ATP-binding Cassette Subfamily C Member 2 Research Articles

ABCC2 induces metabolic vulnerability and cellular ferroptosis via enhanced glutathione efflux in gastric cancer.

Although it is traditionally believed that ATP binding cassette subfamily C member 2 (ABCC2) is a multidrug resistance-associated protein correlated with a worse prognosis, our previous and several other studies demonstrated the contrary to be true in gastric cancer (GC). We aim to explore the underlying mechanism of this discovery. Our study utilized whole-exome sequencing (WES), RNA sequencing, and droplet digital PCR (ddPCR) analysis of 80 gastric cancer samples, along with comprehensive immunohistochemical (IHC) analysis of 1044 human GC tissue samples.By utilizing CRISPRCas9 to genetically modify cell lines with the ABCC2-24C > T (rs717620) point mutation and conducting dual-luciferase reporter assays, we identified that transcription factors SOX9 and ETS1 serve as negative regulators of ABCC2 expression. Seahorse assay and mass spectrometry were used to discover altered metabolic patterns. Gain and loss-of-function experiments in GC cell lines and preclinical models were carried out to validate ABCC2 biological function. ABCC2 high expression correlated with better prognosis, and rs717620 can influence ABCC2 expression by disrupting the binding of ETS1 and SOX9. Gain and loss-of-function experiments in GC cell lines demonstrated amino acid deprivation reduces proliferation, migration, and drug resistance in ABCC2-high GC cells. ABCC2 leads to reduced intracellular amino acid pools and disruption of cellular energy metabolism. This phenomenon depended on ABCC2-mediated GSH extrusion, resulting in alterations in redox status, thereby increasing the cell's susceptibility to ferroptosis. Furthermore, patient-derived organoids and patient-derived tumor-like cell clusters were used to observe impact of ABCC2 on therapeutic effect. In the xenograft model with high ABCC2 expression, we observed that constricting amino acid intake in conjunction with GPX4 inactivation resulted in notable tumor regression. Our findings demonstrate a significant role of ABCC2 in amino acid metabolism and ferroptosis by mediating GSH efflux in GC. This discovery underlines the potential of combining multiple ferroptosis targets as a promising therapeutic strategy for GC with high ABCC2 expression. ABCC2 plays a crucial role in inducing metabolic vulnerability and ferroptosis in gastric cancer through enhanced glutathione efflux. The ABCC2 24C > T polymorphism is a key factor influencing its expression. These results highlight the potential of ABCC2 as a predictive biomarker and therapeutic target in gastric cancer.

Targeting METTL3 enhances the chemosensitivity of non-small cell lung cancer cells by decreasing ABCC2 expression in an m6A-YTHDF1-dependent manner.

Patients with non-small cell lung cancer (NSCLC) are easily resistant to first-line chemotherapy with paclitaxel (PTX) or carboplatin (CBP). N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) has crucial functions in m6A modification and tumorigenesis. However, its role in chemoresistance of NSCLC is still elusive. Here, we demonstrated that METTL3 inhibitor STM2457 significantly reduced the IC50 values of PTX or CBP in NSCLC cells, and they showed a synergistic effect. Comparing with monotherapy, a combination of STM2457 and PTX or CBP exhibited more potent in vitro and in vivo anti-tumor efficacy. In addition, we found that ATP binding cassette subfamily C member 2 (ABCC2) was responsively elevated in cytomembrane after PTX or CBP treatment, and targeting METTL3 could reverse this effect. Mechanistically, targeting METTL3 decreased the m6A modification of ABCC2 mRNA and accelerated its mRNA degradation. Further studies revealed that YTHDF1 could bind and stabilize the m6A-modified mRNA of ABCC2, while YTHDF1 knockdown promoted it mRNA degradation. These results, taken together, demonstrate that targeting METTL3 enhances the sensitivity of NSCLC cells to PTX or CBP by decreasing the cytomembrane-localized ABCC2 in an m6A-YTHDF1-dependent manner, and suggest that METTL3 may be a potential therapeutic target for acquired resistance to PTX or CBP in NSCLC.

Concurrence of novel mutations causing Gilbert’s and Dubin–Johnson syndrome with poor clinical outcomes in a Han Chinese family

Dual-hereditary jaundice (Dubin–Johnson syndrome (DJS) and Gilbert’s syndrome (GS)) is a rare clinical entity resulting from defects of the ATP binding cassette subfamily C member 2 (ABCC2) and UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genes with autosomal recessive inheritance. In this study, we aimed to investigate the mutation profiles and characterize the phenotypes in a Han Chinese family with DJS and GS. Genetic screening for variants in the ABCC2 and UGT1A1, immunohistochemistry for expression of ABCC2, and histopathological examination were carried out. The proband and his brother had unconjugated and conjugated hyperbilirubinemia after birth. The proband’s sister had only conjugated hyperbilirubinemia after birth. The proband developed into pleural effusions and ascites, pericardial thickening, intrahepatic and extrahepatic biliary duct dilatation, and enlarged gallbladder at age 50. Hepatocellular carcinoma occurred in the proband’s brother at age 46. Seven compound defects of the ABCC2 gene [c.2414delG, p.(Ile1489Gly), p.(Thr1490Pro), and p.(Ile1491Gln)] and the UGT1A1 gene (c.-3279T>G, p.(Gly71Arg), and p.(Pro451Leu)) were identified in family members. Accumulation of pigment in hepatocytes characteristic of that in DJS was present in the proband and his brother. Expression of ABCC2 protein was markedly diminished in the patient’s liver. Our results show a different genetic profile of DJS and GS in a Han Chinese family, indicating a more complex pattern of dual-hereditary jaundice among different populations. The present study illuminates the underpinnings of DJS and GS and extends the mutation profiles and phenotypes of these two syndromes in dual-hereditary jaundice.

Clinical characteristics and liver profiles of Dubin-Johnson syndrome in neonates: Multicenter retrospective study

ObjectivesDubin-Johnson syndrome (DJS) is a rare benign autosomal recessive disorder characterized by cholestasis in neonates. The aim of the present study was to describe the clinical characteristics, hepatic profiles, histopathology, gene mutations, and treatment outcomes of neonatal DJS. Material and methodsA multicenter retrospective study was undertaken with patients who had DJS. The authors identified DJS in neonates and reviewed medical records for details. The diagnosis of DJS was based on the presence of unexplained prolonged conjugated hyperbilirubinemia and presence of a mutation in the ATP Binding Cassette Subfamily C Member 2 (ABCC2) gene detected in genomic DNA extracted from circulating blood cells. ResultsEleven children with DJS were identified in the study. The study population comprised eight males and three females. The median age at presentation was 21 days. Dysmorphic features were not recorded in any of the patients. Cholestasis, high serum bile acids, and normal transaminase levels were found in all patients (100%). Serum alkaline phosphatase and gamma glutamyl transferase were elevated in four patients (36%). Hypoalbuminemia and coagulopathy were not noted in these patients. Consanguinity was present in nine patients (82%). All patients had normal abdominal ultrasound findings. Genetic molecular testing showed that 82% of the patients reported a pathogenic variant of the ABCC2 gene defect with the same variant c.2273G>T (Gly 758 val) chromosome 10. All patients were alive without liver transplantation. ConclusionsThis is the largest study worldwide describing that neonatal DJS is a benign cholestatic disease with favorable outcomes. Low-grade direct hyperbilirubinemia, normal transaminases, and elevated serum bile acids are the main characteristic findings of DJS.

Knockdown of ADORA2A antisense RNA 1 inhibits cell proliferation and enhances imatinib sensitivity in chronic myeloid leukemia

ABSTRACT Long non-coding RNAs (LncRNAs) exert important regulatory roles in chronic myeloid leukemia (CML). In this study, we aimed to investigate the potential role and molecular mechanism of lncRNA ADORA2A antisense RNA 1 (ADORA2A-AS1) in CML. We found that the expression of ADORA2A-AS1 was upregulated in CML. Further, knockdown of ADORA2A-AS1 inhibited the proliferation, induced apoptosis, arrested cell cycle, and enhanced imatinib sensitivity in CML cells. Besides, ADORA2A-AS1 promoted the expression of transforming growth factor-beta receptor 1 (TGFBR1) and ATP binding cassette subfamily C member 2 (ABCC2) via sponging miR-665, thereby exerting a tumor-promoting activity. Collectively, our results confirmed the oncogenic effect of ADORA2A-AS1 in CML, indicating that ADORA2A-AS1 is a promosing therapeutic target for CML.

ABCC2 is a functional receptor of Bacillus thuringiensis Cry1Ca in Spodoptera litura

Spodoptera litura is a serious polyphagous pest in the whole world, which has developed resistance to most conventional insecticides and even some Bacillus thuringiensis (Bt) toxins. Cry1Ca has excellent insecticide activity against S. litura with potential application to control S. litura and delay the development of insect resistance. However, the mode of action of Cry1Ca in S. litura is poorly understood. Here, Cry1Ca-binding proteins were identified from S. litura by using pull down assays and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results indicated that aminopeptidase-N (APN), ATP binding cassette subfamily C member 2 (ABCC2), polycalin, actin and V-type proton ATPase subunit A may bind with Cry1Ca. Further study confirmed that ABCC2 fragment expressed in vitro can bind to Cry1Ca as demonstrated by Ligand blot and homologous competition experiments. The over-expression of endogenous SlABCC2 in Sf9 cells increased Cry1Ca cytotoxicity. Correspondingly, the vivo loss of function analyses by SlABCC2 small interfering RNAs (siRNAs) in S. litura larvae decreased the toxicity of Cry1Ca to larvae. Altogether, these results show that ABCC2 of S. litura is a functional receptor that is involved in the action mode of Cry1Ca.

The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients.

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.

Downregulated let-7d positively stimulates rectum adenocarcinoma cell malignant biological behaviors by upregulating ATP binding cassette subfamily C member 2

Background: Let-7d has been reported to serve as a tumor suppressor in numerous cancers, however, the function in rectum adenocarcinoma has not been illuminated. In this study, we aimed to explore whether let-7d functions in rectum adenocarcinoma and its functional significance links to ATP binding cassette subfamily C member 2 (ABCC2). Methods: The expression patterns of let-7d and ABCC2 were gained from TCGA database. Then, cell proliferation, invasion and migration assays were conducted to detect the influence on rectum adenocarcinoma cells behaviors after over-expression of let-7d. Subsequently, the potential target gene of let-7d was predicted and identified through bioinformatics prediction analysis and luciferase reporter assay. Analyses against prognostic value and independent predictor were acquired from Kaplan-Meier, Univariate and Multivariate analysis of Cox regression. Finally, con-transfection experiments were performed to investigate let-7d/ABCC2 pairs function on rectum adenocarcinoma cells after co-transfected with let-7d mimic and si-ABCC2. mRNA and protein levels were assessed by reverse transcription quantitative polymerase chain reaction (qRT-PCR) and western blot. Results: The data from TCGA indicated that let-7d was down-regulated in rectum adenocarcinoma samples, whilst ABCC2 was showed a trend of high expression and its overexpression hinted to worse overall survival of rectum adenocarcinoma patients. Cells proliferation, invasion and migration properties were restrained after over-expression of let-7d in SW837 cells. Further investigations showed that over-expression of let-7d induced the inhibitory effect on SW837 cells proliferative, migrant and invasive capacities was augmented by silencing ABCC2. Conclusions: All results in this study indicated that up-regulation of let-7d could suppress SW837 cells growth, invasion and migration abilities by reducing ABCC2 expression, providing a new insight into molecular mechanism of let-7d/ABCC2 as a significant mediator for tumor progression and development of rectum adenocarcinoma.

Downregulated let-7d positively stimulates rectum adenocarcinoma cell malignant biological behaviors by upregulating ATP binding cassette subfamily C member 2.

BackgroundLet-7d has been reported to serve as a tumor suppressor in numerous cancers, however, the function in rectum adenocarcinoma has not been illuminated. In this study, we aimed to explore whether let-7d functions in rectum adenocarcinoma and its functional significance links to ATP binding cassette subfamily C member 2 (ABCC2).MethodsThe expression patterns of let-7d and ABCC2 were gained from TCGA database. Then, cell proliferation, invasion and migration assays were conducted to detect the influence on rectum adenocarcinoma cells behaviors after over-expression of let-7d. Subsequently, the potential target gene of let-7d was predicted and identified through bioinformatics prediction analysis and luciferase reporter assay. Analyses against prognostic value and independent predictor were acquired from Kaplan-Meier, Univariate and Multivariate analysis of Cox regression. Finally, con-transfection experiments were performed to investigate let-7d/ABCC2 pairs function on rectum adenocarcinoma cells after co-transfected with let-7d mimic and si-ABCC2. mRNA and protein levels were assessed by reverse transcription quantitative polymerase chain reaction (qRT-PCR) and western blot.ResultsThe data from TCGA indicated that let-7d was down-regulated in rectum adenocarcinoma samples, whilst ABCC2 was showed a trend of high expression and its overexpression hinted to worse overall survival of rectum adenocarcinoma patients. Cells proliferation, invasion and migration properties were restrained after over-expression of let-7d in SW837 cells. Further investigations showed that over-expression of let-7d induced the inhibitory effect on SW837 cells proliferative, migrant and invasive capacities was augmented by silencing ABCC2.ConclusionsAll results in this study indicated that up-regulation of let-7d could suppress SW837 cells growth, invasion and migration abilities by reducing ABCC2 expression, providing a new insight into molecular mechanism of let-7d/ABCC2 as a significant mediator for tumor progression and development of rectum adenocarcinoma.

Prognostic implication of ABC transporters and cancer stem cell markers in patients with stage III colon cancer receiving adjuvant FOLFOX‑4 chemotherapy

Cancer stem cell (CSC) and ATP-binding cassette (ABC) transporters are associated with treatment resistance and outcomes of patients with cancer. The present study investigated the prognostic implications of pre-therapeutic expression of ABC transporters and CSC markers in patients with colon cancer (CC) who received adjuvant 5-fluorouracil, leucovorin and oxaliplatin combination therapy (FOLFOX-4). The immunohistochemical expression of 3 ABC transporters, including ABC subfamily C member 2 (ABCC2), ABCC3 and ABC subfamily G member 2 (ABCG2), and 3 CSC markers, including sex determining region Y-box 2 (SOX2), leucine-rich repeat-containing G protein-coupled receptor 5 and aldehyde dehydrogenase 1, were determined in 164 CC tissues from patients with stage III CC, who underwent postoperative FOLFOX-4 chemotherapy. The association between the protein expression and patients' prognoses was statistically analyzed. ABCG2 was associated with favorable overall survival rate (OS; P=0.001), and ABCC2, ABCG2 and SOX2 were associated with increased disease-free survival rate (DFS; P=0.001, 0.002 and 0.013, respectively). In multivariate analyses, ABCG2 was an independent prognostic factor for OS [hazard ratio (HR)=2.877; P=0.046], and ABCC2 and SOX2 were independent prognostic factors for DFS (HR=2.831; P=0.014; HR=2.558, P=0.020, respectively). ABCC2, ABCG2 and SOX2 may be promising prognostic markers for patients with CC receiving FOLFOX-4 therapy.

Genetic variability of the ABCC2 gene and clinical outcomes in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients.

Pharmacogenetic variants and response to neoadjuvant single-agent doxorubicin or docetaxel: a study in locally advanced breast cancer patients participating in the NCT00123929 phase 2 randomized trial.

Taxanes and anthracyclines are widely used in the treatment of breast cancer, although the benefit is limited to a proportion of patients and predictive biomarkers for clinical outcome remain elusive. We carried out a pharmacogenetic study in 181 patients with locally advanced breast cancer enrolled in a phase 2 randomized clinical trial (NCT00123929), where patients were randomly assigned to receive neoadjuvant single-agent docetaxel 100 mg/m(2) (n=84) or doxorubicin 75 mg/m(2) (n=97). We studied the association of 226 single nucleotide polymorphisms (SNPs) in 15 key drug biotransformation genes with neoadjuvant pathological tumor response residual cancer burden index to docetaxel and to doxorubicin. We identified a significant association for rs162561, an intronic SNP located in the cytochrome P450 family 1 subfamily B member 1 (CYP1B1) gene, with tumor response in patients treated with single-agent docetaxel (dominant model: β=1.02, 95% confidence interval=0.49-1.55; P=1.77×10(-4)), and for rs717620, an SNP located in the promoter of the ATP-binding cassette subfamily C member 2 (ABCC2) gene, in patients treated with neoadjuvant doxorubicin (recessive model: β=1.67; 95% confidence interval=0.26-3.11; P=0.02). We identified two polymorphisms in CYP1B1 and ABCC2 associated with tumor pathological response following docetaxel or doxorubicin neoadjuvant monotherapy, respectively. Although further validation is required, these variants could be potential predictive genetic markers for treatment outcome in breast cancer patients.

Establishment of preclinical chemotherapy models for gastroenteropancreatic neuroendocrine carcinoma.

Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a rare and devastating malignancy, and preclinical studies are needed to evaluate potential therapeutic regimens. Here, we examined the antitumor effects of cisplatin (CDDP), etoposide (ETP) and irinotecan (CPT-11) and their combinations on GEP-NEC using three small-cell GEP-NEC cell lines (pancreatic NEC, A99; esophageal NEC, TYUC-1; duodenum NEC, TCC-NECT-2). In vitro studies were conducted using cell viability assays. In vivo experiments were conducted in mice inoculated with A99 or TCC-NECT-2 and treated with no agent, CDDP, CDDP+ETP (EP) or CDDP+CPT-11 (IP). TYUC-1 was the most susceptible to all agents, whereas A99 was refractory. Classical isobolograms showed synergism in both the EP and IP combinations for the three cell lines. In the TCC-NECT-2 mouse model, the IP regimen showed a significant antitumor effect, and CDDP alone showed a marginal effect compared to the control. In contrast, no effect was detected in the A99 model, probably because A99 was established from a metastatic tumor after chemotherapy with EP. Gene expression analysis of the ATP-binding cassette transporters revealed that ATP binding cassette subfamily B member1 (ABCB1) was conspicuously expressed in A99, and ABCB1 and ATP binding cassette subfamily C member2 (ABCC2) were deficient in TYUC-1, which might explain a part of different CDDP susceptibilities between cell lines. These preclinical models indicate that CDDP is a key agent, and IP regimen might be a reasonable option, although its efficacy is moderate. Our data on the platinum-based regimen will be useful as reference information in developing new agents for GEP-NEC.

Clinical, Pathologic, and Genetic Features of Neonatal Dubin-Johnson Syndrome: A Multicenter Study in Japan

To clarify the clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome. Ten patients with neonatal Dubin-Johnson syndrome were recruited from 6 pediatric centers in Japan between September 2013 and October 2016. Clinical and laboratory course, macroscopic and microscopic liver findings, and molecular genetic findings concerning ATP-binding cassette subfamily C member 2 (ABCC2) were retrospectively and prospectively examined. All neonates exhibited cholestasis, evident as prolonged jaundice with or without acholic stools and elevations of serum direct bilirubin as well as γ-glutamyltransferase or total bile acids. Only 38% (3 of 8) of patients who underwent liver biopsy showed a grossly black liver or melanin-like pigment deposits in hepatocytes; their biopsies were performed in early infancy. Immunohistochemically, all liver specimens showed no expression of multidrug resistance-associated protein 2 but increased expression of the bile salt export pump protein. Homozygous or compound heterozygous pathogenic variants of ABCC2 were identified in all patients, representing 11 distinct pathogenic variants including 2 not previously reported. Immunohistochemical staining of the liver for multidrug resistance-associated protein 2 and molecular genetic analysis of ABCC2 are crucial for accurate diagnosis of neonatal Dubin-Johnson syndrome.

ERLIN1 mutations cause teenage-onset slowly progressive ALS in a large Turkish pedigree.

Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with mostly dominant inheritance and a life expectancy of 2-5 years; however, a quite common occurrence of atypical forms of the disease, due to recessive inheritance, has become evident with the use of NGS technologies. In this paper, we describe a family with close consanguinity for at least four generations, suffering from a slowly progressive form of ALS. Spastic walking is observed since teenage years, while bulbar symptoms start much later, at the fifth or sixth decade of life. Patients usually die because of respiratory failure. Using whole-exome sequencing, we identified a novel homozygous p.(Val94Ala) (c.281T>C) (NG_052910.1) (NM_006459) variation in the endoplasmic reticulum lipid raft associated protein 1 (ERLIN1) gene, which segregates with the disease in the family. Here we suggest that ERLIN1 variants, previously shown in juvenile hereditary spastic paraplegia cases, may also be the cause of a slowly progressive early-onset ALS, starting with upper motor neuron features and developing into classical ALS with the addition of lower motor neuron dysfunction. We also demonstrate that ATP-binding cassette subfamily C member 2 (ABCC2) gene, responsible for hyperbilirubinemia, is linked to ERLIN1.

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder.

Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy. Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity. CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel. Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201. Clin Cancer Res; 23(2); 503-13. ©2016 AACR.

Associations of genetic polymorphisms of the transporters organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), and ATP-binding cassette subfamily C member 2 (ABCC2) with platinum-based chemotherapy response and toxicity in non-small cell lung cancer patients.

BackgroundPlatinum-based chemotherapy is the first-line treatment of non-small cell lung cancer (NSCLC); it is therefore important to discover biomarkers that can be used to predict the efficacy and toxicity of this treatment. Four important transporter genes are expressed in the kidney, including organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), ATP-binding cassette subfamily B member 1 (ABCB1), and ATP-binding cassette subfamily C member 2 (ABCC2), and genetic polymorphisms in these genes may alter the efficacy and adverse effects of platinum drugs. This study aimed to evaluate the association of genetic polymorphisms of these transporters with platinum-based chemotherapy response and toxicity in NSCLC patients.MethodsA total of 403 Chinese NSCLC patients were recruited for this study. All patients were newly diagnosed with NSCLC and received at least two cycles of platinum-based chemotherapy. The tumor response and toxicity were evaluated after two cycles of treatment, and the patients’ genomic DNA was extracted. Seven single-nucleotide polymorphisms in four transporter genes were selected to investigate their associations with platinum-based chemotherapy toxicity and response.ResultsOCT2 rs316019 was associated with hepatotoxicity (P = 0.026) and hematological toxicity (P = 0.039), and MATE1 rs2289669 was associated with hematological toxicity induced by platinum (P = 0.016). In addition, ABCC2 rs717620 was significantly associated with the platinum-based chemotherapy response (P = 0.031). ABCB1 polymorphisms were associated with neither response nor toxicity.ConclusionOCT2 rs316019, MATE1 rs2289669, and ABCC2 rs717620 might be potential clinical markers for predicting chemotherapy toxicity and response induced by platinum-based treatment in NSCLC patients.Trial registration Chinese Clinical Trial Registry ChiCTR-RNC-12002892

Association of ABCC2 −24C&gt;T Polymorphism with High-Dose Methotrexate Plasma Concentrations and Toxicities in Childhood Acute Lymphoblastic Leukemia

Methotrexate (MTX) is a key agent for the treatment of childhood acute lymphoblastic leukemia (ALL). Increased MTX plasma concentrations are associated with a higher risk of adverse drug effects. ATP-binding cassette subfamily C member 2 (ABCC2) is important for excretion of MTX and its toxic metabolite. The ABCC2 −24C>T polymorphism (rs717620) reportedly contributes to variability of MTX kinetics. In the present study, we assessed the association between the ABCC2 −24C>T polymorphism and methotrexate (MTX) toxicities in childhood ALL patients treated with high-dose MTX. A total of 112 Han Chinese ALL patients were treated with high-dose MTX according to the ALL-Berlin-Frankfurt-Muenster 2000 protocol. Our results showed that presence of the −24T allele in ABCC2 gene led to significantly higher MTX plasma concentrations at 48 hours after the start of infusion, which would strengthen over repeated MTX infusion. The −24T allele in ABCC2 gene was significantly associated with higher risks of high-grade hematologic (leucopenia, anemia, and thrombocytopenia) and non-hematologic (gastrointestinal and mucosal damage/oral mucositis) MTX toxicities. This study provides the first evidence that the −24T allele in ABCC2 gene is associated with the severity of MTX toxicities, which add fresh insights into clinical application of high-dose MTX and individualization of MTX treatment.

Influence of 144 candidate genetic polymorphisms on statin treatment in Han Chinese

ObjectiveWe aimed to assess the influence of candidate genetic variation on statin efficacy in a cardiovascular disease (CVD)-high-risk Chinese population to elucidate the inherited genetic underpinnings, which would further direct...

Cytochrome P450 2D6 (CYP2D6); ATP-binding cassette sub-family C member 2 (ABCC2)

Cytochrome P450 2D6 (CYP2D6); ATP-binding cassette sub-family C member 2 (ABCC2)