCLC) patients with EGFR-activating mutations or the T790M resistance mutation. However, the efficacy of osimertinib is limited due to acquired resistance, highlighting the need to elucidate resistance mechanisms to facilitate the development of improved treatment strategies. Here, we screened for significantly upregulated genes encoding protein kinases in osimertinib-resistant NSCLC cells and identified NUAK1 as a pivotal regulator of osimertinib resistance. NUAK1 was highly expressed in osimertinib-resistant NSCLC and promoted the emergence of osimertinib resistance. Genetic or pharmacological blockade of NUAK1 restored the sensitivity of resistant NSCLC cells to osimertinib in vitro and in vivo. Mechanistically, NUAK1 directly interacted with and phosphorylated NADK at serine 64 (S64), which mitigated osimertinib-induced accumulation of reactive oxygen species (ROS) and contributed to the acquisition of osimertinib resistance in NSCLC. Furthermore, virtual drug screening identified T21195 as an inhibitor of NADK-S64 phosphorylation, and T21195 synergized with osimertinib to reverse acquired resistance by inducing ROS accumulation. Collectively, these findings highlight the role of the NUAK1-NADK axis in governing osimertinib resistance in NSCLC and indicate the potential of targeting this axis as a strategy for circumventing resistance.

MiR-149-3p Enhances Drug Sensitivity of AML Cells by Inhibiting Warburg Effect Through PI3K/AKT Pathway.

Acute myeloid leukemia (AML) is a kind of heterogeneous hematologic malignancy with high incidence, which is usually treated by intensive and maintenance treatment with large dose of conventional chemotherapy drugs. However, cell resistance is still an unsolved problem. The abnormal expression of miRNAs is closely related to the pathogenesis and progression of AML, and affects the drug resistance of cancer cells. miR-149-3p plays an important role in the resistance of cancer cells to cisplatin, and plays an excellent anti-tumor activity. By studying the function of miR-149-3p, it is expected to find new therapeutic methods to reverse chemotherapy resistance. In order to explore the mechanism of action of miR-149-3p on AML chemotherapeutic drug sensitivity, we explored the relationship between the Warburg effect and AML chemotherapeutic drug resistance. Based on AML cells, transfection of miR-149-3p inhibitor/NC and Warburg effect inhibitor (2DG) and PI3K/AKT pathway inhibitor (LY294002) were used to investigate the mechanism of IFN-γ regulating chemotherapy resistance of AML cells through Warburg effect. Down-regulation of miR-149-3p significantly inhibited drug sensitivity of AML cells. Down-regulation of miR-149-3p significantly promoted proliferation and invasion of AML cells while inhibiting apoptosis by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax. Down-regulation of miR-149-3p significantly promoted the expression of Warburg effect-related proteins hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and Glucose transporter 1 (GLUT1), glucose consumption, lactic acid, and intracellular ATP production. After inhibiting the Warburg effect with 2DG, the effect of miR-149-3p was inhibited, suggesting that upregulation of miR-149-3p reversed AML cell resistance by inhibiting the Warburg effect. In addition, miR-149-3p interacted with AKT1. Down-regulation of miR-149-3p increased the expression of inosine phosphate 3 kinase (PI3K), protein kinase B (AKT), and multi-drug resistance protein (MDR1). LY294002 inhibited the expression of these proteins, and down-regulation of miR-149-3p reversed the effect of LY294002 and improved the drug resistance of cells. Upregulation of miR-149-3p expression may potentially be a therapeutic target for AML resistance. It has been shown to inhibit PI3K/AKT pathway activation, thereby inhibiting the Warburg effect, and affecting cell proliferation, apoptosis, and drug resistance.

Metabolic factors and perinatal outcomes among pregnant individuals with mild glucose intolerance

AimsMetabolic characteristics and outcomes were compared among pregnant individuals with varying levels of glucose intolerance. Methods827 participants from a randomized clinical trial comparing the IADPSG and Carpenter Coustan Criteria were grouped as follows: normal glucose tolerance, mild glucose intolerance (100 g OGTT with one abnormal value) and treated GDM (diagnosed by Carpenter Coustan or IADPSG criteria). Differences in metabolic characteristics and perinatal outcomes were assessed using inverse probability of treatment weighting. ResultsMild glucose intolerance had lower insulin sensitivity and beta cell response than normal glucose tolerance, and similar findings to treated GDM. Small for gestational age (SGA) (OR 0.13, 95% CI 0.08–0.24) and neonatal composite morbidity were lower (OR 0.53, 95% CI 0.38–0.74), and maternal composite morbidity higher (OR 2.03, 95% CI 1.57–2.62) when comparing mild intolerance to normal glucose tolerance. Large for gestational age (OR 3.42 95% CI 1.39–8.41) was higher while SGA (OR 0.21, 95% CI 0.05–0.81) and neonatal composite morbidity (OR 0.31, 95% CI 0.17–0.57) were lower with mild glucose intolerance compared to treated GDM. ConclusionsMild glucose intolerance has a similar metabolic profile to treated GDM, and outcome differences are likely related to knowledge of diagnosis and treatment.Clinical trials registry: NCT02309138.

Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR-342-5p/CFL1

BackgroundIncreased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance.MethodsMicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro.ResultsHere we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner.ConclusionOur findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.

LncRNA HIF1A-AS2 promotes triple-negative breast cancer progression and paclitaxel resistance via MRPS23 protein

Dysregulation of lncRNAs is a critical factor in the migration and invasion of tumors. Here our study reveals that lncRNA HIF1A-AS2 is highly expressed in breast cancer tissues and various TNBC cell lines. Moreover, we present compelling evidence supporting the role of HIF1A-AS2 in promoting TNBC cell proliferation, metastasis, invasion, and resistance to paclitaxel treatment. Additionally, our transcriptome sequencing analysis identifies MRPS23 as a potential downstream target protein regulated by HIF1A-AS2 and knockdown of HIF1A-AS2 leads to decreased expression of MRPS23 in TNBC cells. Moreover, MRPS23 exhibits similar effects on enhancing cell proliferation, metastasis, invasion, and paclitaxel resistance in TNBC cells. Furthermore, downregulating HIF1A-AS2 suppresses the enhanced functionality observed in TNBC cells due to upregulated MRPS23 expression. These findings suggest that modulation of MRPS23 protein expression by HIF1A-AS2 may influence cellular processes and paclitaxel sensitivity in TNBC cells.

Dissociation of Human and Mouse Tumor Tissue Samples for Single-cell RNA Sequencing.

Human tumor samples hold a plethora of information about their microenvironment and immune repertoire. Effective dissociation of human tissue samples into viable cell suspensions is a required input for the single-cell RNA sequencing (scRNAseq) pipeline. Unlike bulk RNA sequencing approaches, scRNAseq enables us to infer the transcriptional heterogeneity in tumor specimens at the single-cell level. Incorporating this approach in recent years has led to many discoveries, such as identifying immune and tumor cellular states and programs associated with clinical responses to immunotherapies and other types of treatments. Moreover, single-cell technologies applied to dissociated tissues can be used to identify accessible chromatin regions T and B cell receptor repertoire, and the expression of proteins, using DNA barcoded antibodies (CITEseq). The viability and quality of the dissociated sample are critical variables when using these technologies, as these can dramatically affect the cross-contamination of single cells with ambient RNA, the quality of the data, and interpretation. Moreover, long dissociation protocols can lead to the elimination of sensitive cell populations and the upregulation of a stress response gene signature. To overcome these limitations, we devised a rapid universal dissociation protocol, which has been validated on multiple types of human and murine tumors. The process begins with mechanical and enzymatic dissociation, followed by filtration, red blood lysis, and live dead enrichment, suitable for samples with a low input of cells (e.g., needle core biopsies). This protocol ensures a clean and viable single-cell suspension paramount to the successful generation of Gel Bead-In Emulsions (GEMs), barcoding, and sequencing.

Metal-free phenothiazine dyes with alkoxy chains modified at different position for dye-sensitized solar cells

Long alkyloxy or alkoxyphenyl chains are commonly introduced to organic dye sensitizers in dye-sensitized solar cells (DSSCs) to inhibit the aggregation of sensitizer on the TiO2, thereby minimizing charge recombination. Here, we synthesized four D-D-π-A sensitizers (TP-C6, TP-PhOC6, C6O-TP-C6, C6O-TP-PhOC6), that feature alkyl-/alkoxyphenyl- moiety in phenothiazine (PTZ) donor’s N-position, and either alkoxy or no alkoxy groups in triphenylamine (TPA) auxiliary donor. Then, their photophysical, electrochemical and DSSCs properties were investigated. The UV-Vis and electrochemical studies revealed that all four dyes exhibited good light absorption ability and appropriate HOMO-LUMO energy levels. The introduction of alkoxy at the donor or auxiliary donor can result in a significant redshift in absorption. Among them, TP-PhOC6, which incorporates an alkoxy phenyl group at the N-position of PTZ and lacks alkoxy in TPA, induces a greater redshift in ICT absorption with strong absorption intensity. Additionally, in TP-PhOC6 based DSSC, mitigated charge recombination was observed. As a result, this device exhibited the strongest and widest IPCE spectrum, the highest Jsc (12.77 mA/cm²) and Voc (0.85 V), leading to the highest PCE (6.59 %).

Disulfidptosis-related gene expression reflects the prognosis of drug-resistant cancer patients and inhibition of MYH9 reverses sorafenib resistance

The onset of drug resistance in advanced cancer patients markedly diminishes their prognosis. Recently, disulfidptosis, a novel form of cell death, has been identified, triggered by excessive disulfide formation leading to cell shrinkage and F-actin contraction. Previous studies have identified 15 essential genes (FLNA, FLNB, MYH9, TLN1, ACTB, MYL6, MYH10, CAPZB, DSTN, IQGAP1, ACTN4, PDLIM1, CD2AP, INF2, SLC7A11) associated with disulfidptosis. This study sourced pan-cancer mRNA expression data from Xena to thoroughly evaluate the molecular and clinical characteristics of disulfidptosis-related genes. Through unsupervised clustering, mRNA expression data identified the expression levels of disulfidptosis-related genes and potential clusters related to this form of cell death. Kaplan-Meier survival curves illustrated the correlation between different clusters and overall survival. The findings reveal that high expression of disulfidptosis-related genes is linked to poor survival in liver cancer. The GDSC database was utilized to analyze the relationship between disulfidptosis-related genes and the AUC of 198 drugs. The results demonstrate that 12 disulfidptosis-related genes influence sorafenib resistance, as revealed by the intersection of differential genes related to sorafenib resistance from the GSE109211 dataset. Among them, the MYH9 gene was found to play a crucial role in both. Finally, experimental evidence confirmed that MYH9 mitigates sorafenib resistance in hepatocellular carcinoma through disulfidptosis-like changes. This study identifies disulfidptosis as a promising avenue for enhancing the sensitivity of tumor cells to drugs, offering new therapeutic perspectives for future research on disulfidptosis and drug resistance in cancer patients.

Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon

Multiple myeloma (MM) is the second most common hematological tumor in adults. Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective drugs for the treatment of multiple myeloma. Len can recruit IKZF1 and IKZF3 to cereblon (CRBN), a substrate receptor of the cullin 4-RING E3 ligase (CRL4), promote their ubiquitination and degradation, and finally inhibit the proliferation of myeloma cells. However, MM patients develop resistance to IMiDs over time, leading to disease recurrence and deterioration. To explore the possible approaches that may enhance the sensitivity of IMiDs to MM, in this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.

Halogenated retinoid derivatives as dual RARα and RXRα modulators for treating acute promyelocytic leukemia cells

Acute promyelocytic leukemia (APL), a distinctive subtype of acute myeloid leukemia (AML), is characterized by the t(15; 17) translocation forming the PML-RARα fusion protein. Recent studies have revealed a crucial role of retinoid X receptor α (RXRα) in PML-RARα′s tumorigenesis. This necessitates the development of dual RARα and RXRα targeting compounds for treating APL. Here, we developed a pair of brominated retinoid isomers, 5a and 5b, exhibiting RARα agonistic selectivity among the RAR subtypes and RXRα partial agonistic activities. In the treatment of APL cells, low doses (RARα activation range) of 5a and 5b degrade PML-RARα and strongly induce differentiation, while higher doses (RXRα activation range) induce G2/M arrest and apoptosis in both all-trans retinoic acid (ATRA)-sensitive and resistant cells. We replaced the bromine in 5a with chlorine or iodine to obtain compounds 7 or 8a. Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G2/M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL.

POU5F1B is responsible for the acquired resistance to dabrafenib in papillary thyroid cancer cells with the BRAF V600E mutation.

Dabrafenib, an inhibitor of the B-Raf proto-oncogene (BRAF) V600E mutant, has become the major drug for targeted therapy of papillary thyroid cancer (PTC) with the BRAF V600E mutant; however, acquired resistance is inevitable. To identify key transcription factors (TFs) involved in dabrafenib resistance and identify targets to reverse dabrafenib resistance. Dabrafenib-resistant PTC cell lines BCPAP/DabR and K1/DabR were established, and phenotypic assays were performed to validate the malignant phenotype. RNA sequencing and bioinformatics analyses were used to identify differentially expressed genes (DEGs) and screen TFs involved in resistant phenotype-related pathways. The role of the key TF POU5F1B in dabrafenib resistance was further validated using gene gain-and-loss assays. BCPAP/DabR and K1/DabR were resistant to dabrafenib, with a resistance index of 5-8. Resistant cells exhibited slower proliferation, strong migration, and spheroid-forming abilities. RNA sequencing screened 6233 DEGs in the resistant group, including 2687 protein-coding RNA (mRNA). Venn analysis indicated that three genes, E2F2, WNT4, and POU5F1B, were involved in resistant phenotype-related pathways and were included in the TF regulatory network. Four TFs of the three genes, POU5F1B, TBX4, FOXO4, and FOXP3, were validated, and POU5F1B showed the highest validated fold-change. Overexpression of POU5F1B in sensitive cells resulted in resistance to dabrafenib and induced a malignant phenotype, whereas silencing it sensitized the resistant cells and reversed the resistant phenotype. This study successfully established two dabrafenib-resistant PTC cell lines, and POU5F1B could be a potential target for reversing dabrafenib resistance.

The influence of apigenin on cellular responses to radiation: From protection to sensitization.

Apigenin, a dietary flavonoid, has gained increasing attention for its potential therapeutic applications in radiation protection and radiosensitization. Ionizing radiation (IR) can harm healthy cells, but as radiotherapy remains crucial in cancer treatment. Owing to the remarkable application of radiotherapy in the treatment of cancers, it is vital to protect healthy cells from radiation hazards while increasing the sensitivity of cancer cells to radiation. This article reviews the current understanding of apigenin's radioprotective and radiosensitive properties with a focuses on the involved signaling pathways and key molecular targets. When exposed to irradiation, apigenin reduces inflammation via cyclooxygenase-2 inhibition and modulates proapoptotic and antiapoptotic biomarkers. Apigenin's radical scavenging abilities and antioxidant enhancement mitigate oxidative DNA damage. It inhibits radiation-induced mammalian target of rapamycin activation, vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP), and STAT3 expression, while promoting AMPK, autophagy, and apoptosis, suggesting potential in cancer prevention. As a radiosensitizer, apigenin inhibits tumor growth by inducing apoptosis, suppressing VEGF-C, tumor necrosis factor alpha, and STAT3, reducing MMP-2/9 activity, and inhibiting cancer cell glucose uptake. Cellular and animal studies support apigenin's radioprotective and anticancer potential, making it a potential candidate for further research. Investigation into apigenin's therapeutic efficacy in diverse cancer types and radiation damage is essential.

Imaging-Guided Metabolic Radiosensitization of Pediatric Rhabdoid Tumors.

Tumor hypoxia leads to increased resistance to radiation therapy (RT), resulting in markedly worse clinical outcomes in the treatment and management of pediatric malignant rhabdoid tumors (MRT). To alleviate hypoxia in MRT, we repurposed an FDA approved, mitochondrial oxidative phosphorylation (OXPHOS) inhibitor, Atovaquone (AVO), to inhibit oxygen consumption and thereby enhance the sensitivity of tumor cells to low dose RT in MRT by hypoxia alleviation. Additionally, to better understand the tumor response induced by AVO and optimize the combination with RT, we employed an emerging, noninvasive imaging modality, known as multispectral optoacoustic tomography (MSOT), to monitor and evaluate real-time dynamic changes in tumor hypoxia and vascular perfusion. Oxygen-Enhanced (OE)-MSOT could measure the change of tumor oxygenation in the MRT xenograft models after AVO and RT treatments, indicating its potential as a response biomarker. OE-MSOT showed that treating MRT mouse models with AVO resulted in a transient increase in oxygen saturation (ΔsO 2 ) in tumors when the mice were subjected to oxygen challenge, while RT or saline treated groups produced no change. In AVO+RT combination groups, the tumors showed an increase in ΔsO 2 after AVO administration followed by a significant decrease after RT, that correlated with a strong anti-tumor response, demarcated by complete regression of tumors, with no relapse on long-term monitoring. These observations were histologically validated. In MRT models of acquired AVO resistance, combination therapy failed to alleviate tumoral hypoxia and elicit any therapeutic benefit. Together, our data highlights the utility of repurposing anti-malarial AVO as an anticancer adjuvant for enabling low dose RT for pediatric patients.

Effect of impaired autophagic flux on breast carcinogenesis through the enhanced LC3-p62-NRF2 feedback loop.

6 Background: Breast cancer affects more women worldwide than any other type of cancer. Although some genes have been identified as potential causes, the exact molecular mechanism of the disease is still unknown. In our study, we aimed to investigate the role of NRF2 and the autophagy markers p62 and LC3 in breast cancer cell lines that have different Tp53 status using a new compound called 6,6'dihydroxythiobinupharidine (DTBN). In our previous research, we have shown that DTBN modulates key cellular signal transduction pathways that are relevant to disease biology, including cancer. Furthermore, we analyzed online databases to determine the correlation between NRF2, p62, LC3, and Tp53 in breast cancer patients. Methods: To evaluate the effect of DTBN on NRF2, p62 and LC3 in different types of breast cancer cell lines with varying TP53 status, we conducted molecular studies by inhibiting NRF2 activity. We synthesized the correlation between NRF2, p62, LC3 and TP53 expression and clinical parameters by analyzing TCGA and GEO datasets. Results: Our findings suggest that DTBN induces cell death and autophagy in all breast cancer cell lines, regardless of their Tp53 status. However, they also led us to hypothesize that NRF2 may hinder the sensitivity of cancer cells to DTBN-induced cell death and autophagy. To test this hypothesis, we inhibited NRF2 activity using an NRF2 inhibitor called brusatol. The results of the study indicate that the inhibition of NRF2 significantly increased cell death and autophagy in DTBN-treated cells. We observed a decrease in the expression of the autophagy marker p62, while an increase in the expression of another autophagy marker LC3. These findings suggest that the interaction between NRF2, LC3 and p62, which is activated in response to DTBN treatment, may serve as a potential anticancer drug target. We have validated the positive correlation between NRF2 and the autophagic gene p62 and LC3, in different Tp53 status breast cancer cell lines by analyzing TCGA and GEO data. Conclusions: Our study shows that high levels of Nrf2, LC3 and p62 expression are significantly associated with increased breast cancer cell proliferation and migration. This implies that patients with breast cancer have lower overall survival and a higher rate of recurrence. Our findings highlight the role of DTBN-induced NRF2 and LC3 expression and reduced p62 expression in breast cancer cells with varying Tp53 status. These results may represent a paradigm for better understanding the cancer cell response to therapies and designing more efficient combined anticancer therapies targeting NRF2, LC3 p62, and Tp53.