ABCC2 Gene Research Articles

Dietary Addition of Selenium Attenuates Cadmium-Induced Liver Injury in Grass Carp (Ctenopharyngodon idellus) by Reducing Oxidative Stress and Apoptosis

In order to investigate the effects of selenium (Se) against cadmium (Cd) toxicity, 180 healthy grass carp were separated into three groups and fed diets containing 0.147 (control group), 0.562, and 1.044 mg/kg of selenium Yeast throughout 60 days. In grass carp livers, malondialdehyde (MDA) content, antioxidant enzyme activities, and apoptosis-related gene expression were examined. As a result of acute exposure to cadmium, MDA content decreased significantly. With time, catalase (CAT), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px) activities changed. The relative transcript levels of heavy metal scavenging genes abcc2 and mt2 were significantly reduced. The relative levels of expression of jnk, bax, caspase-3, caspase-8, and caspase-9 in apoptosis-associated factors were significantly elevated after cadmium exposure. Selenium-supplementation downregulated the expression of apoptosis-related factors. As compared to the control group, liver cells supplemented with selenium had a significantly lower apoptotic index. Comprehensive analysis showed that dietary selenium supplementation significantly attenuated cadmium-induced peroxidative damage and apoptosis in liver by increasing GSH-Px activity, and that cadmium toxicity could be alleviated by the addition of yeast selenium.

Abstract C050: Breast cancer in Ghana: assessment of multidrug-resistant genes among breast cancer patients

Abstract Breast cancer (BC) is the most frequently diagnosed cancer among women globally and chemotherapy plays a crucial role in its management in sub-Saharan Africa. The long-term BC survival rate remains poor due to chemoresistance. Over 80% of currently used chemotherapy drugs are substrates of ABC transporter genes, ABCB1, ABCC1 and ABCG2. Possessing the wild-type genotype and alleles of these genes reduces intracellular drug accumulation and leads to poorer treatment outcomes due to the upregulation of efflux function. This study therefore determined the allelic and genotype frequencies of three variant alleles, rs1045642, rs28706727 and rs2231142 in these transporter genes, and assessed the association between the variant statuses and BC recurrence or metastasis in the Ghanaian BC population. A quantitative, observational, case-control study was conducted using a purposive and convenience sampling method. Sociodemographic and clinical data were collected from study participants using questionnaires and a review of medical records. Extracted blood DNA from participants was used to determine the gene variants in ABCB1, ABCC1 and ABCG2 genes using the TaqMan Allelic Discrimination assays. A significantly high frequency (p ≤ 0.001) of the homozygous wild-type genotypes and alleles (ABCB1 had 77.3%/88% for CC/C, ABCC1 had 95.3%/97.7% for GG/G and ABCG2 had 100%/100% for CC/C) was found in both case and control groups. The wild-type genotypes and alleles of ABCB1, ABCC1 and ABCG2 may contribute to poor BC treatment outcomes among Ghanaian BC patients receiving chemotherapy. Citation Format: Gloria Agyekum Boaitey, Rachel Martini, Nourddine Dean Djeddar, Brian Stonaker, Stevens M. Patino, Jason White, Ernest Osei Bonsu, Yaw Agyekum Boaitey, Christian Obirikorang, Melissa B. Davis, Linda Ahenkorah Fondjo. Breast cancer in Ghana: assessment of multidrug-resistant genes among breast cancer patients [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C050.

Downregulation of APN1 and ABCC2 mutation in Bt Cry1Ac-resistant Trichoplusia ni are genetically independent.

The resistance to the insecticidal protein Cry1Ac from the bacterium Bacillus thuringiensis (Bt) in the cabbage looper, Trichoplusia ni, has previously been identified to be associated with a frameshift mutation in the ABC transporter ABCC2 gene and with altered expression of the aminopeptidase N (APN) genes APN1 and APN6, shown as missing of the 110-kDa APN1 (phenotype APN1¯) in larval midgut brush border membrane vesicles (BBMV). In this study, genetic linkage analysis identified that the APN1¯ phenotype and the ABCC2 mutation in Cry1Ac-resistant T. ni segregated independently, although they were always associated under Cry1Ac selection. The ABCC2 mutation and APN1¯ phenotype were separated into two T. ni strains respectively. Bioassays of the T. ni strains with Cry1Ac determined that the T. ni with the APN1¯ phenotype showed a low level resistance to Cry1Ac (3.5-fold), and the associated resistance is incompletely dominant in the background of the ABCC2 mutation. Whereas the ABCC2 mutation-associated resistance to Cry1Ac is at a moderate level, and the resistance is incompletely recessive in the genetic background of downregulated APN1. Analysis of Cry1Ac binding to larval midgut BBMV indicated that the midgut in larvae with the APN1¯ phenotype had reduced binding affinity for Cry1Ac, but the number of binding sites remained unchanged, and the midgut in larvae with the ABCC2 mutation had both reduced binding affinity and reduced number of binding sites for Cry1Ac. The reduced Cry1Ac binding to BBMV from larvae with the ABCC2 mutation or APN1¯ phenotype correlated with the lower levels of resistance.IMPORTANCEThe soil bacterium Bacillus thuringiensis (Bt) is an important insect pathogen used as a bioinsecticide for pest control. Bt genes coding for insecticidal proteins are the primary transgenes engineered into transgenic crops (Bt crops) to confer insect resistance. However, the evolution of resistance to Bt proteins in insect populations in response to exposure to Bt threatens the sustainable application of Bt biotechnology. Cry1Ac is a major insecticidal toxin utilized for insect control. Genetic mechanisms of insect resistance to Cry1Ac are complex and require to be better understood. The resistance to Cry1Ac in Trichoplusia ni is associated with a mutation in the ABCC2 gene and also associated with the APN expression phenotype APN1¯. This study identified the genetic independence of the APN1¯ phenotype from the ABCC2 mutation and isolated and analyzed the ABCC2 mutation-associated and APN1¯ phenotype-associated resistance traits in T. ni to provide new insights into the genetic mechanisms of Cry1Ac resistance in insects.

Potentiation of growth suppression and modulation of multidrug resistance by gamma and beta interferons in MDA-MB-231 breast cancer cell line.

Multi-drug resistance (MDR) might be acquired by the cancer cells during chemotherapy, and ATP-binding cassette (ABC) transporters play a significant role in MDR. Interferon-γ (IFN-γ) and IFN-β can inhibit cancer cell proliferation; however, the effects and mechanism of these cytokines on the growth and MDR are still unclear. To investigate the effects of IFN-γ and IFN-β, alone or in combination, on viability, resistance, and the expression of ABC transporters of the MDA-MB-231 breast cancer cell line. Using the MDA-MB-231 cell line, we assessed the effects of 20, 100, and 500 IU/ml of IFN-γ and IFN-β, alone or in combination, on cell viability by methyl thiazolyl tetrazolium(MTT) assay; and then we performed the Uptake and Efflux experiment to evaluate the effect of these IFNs on the cell resistance. Then, using quantitative real-time PCR, we evaluated changes in the expression of ABCB1, ABCC1, and ABCG2 mRNA levels. We discovered that IFN-γ and IFN-β might both reduce viability, either alone or in combination. The combination of IFNs also displayed synergistic responses, particularly when utilizing equivalent dosages of 500 or 100 IU/ml. The combination of IFN-γ and IFN-β resulted in a significant increase in Doxorubicin accumulation and down-regulation of the ABCC1 gene at the mRNA level. Our study suggested that equal doses of IFN-γ and IFN-β in combination might result in potentiated responses against cancer, especially, along with chemotherapy agents.

Insights into multidrug resistance mechanisms: Exploring distinct miRNAs as prospective therapeutic agents in triple negative breast cancer

Triple Negative Breast Cancer (TNBC) constitutes 12–17 % of breast cancers and is distinguished by the absence of hormone receptor expression, deviating from other breast cancer types. Coupled with its elevated proliferation index, TNBC develops multidrug resistance, diminishing treatment efficacy, weakening disease prognosis, and leading to an aggressive clinical course. This study aimed to assess ABCB1, ABCC1, ABCG2, and ABCC9 gene expression, which play a primary role in the development of multidrug resistance, alongside miRNAs (miR-466, miR-4539, miR-659-3p, miR-3123, miR-3133, and miR-655-3p) targeting these genes. While ABCB1 (p = 0.433), ABCC1 (p < 0.05), and ABCG2 (p < 0.05) exhibited increased expression in tumor tissues, ABCC9 (p = 0.587) did not. miR-466 (p = 0.802), miR-4539 (p = 0.732), miR-659-3p (p = 0.807), and miR-3123 (p = 0.980) were upregulated, whereas miR-3133 (p < 0.05) and miR-655-3p (p = 0.190) were downregulated. Within the scope of our study, we also evaluated the clinical parameters like tumor size, stage, and neoadjuvant treatment that significantly impacted Progression Free Survival (PFS) and Overall Survival (OS). Considering these results, we found that the metastatic status significantly influenced PFS and OS. Chemotherapeutics were found to not affect survival times. Assessing the impact of miRNAs, which we view as potential therapeutic targets, on average survival revealed that elevated miR-3133 expression was correlated with shorter PFS and OS, whereas decreased miR-655-3p expression was associated with longer PFS and OS. In summary, the relevant miRNAs could serve as predictive biomarkers for drug response and aid in developing miRNA-targeted gene therapy strategies.

The activation of the G-protein-coupled estrogen receptor promotes the aggressiveness of MDA-MB231 cells by targeting the IRE1α/TXNIP pathway

Background and purpose: This study investigated modulating the G protein-coupled estrogen receptor (GPER) on the IRElα/TXNIP pathway and its role in drug resistance in MDA-MB231 cells. Experimental approach: To determine the optimal concentrations of G1 and 4-hydroxytamoxifen (TAM), GPER expression and ERK1/2 phosphorylation were analyzed using qRT-PCR and western blotting, respectively. Cells were treated with individual concentrations of G1 (1000 nM), G15 (1000 nM), and TAM (2000 nM), as well as combinations of these treatments (G1 + G15, TAM + G15, and G1 + TAM) for 24 and 48 h. The expression levels of GPER, IRE1α, miR-17-5p, TXNIP, ABCB1, and ABCC1 genes and TXNIP protein expression were evaluated. Finally, apoptosis and cell migration were examined using flow cytometry and the wound-healing assay, respectively. Findings/Results: Activating GPER with its specific agonist G1 and TAM significantly increased IRE1α levels in MDA-MB231 cells. IRE1α through splicing XBP1 led to unfolded protein response. In addition, decreased TXNIP gene and protein expression reduced apoptosis, increased migration, and upregulated the genes associated with drug resistance. Conclusion and implication: Our investigation revealed that blocking the GPER/IRE1α/TXNIP pathway in MDA-MB231 cells could enhance treatment efficacy and improve chemotherapy responsiveness. The distinct unfolded protein response observed in MDA-MB231 cells may stem from the unique characteristics of these cells, which lack receptors for estrogen, progesterone, and HER2/neu hormones, possessing only the GPER receptor (ER-/PR-/HER2-/GPER+). This study introduced a new pathway in TNBC cells, indicating that targeting GPER could be crucial in comprehensive therapeutic strategies in TNBC cells.

ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer.

Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38-7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09-17.55] months versus negative expression 13.3 [95% CI 7.32-19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade ≥ 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08-9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed.

ABCC1 Is a ΔNp63 Target Gene Overexpressed in Squamous Cell Carcinoma.

The transcription factor ΔNp63 plays a pivotal role in maintaining the integrity of stratified epithelial tissues by regulating the expression of distinct target genes involved in lineage specification, cell stemness, cell proliferation and differentiation. Here, we identified the ABC transporter subfamily member ABCC1 as a novel ΔNp63 target gene. We found that in immortalized human keratinocytes and in squamous cell carcinoma (SCC) cells, ∆Np63 induces the expression of ABCC1 by physically occupying a p63-binding site (p63 BS) located in the first intron of the ABCC1 gene locus. In cutaneous SCC and during the activation of the keratinocyte differentiation program, ∆Np63 and ABCC1 levels are positively correlated raising the possibility that ABCC1 might be involved in the regulation of the proliferative/differentiative capabilities of squamous tissue. However, we did not find any gross alteration in the structure and morphology of the epidermis in humanized hABCC1 knock-out mice. Conversely, we found that the genetic ablation of ABCC1 led to a marked reduction in inflammation-mediated proliferation of keratinocytes, suggesting that ABCC1 might be involved in the regulation of keratinocyte proliferation upon inflammatory/proliferative signals. In line with these observations, we found a significant increase in ABCC1 expression in squamous cell carcinomas (SCCs), a tumor type characterized by keratinocyte hyper-proliferation and a pro-inflammatory tumor microenvironment. Collectively, these data uncover ABCC1 as an additional ∆Np63 target gene potentially involved in those skin diseases characterized by dysregulation of proliferation/differentiation balance.

In silico and biological analyses of missense variants of the human biliary efflux transporter ABCC2: effects of novel rare missense variants.

The ATP-dependent biliary efflux transporter ABCC2, also known as multidrug resistance protein 2 (MRP2), is essential for the cellular disposition and detoxification of various xenobiotics including drugs as well as endogenous metabolites. Common functionally relevant ABCC2 genetic variants significantly alter drug responses and contribute to side effects. The aim of this study was to determine functional consequences of rare variants identified in subjects with European ancestry using in silico tools and in vitro analyses. Targeted next-generation sequencing of the ABCC2 gene was used to identify novel variants in European subjects (n = 143). Twenty-six in silico tools were used to predict functional consequences. For biological validation, transport assays were carried out with membrane vesicles prepared from cell lines overexpressing the newly identified ABCC2 variants and estradiol β-glucuronide and carboxydichlorofluorescein as the substrates. Three novel rare ABCC2 missense variants were identified (W227R, K402T, V489F). Twenty-five in silico tools predicted W227R as damaging and one as potentially damaging. Prediction of functional consequences was not possible for K402T and V489F and for the common linked variants V1188E/C1515Y. Characterisation in vitro showed increased function of W227R, V489F and V1188E/C1515Y for both substrates, whereas K402T function was only increased for carboxydichlorofluorescein. In silico tools were unable to accurately predict the substrate-dependent increase in function of ABCC2 missense variants. In vitro biological studies are required to accurately determine functional activity to avoid misleading consequences for drug therapy.

Systematic review: genetic polymorphisms in the pharmacokinetics of high-dose methotrexate in pediatric acute lymphoblastic leukemia patients.

Variations in pharmacokinetic responses to high-dose methotrexate are essential for the prognosis and management of toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL) patients. This systematic review aimed to identify and evaluate genetic polymorphisms that are significantly associated with the pharmacokinetic parameters of methotrexate during the consolidation phase of pediatric ALL treatment. Using the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, we systematically reviewed the literature from 2013 to 2023. The databases used were PubMed and Scopus. The outcomes of interest are the study design, patient characteristics, sample size, chemotherapy protocol utilized, pharmacokinetic parameters identified, and genetic polymorphisms implicated. We included 31 articles in the qualitative synthesis and found that the SLCO1B1, ABCB1, ABCC2, and MTHFR genes appear to play significant roles in MTX metabolism and clearance. Among these, variations in SLCO1B1 have the most significant and consistent impact on methotrexate clearance. These implicated variants may contribute to the precision and tailoring of HD-MTX treatment in pediatric ALL patients.

Molecular genetic indicators of the probability of early myocardial systolic dysfunction signs in doxorubicin chemotherapy in patients with breast cancer of moderate and low HFA-ICOS risk groups

Aim. To study the association of rs2232228 (HAS3 gene), rs2229774 (RARG gene), rs1056892 (CBR3 gene), rs1786814 (CELF4 gene), rs1695 (GSTP1 gene), rs8187710 (ABCC2 gene), rs7853758 (SLC28A3 gene), rs243865 (MMP­2 gene), rs243866 (MMP­2 gene), rs35068180 (MMP­3 gene), rs522616 (MMP­3 gene), rs679620 (MMP­3 gene), rs17576 (MMP­9 gene), rs3918242 (MMP­9 gene) with the probability of early doxorubicin cardiotoxicity signs in patients with breast cancer of moderate and low HFA-ICOS risk groups.Material and methods. The study included 100 patients (women, over 18 years old) diagnosed with breast cancer who received chemotherapy using doxorubicin.To identify early cardiotoxicity signs, echocardiography was performed before, immediately after and 12 months after the end of chemotherapy. The status of polymorphic variants of the studied genes was determined by real-time polymerase chain reaction.Results. Based on the decrease in global longitudinal myocardial strain (&gt;12%) immediately after and 12 months after the end of chemotherapy, the patients were divided into two following groups: A — early signs of myocardial dysfunction can be diagnosed after the end of chemotherapy (19%); B — early signs of myocardial dysfunction are detected for the first time only 12 months after the chemotherapy end (17%). In patients from category A, a number of allelic variants and genotypes with potential as independent factors for predicting the early signs of myocardial dysfunction were identified, with an emphasis on targets involved in metabolism and detoxification of doxorubicin and its derivatives. In category B, the greatest differences in the frequencies of allelic variants and genotypes were found among target genes encoding matrix metalloproteinases involved in the processes of response to the intensification of oxidative stress caused by doxorubicin and its derivatives.Conclusion. In total, patients in the low- and moderate-risk groups can be divided into at least 2 categories based on molecular genetic testing. For these categories, the development of early signs of doxorubicin-related myocardial dysfunction before the start of chemotherapy can be predicted.

Integrated Transcriptome and Metabolome to Elucidate the Mechanism of Aluminum-Induced Blue-Turning of Hydrangea Sepals

Hydrangea macrophylla is an ornamental plant with varied calyx colors. Interestingly, from red, to purple, to blue, the colors of all Hydrangea macrophylla are formed by unique delphinidin-3-O-glucoside and aluminum ions (Al3+) and 5-O-p-coumaroylquinic acid. The sepals of ‘Blue Mama’ changed from pink to blue, and the contents of delphinidin-3-O-glucoside and aluminum ions increased under 3 g/L aluminum sulfate treatment. However, the mechanism of the effect of aluminum ions on the synthesis and metabolism of anthocyanins in Hydrangea macrophylla is still unclear. In this project, transcriptome sequencing and anthocyanin metabolome analysis were performed on the sepals of ‘Blue Mama’ during flower development at the bud stage (S1), discoloration stage (S2) and full-bloom stage (S3) under aluminum treatment. It was found that delphinidin, delphinidin-3-O-glucoside and delphinidin-3-O-galactoside were the main differential metabolites. The structural genes CHS, F3H, ANS, DFR and BZI in the anthocyanin synthesis pathway were up-regulated with the deepening in sepal color. There was no significant difference between the aluminum treatment and the non-aluminum treatment groups. However, seven transcription factors were up-regulated and expressed to regulate anthocyanin synthesis genes CHS, F3H, BZI and 4CL, promoting the sepals to turn blue. The KEGG enrichment pathway analysis of differentially expressed genes showed that the glutathione metabolism and the ABC transporter pathway were closely related to anthocyanin synthesis and aluminum-ion transport. GST (Hma1.2p1_0158F.1_g069560.gene) may be involved in the vacuolar transport of anthocyanins. The expression of anthocyanin transporter genes ABCC1 (Hma1.2p1_0021F.1_g014400.gene), ABCC2 (Hma1.2p1_0491F.1_g164450.gene) and aluminum transporter gene ALS3 (Hma1.2p1_0111F.1_g053440.gene) were significantly up-regulated in the aluminum treatment group, which may be an important reason for promoting the transport of anthocyanin and aluminum ions to vacuoles and making the sepals blue. These results preliminarily clarified the mechanism of aluminum ion in the synthesis and transport of anthocyanin in Hydrangea macrophylla, laying a foundation for the further study of the formation mechanism of ‘blue complex’ in Hydrangea macrophylla.

Induction effect of antiretroviral bictegravir on the expression of Abcb1, Abcg2 and Abcc1 genes associated with P-gp, BCRP and MRP1 transporters present in rat peripheral blood mononuclear cells

ABSTRACT Background Antiretrovirals have the potential to cause drug interactions leading to inefficacy or toxicity via induction of efflux transporters through nuclear receptors, altering drug concentrations at their target sites. Research Design and Methods This study used molecular dynamic simulations and qRT-PCR to investigate bictegravir’s interactions with nuclear receptors PXR and CAR, and its effects on efflux transporters (P-gp, BCRP, MRP1) in rat PBMCs. PBMC/plasma drug concentrations were measured using LC-MS/MS to assess the functional impact of transporter expression. Results Bictegravir significantly increased the expression of ABC transporters, with Car identified as a key mediator. This suggests that bictegravir’s influence on nuclear receptors could affect drug transport and efficacy at the cellular level. Conclusions Bictegravir activates nuclear receptors enhancing efflux transporter expression. Understanding these interactions is crucial for preventing drug–drug interactions and reducing toxicity in clinical use. Combining CAR antagonists with bictegravir may prevent drug resistance and toxicity. However, these findings are based on preclinical data and necessitate further clinical trials to confirm their applicability in clinical settings.

Hepatic transcriptome, transcriptional effects and antioxidant responses in Poecilia vivipara exposed to sanitary sewage

Aquatic environments are subject to threats from multiple human activities, particularly through the release of untreated sanitary sewage into the coastal environments. These effluents contain a large group of natural or synthetic compounds referred to as emerging contaminants. Monitoring the types and quantities of toxic substances in the environment, especially complex mixtures, is an exhausting and challenging task. Integrative effect-based tools, such as biomarkers, are recommended for environmental quality monitoring programs. In this study, fish Poecilia vivipara were exposed for 24 and 96 h to raw untreated sewage diluted 33 % (v/v) in order to identify hepatic genes to be used as molecular biomarkers. Through a de novo hepatic transcriptome assembly, using Illumina MiSeq, 54,285 sequences were assembled creating a reference transcriptome for this guppy species. Transcripts involved in biotransformation systems, antioxidant defenses, ABC transporters, nuclear and xenobiotic receptors were identified and evaluated by qPCR. Sanitary sewage induced transcriptional changes in AhR, PXR, CYP2K1, CYP3A30, NQO1, UGT1A1, GSTa3, GSTmu, ST1C1, SOD, ABCC1 and SOX9 genes from liver of fish, particularly after 96 h of exposure. Changes in hepatic enzyme activities were also observed. The enzymes showed differences in fish exposed to both periods, while in the gills there was a prevalence of significant results after 96 h. The observed differences were associated to gender and/or to sewage exposure. The obtained results support the use of P. vivipara as sentinel and model organism for ecotoxicological studies and evidence the importance of understanding the differential responses associated to gender.

Role of ABCC2 gene polymorphism on deferasirox hepatic toxicity in thalassemia patients

Objectives: To investigate the relationship between ABCC2 gene polymorphism (G&gt;A, rs 8187710) and (C&gt;T, rs 717620) and hepatotoxicity in thalassemia patient treated deferasirox . Methods: The present work included a cross sectional study, 100 patients suffering iron overload and thalassemia out of 650 patients in (thalassemia center) and 100 healthy patients to compare the parameters of liver function tests of thalassemia patients with healthy group. The allele specific polymerase chain reaction technique (pcr) was used to detect the (G&gt;A, rs 8187710) and (C&gt;T, rs 717620 single nucleotide polymorphism (SNP). Results : 58 patients with rs 8187710 who are wild (GG) and 32 patients hetero(GA)and 56 patients with rs 717620 who wild (CC) and 31 hetero (CT) are exposed to hepatotoxicity than patients with homo groups Conclusion: According to the results of the currents study, the (G&gt;A, rs 8187710) and (C&gt;T, rs 717620) single nucleotide polymorphism (SNP) was associated with hepatotoxicity in patients treated deferasirox.

Contribution of the transcription factor SfGATAe to Bt Cry toxin resistance in Spodoptera frugiperda through reduction of ABCC2 expression

Insect resistance evolution poses a significant threat to the advantages of biopesticides and transgenic crops utilizing insecticidal Cry-toxins from Bacillus thuringiensis (Bt). However, there is limited research on the relationship between transcriptional regulation of specific toxin receptors in lepidopteran insects and their resistance to Bt toxins. Here, we report the positive regulatory role of the SfGATAe transcription factor on the expression of the ABCC2 gene in Spodoptera frugiperda. DNA regions in the SfABCC2 promoter that are vital for regulation by SfGATAe, utilizing DAP-seq technology and promoter deletion mapping. Through yeast one-hybrid assays, DNA pull-down experiments, and site-directed mutagenesis, we confirmed that the transcription factor SfGATAe regulates the core control site PBS2 in the ABCC2 target gene. Tissue-specific expression analysis has revealed that SfGATAe is involved in the regulation and expression of midgut cells in the fall armyworm. Silencing SfGATAe in fall armyworm larvae resulted in reduced expression of SfABCC2 and decreased sensitivity to Cry1Ac toxin. Overall, this study elucidated the regulatory mechanism of the transcription factor SfGATAe on the expression of the toxin receptor gene SfABCC2 and this transcriptional control mechanism impacts the resistance of the fall armyworm to Bt toxins.

New Paralogs of the Heliothis virescens ABCC2 Transporter as Potential Receptors for Bt Cry1A Proteins.

The ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins. These active transporters are involved in the export of different substances such as xenobiotics. ABC transporters from subfamily C (ABCC) have also been described as functional receptors for different insecticidal proteins from Bacillus thuringiensis (Bt) in several lepidopteran species. Numerous studies have characterized the relationship between the ABCC2 transporter and Bt Cry1 proteins. Although other ABCC transporters sharing structural and functional similarities have been described, little is known of their role in the mode of action of Bt proteins. For Heliothis virescens, only the ABCC2 transporter and its interaction with Cry1A proteins have been studied to date. Here, we have searched for paralogs to the ABCC2 gene in H. virescens, and identified two new ABC transporter genes: HvABCC3 and HvABCC4. Furthermore, we have characterized their gene expression in the midgut and their protein topology, and compared them with that of ABCC2. Finally, we discuss their possible interaction with Bt proteins by performing protein docking analysis.

Abstract 1645: Telomere-related genes associated with clinical-pathological in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) stands as one of the leading causes of cancer deaths worldwide. Studies have suggested that telomeres shortening is linked to genetic instability, higher risk of developing pancreatic cancer and pancreatic tumorigenesis. However, previous research has predominantly focused on either telomere length or specific telomere-related genes in pancreatic cancer. Therefore, it is essential to elucidate the association between telomere-related genes and pancreatic cancer to identify novel therapeutic strategies and establish prognostic biomarkers. Telomere-relevant genes were downloaded from the TelNet database. Expression data from primary tumour of The Cancer Genome Atlas-PAAD (TCGA-PAAD) cohort, the Genome Sequence Archive CRA001160 dataset and the GTEx database were obtained for screen for differentially expressed genes (DEGs). Gene set enrichment analisis was performed using the Enrichr software. The gene essentiality queried from the gene dependency database of the Achilles-DepMap project was also assessed. Finally, data of The Cancer Genome Atlas-PanCancer CaPa cohort and healthy pancreas from the GTEx database, obtained from the UCSC Xena project, were used to correlate gene expression with stemness signatures and clinical-pathological variables. We identified 300 telomere-associated DEGs, Of these, 73 genes were common to studies and they were to be enriched in biological processes related to the cell cycle and telomere homeostasis. The differentially expresed of ASS1, S100P, IGF2BP2, MET, ABCC3 and RAC1 genes were significantly associated with overall survival and recurrence-free survival, conferring them prognostic value. Furthermore, the expression profiles of these genes are significantly associated with the histological grade of the disease, as well as with tumour T-N classification, the presence of residual tumour, the degree of response to treatment and stemness signatures. Among these, three genes of particular interest (KLF3, RAC1 and ABI1) were identified and shown to be highly essential in pancreatic cancer cell lines. In summary, we have identified a telomere gene-related signature for pancreatic cancer, highlighting the prognostic value of KLF3, RAC1, and ABI1 genes. This signature is significantly associated with clinical-pathological variables of the disease, potentially offering new insights for individualized therapy. Citation Format: Erika Curiel Gómez, Vilma Maldonado Lagunas, Jorge Meléndez Zajgla. Telomere-related genes associated with clinical-pathological in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1645.

PIM Kinase Inhibition Sensitizes Neuroblastoma to Doxorubicin

BackgroundChemoresistance contributes to relapse in high-risk neuroblastoma. Cancer cells acquire resistance through multiple mechanisms, including drug efflux pumps. In neuroblastoma, multidrug resistance-associated protein-1 (MRP1/ABCC1) efflux pump expression correlates with worse outcomes. These pumps are regulated by PIM kinases, a family of serine–threonine kinases, overexpressed in neuroblastoma. We hypothesized PIM kinase inhibition would sensitize neuroblastoma cells by modulating MRP1. MethodsKocak database query evaluated ABCC1, PIM1, PIM2, and PIM3 expression in neuroblastoma patients. SK-N-AS and SK-N-BE(2) cells were treated with doxorubicin or the pan-PIM kinase inhibitor, AZD1208. Flow cytometry assessed intracellular doxorubicin accumulation. AlamarBlue assay measured viability. The lethal dose 50% (LD50) of each drug and combination indices (CI) were calculated and isobolograms constructed to determine synergy. ResultsKocak database query demonstrated positive correlation between PIM genes and ABCC1. PIM kinase inhibition increased intracellular doxorubicin accumulation in both cell lines, suggesting PIM kinase regulation of MRP1. Isobolograms showed synergy between AZD1208 and doxorubicin. ConclusionsThe correlation between PIM and ABCC1 gene expression suggests PIM kinases may contribute to neuroblastoma chemotherapeutic resistance. PIM kinase inhibition increased intracellular doxorubicin accumulation. Combination treatment with AZD1208 and doxorubicin decreased neuroblastoma cell viability in a synergistic fashion. These findings support further investigations of PIM kinase inhibition in neuroblastoma. Type of StudyBasic Science Research. Level of EvidenceNA.

ABCC2 p.R393W variant contributes to Dubin-Johnson syndrome by targeting MRP2 to proteasome degradation

BackgroundDubin-Johnson syndrome (DJS), a rare autosomal recessive liver condition, is caused by biallelic loss-of-function mutations of the ABCC2 gene. This study aimed to investigate genetic variations in the drug efflux...