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Wang Y, Ding N, Zhao Y, Wang F, Liu W, Chen Z, Sun W, Gu L, Zhang Y. Design, synthesis, and biological evaluation of β-carboline derivatives as ABCB1 inhibitors for reversing multidrug resistance. Eur J Med Chem 2025; 288:117390. [PMID: 39965407 DOI: 10.1016/j.ejmech.2025.117390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/30/2025] [Accepted: 02/10/2025] [Indexed: 02/20/2025]
Abstract
The scarcity of ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein, P-gp) inhibitors suitable for clinical application in improving multidrug resistance (MDR) promotes the development of drugs aimed at reversing MDR. In this work, we reported a comprehensive study for the first time about the reversal activity of β-carboline derivatives on ABCB1-mediated MDR. Among 48 synthesized derivatives, compound K27 significantly increased the sensitivity of ABCB1-mediated MDR SW620/AD300 cells to paclitaxel (PTX) (IC50 = 15.33 ± 5.4 nM, RF = 171.2) and hardly showed toxicity even at a high concentration of 20 μM when used alone. The in vitro studies indicated that compound K27 distinctly enhanced the arresting effect of PTX on the SW620/AD300 cell cycle, thereby inhibiting their proliferation. Mechanistically, compound K27 was confirmed to directly bind to ABCB1 to inhibit efflux function, reducing cellular efflux and ensuring stable intracellular concentration of PTX without affecting ABCB1's normal expression. Importantly, the combination of compound K27 and PTX exhibited potent tumor suppression in vivo without generating toxicity. These results demonstrated that β-carboline compounds represented by compound K27 may be potent ABCB1 inhibitors with considerable potential in effectively reversing ABCB1-mediated MDR, showing promising prospects.
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Affiliation(s)
- Yuanyuan Wang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Nanjin Ding
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yunpeng Zhao
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fengqing Wang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wen Liu
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhe Chen
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Weiguang Sun
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Lianghu Gu
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Yonghui Zhang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Steigert S, Brouwers J, Vanuytsel T, Verbandt S, Tejpar S, Oswald S, Augustijns P. Protein abundance of drug transporters and drug-metabolizing enzymes in paired healthy and tumor tissue from colorectal cancer patients. Int J Pharm 2025; 671:125216. [PMID: 39809348 DOI: 10.1016/j.ijpharm.2025.125216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/08/2025] [Accepted: 01/11/2025] [Indexed: 01/16/2025]
Abstract
The widespread prevalence of colorectal cancer and its high mortality rate emphasize the urgent need for more effective therapies. When developing new drug products, a key aspect is ensuring that sufficiently high concentrations of the active drug are reached at the site of action. Drug transporters and drug-metabolizing enzymes can significantly influence the absorption and local accumulation of drugs in intestinal tissue. To understand how their presence may affect local drug disposition, the protein abundance of multiple drug transporters and drug-metabolizing enzymes was quantified in paired healthy colonic mucosa and colorectal adenocarcinoma tissue from colorectal cancer patients, utilizing mass spectrometry-based targeted proteomics. Statistically significant changes in protein expression were observed for two transporters (MRP1 and BCRP) and three of the studied enzymes (CES1, CES2 and UGT2B17). MRP1 displayed higher levels in cancerous tissue compared to healthy mucosa samples, while BCRP, CES1, CES2 and UGT2B17 showed the opposite. Other proteins of interest which could be quantified in colonic samples were the drug transporters P-gp, MRP3, MRP4, OATP2B1, MCT1 and enzymes CYP4F2, CYP2J2 and UGT1A1. The insights from this study enhance our understanding of the extent to which drug disposition in tumor tissue of colorectal cancer patients could be impacted by drug transporters and drug-metabolizing enzymes and may facilitate a more accurate prediction of local drug concentrations.
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Affiliation(s)
- Sebastian Steigert
- Drug Delivery and Disposition, KU Leuven, Gasthuisberg ON2, Herestraat 49 - box 921, 3000 Leuven, Belgium
| | - Joachim Brouwers
- Drug Delivery and Disposition, KU Leuven, Gasthuisberg ON2, Herestraat 49 - box 921, 3000 Leuven, Belgium
| | - Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders, TARGID, KU Leuven, Gasthuisberg ON1, Herestraat 49 - box 701, 3000 Leuven, Belgium
| | - Sara Verbandt
- Digestive Oncology, Department of Oncology, Gasthuisberg ON4, Herestraat 49 - box 603, 3000 Leuven, Belgium
| | - Sabine Tejpar
- Digestive Oncology, Department of Oncology, Gasthuisberg ON4, Herestraat 49 - box 603, 3000 Leuven, Belgium
| | - Stefan Oswald
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, 18057 Rostock, Germany
| | - Patrick Augustijns
- Drug Delivery and Disposition, KU Leuven, Gasthuisberg ON2, Herestraat 49 - box 921, 3000 Leuven, Belgium.
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Kaidi D, Odin E, Wettergren Y, Bexe Lindskog E. Prognostic value of folate-associated gene expression in stage II colon cancer. J Cancer Res Clin Oncol 2025; 151:92. [PMID: 39998667 PMCID: PMC11861115 DOI: 10.1007/s00432-025-06141-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/13/2025] [Indexed: 02/27/2025]
Abstract
PURPOSE Prognostic variability in stage II colon cancer underscores the need for better risk stratification. Analyzing folate-associated gene expression in stage II colon cancer could provide researchers and clinicians with deeper insights into tumor biology and potentially aid in identifying early prognostic and/or predictive biomarkers. METHODS Patients with stage II colon cancer and recurrence (n = 48) were matched to patients with a 5 year recurrence-free follow-up (n = 133). Gene expression of ABCC3, AMT, FPGS, GGH, MFT, PCFT, RFC-1, and TYMS was analyzed in tumor tissue and matching colon mucosa using qPCR and evaluated in relation to time to recurrence (TTR), as well as to demographic and clinicopathological variables. RESULTS Independent of other covariates, TYMS expression in tumors, pT4 stage, and emergency surgery were associated with TTR. There were significant differences in expression levels of all examined genes between tumor and mucosa. ABCC3, GGH, and RFC-1 expression levels differed in mucosa between microsatellite instability-high (MSI-H) compared to microsatellite stable/microsatellite instability-low (MSS/MSI-L) tumors, whereas tumoral expression of AMT, GGH, and TYMS differed between MSI-H and MSS/MSI-L tumors. Depending on tumor location, the expression of ABCC3, AMT, GGH, and RFC-1 in mucosa, as well as the tumoral expression of AMT, GGH, PCFT and RFC-1 differed. CONCLUSION Low tumoral expression of TYMS was associated with worse TTR, independent of MSI status, pT stage, and emergency surgery. The indication of a better outcome for patients with MSI-H status and high tumoral TYMS expression might be of particular interest in the stratification of patients for immunotherapy.
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Affiliation(s)
- Donia Kaidi
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Östra, 416 85, Gothenburg, Sweden
| | - Elisabeth Odin
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Östra, 416 85, Gothenburg, Sweden
| | - Elinor Bexe Lindskog
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Östra, 416 85, Gothenburg, Sweden.
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Zuo Y, Li T, Yang S, Chen X, Tao X, Dong D, Liu F, Zhu Y. Contribution and expression of renal drug transporters in renal cell carcinoma. Front Pharmacol 2025; 15:1466877. [PMID: 40034145 PMCID: PMC11873565 DOI: 10.3389/fphar.2024.1466877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 12/23/2024] [Indexed: 03/05/2025] Open
Abstract
Renal cell carcinoma (RCC) is a common substantive tumor. According to incomplete statistics, RCC incidence accounts for approximately 90% of renal malignant tumors, and is the second most prevalent major malignant tumor in the genitourinary system, following bladder cancer. Only 10%-15% of chemotherapy regimens for metastatic renal cell carcinoma (mRCC) are effective, and mRCC has a high mortality. Drug transporters are proteins located on the cell membrane that are responsible for the absorption, distribution, and excretion of drugs. Lots of drug transporters are expressed in the kidneys. Changes in carrier function weaken balance, cause disease, or modify the effectiveness of drug treatment. The changes in expression of these transporters during cancer pathology results in multi-drug resistance to cancer chemotherapy. In the treatment of RCC, the study of drug transporters helps to optimize treatment regimens, improve therapeutic effects, and reduce drug side effects. In this review, we summarize advances in the role of renal drug transporters in the genesis, progression, and treatment of RCC.
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Affiliation(s)
- Yawen Zuo
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Tong Li
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shilei Yang
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xuyang Chen
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xufeng Tao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Deshi Dong
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fang Liu
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yanna Zhu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
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Moiz S, Saha B, Mondal V, Bishnu D, Das B, Bose B, Das S, Banerjee N, Dutta A, Chatterjee K, Goswami S, Mukhopadhyay S, Basu S. Differential Expression of miRNAs Between Young-Onset and Late-Onset Indian Colorectal Carcinoma Patients. Noncoding RNA 2025; 11:10. [PMID: 39997610 PMCID: PMC11858122 DOI: 10.3390/ncrna11010010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/13/2025] [Accepted: 01/21/2025] [Indexed: 02/26/2025] Open
Abstract
Reports indicate a worldwide increase in the incidence of Early-Onset Colorectal Carcinoma (EOCRC) (<50 years old). In an effort to understand the different modes of pathogenesis in early-onset CRC, colorectal tumors from EOCRC (<50 years old) and Late-Onset patients (LOCRC; >50 years old) were screened to eliminate microsatellite instability (MSI), nuclear β-catenin, and APC mutations, as these are known canonical factors in CRC pathogenesis. Small-RNA sequencing followed by comparative analysis revealed differential expression of 23 miRNAs (microRNAs) specific to EOCRC and 11 miRNAs specific to LOCRC. We validated the top 10 EOCRC DEMs in TCGA-COAD and TCGA-READ cohorts, followed by validation in additional EOCRC and LOCRC cohorts. Our integrated analysis revealed upregulation of hsa-miR-1247-3p and hsa-miR-148a-3p and downregulation of hsa-miR-326 between the two subsets. Experimentally validated targets of the above miRNAs were compared with differentially expressed genes in the TCGA dataset to identify targets with physiological significance in EOCRC development. Our analysis revealed metabolic reprogramming, downregulation of anoikis-regulating pathways, and changes in tissue morphogenesis, potentially leading to anchorage-independent growth and progression of epithelial-mesenchymal transition (EMT). Upregulated targets include proteins present in the basal part of intestinal epithelial cells and genes whose expression is known to correlate with invasion and poor prognosis.
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Affiliation(s)
- Sumaiya Moiz
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
| | - Barsha Saha
- Biotechnology Research and Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani 741251, India; (B.S.); (S.G.)
- Regional Centre for Biotechnology, 3rd Milestone, Faridabad-Gurugram Expressway, Faridabad 121001, India
| | - Varsha Mondal
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA
| | - Debarati Bishnu
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
| | - Biswajit Das
- Department of Histopathology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India; (B.D.); (N.B.); (A.D.); (K.C.)
| | - Bodhisattva Bose
- Department of Surgical Oncology, All India Institute of Medical Sciences (AIIMS), Rishikesh 249203, India;
- Department of General Surgery, Nil Ratan Sircar Medical College and Hospital, Kolkata 700014, India
| | - Soumen Das
- Department of Surgical Oncology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India;
| | - Nirmalya Banerjee
- Department of Histopathology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India; (B.D.); (N.B.); (A.D.); (K.C.)
- Department of Histopathology, Narayana Superspeciality Hospital, Kolkata 700099, India
| | - Amitava Dutta
- Department of Histopathology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India; (B.D.); (N.B.); (A.D.); (K.C.)
| | - Krishti Chatterjee
- Department of Histopathology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India; (B.D.); (N.B.); (A.D.); (K.C.)
- Department of Pathology, Neotia Bhagirathi Woman and Child Care Centre, Kolkata 700017, India
| | - Srikanta Goswami
- Biotechnology Research and Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani 741251, India; (B.S.); (S.G.)
- Regional Centre for Biotechnology, 3rd Milestone, Faridabad-Gurugram Expressway, Faridabad 121001, India
| | - Soma Mukhopadhyay
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
| | - Sudarshana Basu
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
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Marques AVL, Ruginsk BE, Prado LDO, de Lima DE, Daniel IW, Moure VR, Valdameri G. The association of ABC proteins with multidrug resistance in cancer. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119878. [PMID: 39571941 DOI: 10.1016/j.bbamcr.2024.119878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 11/07/2024] [Accepted: 11/10/2024] [Indexed: 11/28/2024]
Abstract
Multidrug resistance (MDR) poses one of the primary challenges for cancer treatment, especially in cases of metastatic disease. Various mechanisms contribute to MDR, including the overexpression of ATP-binding cassette (ABC) proteins. In this context, we reviewed the literature to establish a correlation between the overexpression of ABC proteins and MDR in cancer, considering both in vitro and clinical studies. Initially, we presented an overview of the seven subfamilies of ABC proteins, along with the subcellular localization of each protein. Subsequently, we identified a panel of 20 ABC proteins (ABCA1-3, ABCA7, ABCB1-2, ABCB4-6, ABCC1-5, ABCC10-11, ABCE1, ABCF2, ABCG1, and ABCG2) associated with MDR. We also emphasize the significance of drug sequestration by certain ABC proteins into intracellular compartments. Among the anticancer drugs linked to MDR, 29 were definitively identified as substrates for at least one of the three most crucial ABC transporters: ABCB1, ABCC1, and ABCG2. We further discussed that the most commonly used drugs in standard regimens for mainly breast cancer, lung cancer, and acute lymphoblastic leukemia could be subject to MDR mediated by ABC transporters. Collectively, these insights will aid in conducting new studies aimed at a deeper understanding of the clinical MDR mediated by ABC proteins and in designing more effective pharmacological treatments to enhance the objective response rate in cancer patients.
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Affiliation(s)
- Andrezza Viviany Lourenço Marques
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Bruna Estelita Ruginsk
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Larissa de Oliveira Prado
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Diogo Eugênio de Lima
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Isabelle Watanabe Daniel
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Vivian Rotuno Moure
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil.
| | - Glaucio Valdameri
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil.
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Pilotto Heming C, de Souza Barbosa I, Lyra Miranda R, Nogueira Ugarte O, Santório de São José V, Moura Neto V, Aran V. P-Glycoprotein Drives Glioblastoma Survival and Chemotherapy Resistance: Potential as a Promising Liquid Biopsy Biomarker. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(24)00476-0. [PMID: 39788485 DOI: 10.1016/j.ajpath.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/21/2024] [Accepted: 12/03/2024] [Indexed: 01/12/2025]
Abstract
Drug resistance is a major challenge in cancer therapy, and the expression of efflux pumps such as P-glycoprotein (P-gp, ABCB1) often correlates with poor prognosis in various tumors, including glioblastoma (GB). Considering that different roles for these proteins have been established in the biology of various tumors, this study aimed to investigate the functions of P-gp in GB-derived cells by evaluating its survival, migratory, and apoptosis-regulating capabilities, as well as its potential as a liquid biopsy biomarker. P-gp expression was diminished via siRNA to determine its exact role in GB biology. The P-gp mRNA levels were evaluated by using quantitative real-time RT-PCR. With respect to liquid biopsy, circulating cell-free RNA was extracted from plasma belonging to patients diagnosed with GB, and P-gp levels were compared with matching tumor tissues using digital PCR. P-gp silencing significantly decreased viability, increased apoptosis, and enhanced chemotherapy sensitivity in GB cells, although it did not affect migratory patterns. Finally, P-gp expression levels in circulating cell-free RNA from patients with GB matched tumor tissue, whereas healthy volunteers appeared to bear no circulating P-gp. Taken together, the results indicate that P-gp affects GB tumor biology beyond its known role in drug resistance and could integrate a broader molecular signature for future diagnosis via liquid biopsy.
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Affiliation(s)
- Carlos Pilotto Heming
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil; Post-Graduate Program in Anatomic Pathology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Isabel de Souza Barbosa
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil; Post-Graduate Program in Anatomic Pathology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Renan Lyra Miranda
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil
| | | | | | - Vivaldo Moura Neto
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil
| | - Veronica Aran
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil; Post-Graduate Program in Anatomic Pathology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
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Phon BWS, Chelliah SS, Osman DER, Bhuvanendran S, Radhakrishnan AK, Kamarudin MNA. Revisiting ABC Transporters and Their Clinical Significance in Glioblastoma. Pharmaceuticals (Basel) 2025; 18:102. [PMID: 39861164 PMCID: PMC11769420 DOI: 10.3390/ph18010102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/08/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Background: The multiple drug-resistant phenomenon has long since plagued the effectiveness of various chemotherapies used in the treatment of patients with glioblastoma (GBM), which is still incurable to this day. ATP-binding cassette (ABC) transporters function as drug transporters and have been touted to be the main culprits in developing resistance to xenobiotic drugs in GBM. Methods: This review systematically analyzed the efficacy of ABC transporters against various anticancer drugs from 16 studies identified from five databases (PubMed, Medline, Embase, Scopus, and ScienceDirect). Results: Inhibition of ABC transporters, especially ABCB1, improved drug efficacies. Staple GBM phenotypes, such as GBM stem cells and increased activation of the PI3K/Akt/NF-κB pathway, have been implicated in the expression of several ABC transporters. Using the datasets in The Cancer Genome Atlas and Gene Expression Omnibus, we found upregulated ABC transporters that either negatively impacted survival in univariate analyses (ABCA1, ABCA13, ABCB9, ABCD4) or were independent negative prognosis factors for patients with GBM (ABCA13, ABCB9). Our multivariate analysis further demonstrated three ABC transporters, ABCA13 (Hazard Ratio (HR) = 1.31, p = 0.017), ABCB9 (HR = 1.26, p = 0.03), and ABCB5 (HR = 0.77, p = 0.016), with the administration of alkylating agents (HR = 0.41, p < 0.001), were independent negative prognosis factors for patients with GBM. Conclusions: These findings reinforce the important role played by ABC transporters, particularly by ABCA13, ABCB9, and ABCB1, which could be potential targets that warrant further evaluations for alternate strategies to augment the effects of existing alkylating agents and xenobiotic drugs.
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Affiliation(s)
- Brandon Wee Siang Phon
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia; (B.W.S.P.); (S.S.C.); (D.E.-R.O.); (S.B.); (A.K.R.)
| | - Shalini Sundramurthi Chelliah
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia; (B.W.S.P.); (S.S.C.); (D.E.-R.O.); (S.B.); (A.K.R.)
- Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia
| | - Dina El-Rabie Osman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia; (B.W.S.P.); (S.S.C.); (D.E.-R.O.); (S.B.); (A.K.R.)
| | - Saatheeyavaane Bhuvanendran
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia; (B.W.S.P.); (S.S.C.); (D.E.-R.O.); (S.B.); (A.K.R.)
| | - Ammu Kutty Radhakrishnan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia; (B.W.S.P.); (S.S.C.); (D.E.-R.O.); (S.B.); (A.K.R.)
| | - Muhamad Noor Alfarizal Kamarudin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia; (B.W.S.P.); (S.S.C.); (D.E.-R.O.); (S.B.); (A.K.R.)
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Döring H, Kreutzer D, von Veh J, Ritter CA, Hilgeroth A. Evaluation of Novel Diaza Cage Compounds as MRP Modulators in Cancer Cells. Anticancer Agents Med Chem 2025; 25:63-74. [PMID: 39219427 DOI: 10.2174/0118715206331206240828111126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/02/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
AIM Novel MRP modulators are needed to combat MRP-mediated multidrug resistance (MDR) in cancer cells. BACKGROUND Anticancer drug resistance is the main problem in cancer therapy. Causative multidrug efflux pumps are attractive target structures for the development of inhibitors of their activity. OBJECTIVE We synthesized novel cage dimeric 1,4-dihydropyridines to evaluate them as MRP modulators in cancer cells targeting MRP1, MRP2, and MRP4. METHODS Cage compounds were synthesized by solution dimerization of monomeric 1,4-dihydropyridines and a final functionalization reaction. The MRP modulation was determined in cellular efflux assays by the use of the flow cytometry technique as well as cellular fluorescent measurements with each fluorescent substrate of the efflux pumps. RESULTS Difluoro phenyl and methoxy or dimethoxy benzyl substitutions were most favourable for the MRP1 and MRP2 inhibition, whereas monofluor phenyl and dimethoxy benzyl substitutions were most favourable for the MRP4 inhibition. CONCLUSION Effective inhibitors were identified that were demonstrated to restore the respective cancer cell line sensitivity for the anticancer drug as a proof-of-concept that encourages further preclinical studies.
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Affiliation(s)
- Henry Döring
- Institute of Pharmacy, Martin-Luther, University Halle, Wittenberg, Wolfgang, Langenbeck-Str. 4, 06120 Halle, Germany
| | - David Kreutzer
- Institute of Pharmacy, Martin-Luther, University Halle, Wittenberg, Wolfgang, Langenbeck-Str. 4, 06120 Halle, Germany
| | - Jannis von Veh
- Institute of Pharmacy, Martin-Luther, University Halle, Wittenberg, Wolfgang, Langenbeck-Str. 4, 06120 Halle, Germany
| | - Christoph A Ritter
- Institute of Pharmacy, University of Greifswald, Friedrich, Ludwig, Jahn, Str. 17, 17489 Greifswald, Germany
| | - Andreas Hilgeroth
- Institute of Pharmacy, Martin-Luther, University Halle, Wittenberg, Wolfgang, Langenbeck-Str. 4, 06120 Halle, Germany
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10
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Bhattacharjya D, Sivalingam N. Mechanism of 5-fluorouracil induced resistance and role of piperine and curcumin as chemo-sensitizers in colon cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8445-8475. [PMID: 38878089 DOI: 10.1007/s00210-024-03189-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 05/27/2024] [Indexed: 10/30/2024]
Abstract
Among cancer-related deaths worldwide, colorectal cancer ranks second, accounting for 1.2% of deaths in those under 50 years and 0.6% of deaths in those between 50 and 54 years. The anticancer drug 5-fluorouracil is widely used to treat colorectal cancer. Due to a better understanding of the drug's mechanism of action, its anticancer activity has been increased through a variety of therapeutic alternatives. Clinical use of 5-FU has been severely restricted due to drug resistance. The chemoresistance mechanism of 5-FU is challenging to overcome because of the existence of several drug efflux transporters, DNA repair enzymes, signaling cascades, classical cellular processes, cancer stem cells, metastasis, and angiogenesis. Curcumin, a potent phytocompound derived from Curcuma longa, functions as a nuclear factor (NF)-κB inhibitor and sensitizer to numerous chemotherapeutic drugs. Piperine, an alkaloid found in Piper longum, inhibits cancer cell growth, causing cell cycle arrest and apoptosis. This review explores the mechanism of 5-FU-induced chemoresistance in colon cancer cells and the role of curcumin and piperine in enhancing the sensitivity of 5-FU-based chemotherapy. CLINICAL TRIAL REGISTRATION: Not applicable.
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Affiliation(s)
- Dorothy Bhattacharjya
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603 203, Chengalpattu District, Tamil Nadu, India
| | - Nageswaran Sivalingam
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603 203, Chengalpattu District, Tamil Nadu, India.
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11
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El-Daly SM, Gouhar SA, Abdelrahman SS. Inflammation alters the expression pattern of drug transporters during Caco-2 cell stimulation and azoxymethane-induced colon tumorigenesis. J Biochem Mol Toxicol 2024; 38:e23815. [PMID: 39171650 DOI: 10.1002/jbt.23815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/15/2024] [Accepted: 08/13/2024] [Indexed: 08/23/2024]
Abstract
Drug transporters play a pivotal role in modulating drug disposition and are subject to alterations under inflammatory conditions. This study aimed to elucidate the intricate expression patterns of drug transporters during both acute and chronic inflammation, which are closely linked to malignant transformation. To investigate acute inflammation, we employed an in vitro model by subjecting Caco-2 cells to various inflammatory stimuli (IL-1β, TNF-α, or LPS) individually or in combination. The successful induction of inflammation was confirmed by robust increases in IL-6 and NO production. Notably, inflamed Caco-2 cells exhibited significantly diminished levels of ABCB1 and ABCG2, while the expression of ABCC2 was upregulated. For chronic inflammation induction in vivo, we employed the well-established AOM/DSS mouse model known for its association with colitis-driven tumorigenesis. Persistent inflammation was effectively monitored throughout the experiment via elevated IL-6 and NO levels. The sequential stages of tumorigenesis were confirmed through Ki-67 immunohistochemistry. Intriguingly, we observed gradual alterations in the expression patterns of the studied drug transporters during stepwise induction, with ABCB1, ABCG2, and ABCC1 showing downregulation and ABCC2 exhibiting upregulation. Immunohistochemistry further revealed dynamic changes in the expression of ABCB1 and ABCC2 during the induction cycles, closely paralleling the gradual increase in Ki-67 expression observed during the development of precancerous lesions. Collectively, our findings underscore the significant impact of inflammation on drug transporter expression, potentially influencing the process of malignant transformation of the colon.
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Affiliation(s)
- Sherien M El-Daly
- Medical Biochemistry Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Giza, Egypt
| | - Shaimaa A Gouhar
- Medical Biochemistry Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Sahar S Abdelrahman
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
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12
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Eisa A, Hanafy SM, Khalil H, Elshal MF. Sitagliptin synergizes 5-fluorouracil efficacy in colon cancer cells through MDR1-mediated flux impairment and down regulation of NFκB2 and p-AKT survival proteins. J Biochem Mol Toxicol 2024; 38:e23796. [PMID: 39087923 DOI: 10.1002/jbt.23796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/11/2024] [Accepted: 07/24/2024] [Indexed: 08/02/2024]
Abstract
5-fluorouracil (5-FU) is an inexpensive treatment for colon cancer; however, its efficacy is limited by chemoresistance. This study investigates the combination therapy approach of 5-FU with Sitagliptin (Sita), a diabetic drug with potential cancer-modulating effects. The combination was evaluated in vitro and in silico, focusing on the effects of Sita and 5-FU on colon cancer cells. The results showed that the addition of Sita significantly decreased the IC50 of 5-FU compared to 5-Fu monotherapy. The study also found that Sita and 5-FU interact synergistically, with a combination index below 1. Sita successfully lowered the 5-FU dosage reduction index, decreasing the expression of MDR1 mRNA and p-AKT and NFκB2 subunits p100/p52 protein. Molecular docking analyses confirmed Sita's antagonistic action on MDR1 and thymidylate synthase proteins. The study concludes that sitagliptin can target MDR1, increase apoptosis, and significantly reduce the expression of p-AKT and NFκB2 cell-survival proteins. These effects sensitize colon cancer cells to 5-FU. Repurposing sitagliptin may enhance the anticancer effects of 5-FU at lower dosages.
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Affiliation(s)
- Asmaa Eisa
- Molecular Biology Department, Genetic Engineering and Biotechnology Institute, University of Sadat City, Sadat City, Egypt
| | - Shaden M Hanafy
- Molecular Biology Department, Genetic Engineering and Biotechnology Institute, University of Sadat City, Sadat City, Egypt
| | - Hany Khalil
- Molecular Biology Department, Genetic Engineering and Biotechnology Institute, University of Sadat City, Sadat City, Egypt
| | - Mohamed F Elshal
- Molecular Biology Department, Genetic Engineering and Biotechnology Institute, University of Sadat City, Sadat City, Egypt
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13
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Ousalem F, Ngo S, Oïffer T, Omairi-Nasser A, Hamon M, Monlezun L, Boël G. Global regulation via modulation of ribosome pausing by the ABC-F protein EttA. Nat Commun 2024; 15:6314. [PMID: 39060293 PMCID: PMC11282234 DOI: 10.1038/s41467-024-50627-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Having multiple rounds of translation of the same mRNA creates dynamic complexities along with opportunities for regulation related to ribosome pausing and stalling at specific sequences. Yet, mechanisms controlling these critical processes and the principles guiding their evolution remain poorly understood. Through genetic, genomic, physiological, and biochemical approaches, we demonstrate that regulating ribosome pausing at specific amino acid sequences can produce ~2-fold changes in protein expression levels which strongly influence cell growth and therefore evolutionary fitness. We demonstrate, both in vivo and in vitro, that the ABC-F protein EttA directly controls the translation of mRNAs coding for a subset of enzymes in the tricarboxylic acid (TCA) cycle and its glyoxylate shunt, which modulates growth in some chemical environments. EttA also modulates expression of specific proteins involved in metabolically related physiological and stress-response pathways. These regulatory activities are mediated by EttA rescuing ribosomes paused at specific patterns of negatively charged residues within the first 30 amino acids of nascent proteins. We thus establish a unique global regulatory paradigm based on sequence-specific modulation of translational pausing.
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Affiliation(s)
- Farès Ousalem
- Expression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-Chimique, Paris, France
- Biomarqueurs et nouvelles cibles thérapeutiques en oncologie, INSERM U981, Université Paris Saclay, Institut de Cancérologie Gustave Roussy, Villejuif Cedex, France
| | - Saravuth Ngo
- Expression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-Chimique, Paris, France
| | - Thomas Oïffer
- Expression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-Chimique, Paris, France
| | - Amin Omairi-Nasser
- Expression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-Chimique, Paris, France
| | - Marion Hamon
- CNRS, Institut de Biologie Physico-Chimique, Plateforme de Protéomique, FR550, Paris, France
| | - Laura Monlezun
- Expression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-Chimique, Paris, France
| | - Grégory Boël
- Expression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-Chimique, Paris, France.
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14
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Hon KW, Naidu R. Synergistic Mechanisms of Selected Polyphenols in Overcoming Chemoresistance and Enhancing Chemosensitivity in Colorectal Cancer. Antioxidants (Basel) 2024; 13:815. [PMID: 39061884 PMCID: PMC11273411 DOI: 10.3390/antiox13070815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/29/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Despite significant advances in medical treatment, chemotherapy as monotherapy can lead to substantial side effects and chemoresistance. This underscores the need for therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Polyphenols represent a diverse group of natural compounds that can target multiple signaling pathways in cancer cells to induce anti-cancer effects. Additionally, polyphenols have been shown to work synergistically with chemotherapeutics and other natural compounds in cancer cells. This review aims to provide a comprehensive insight into the synergistic mechanisms of selected polyphenols as chemosensitizers in CRC cells. Further research and clinical trials are warranted to fully harness the synergistic mechanisms of selected polyphenols combined with chemotherapy or natural compounds in improving cancer treatment outcomes.
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Affiliation(s)
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;
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15
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Długosz-Pokorska A, Janecki T, Janecka A, Gach-Janczak K. New uracil analog as inhibitor/modulator of ABC transporters or/and NF-κB in taxol-resistant MCF-7/Tx cell line. J Cancer Res Clin Oncol 2024; 150:328. [PMID: 38914845 PMCID: PMC11196363 DOI: 10.1007/s00432-024-05833-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 06/03/2024] [Indexed: 06/26/2024]
Abstract
PURPOSE The global increase in breast cancer cases necessitates ongoing exploration of advanced therapies. Taxol (Tx), an initial breast cancer treatment, induces mitotic arrest but faces limitations due to side effects and the development of resistance. Addressing Tx resistance involves understanding the complex molecular mechanisms, including alterations in tubulin dynamics, NF-κB signaling, and overexpression of ABC transporters (ABCB1 and ABCG2), leading to multidrug resistance (MDR). METHODS Real-time PCR and ELISA kits were used to analyze ABCB1, ABCG2 and NF-κB gene and protein expression levels, respectively. An MDR test assessed the resistance cell phenotype. RESULTS MCF-7/Tx cells exhibited a 24-fold higher resistance to Tx. Real-time PCR and ELISA analysis revealed the upregulation of ABCB1, ABCG2, and NF-κB. U-359 significantly downregulated both ABCB1 and ABCG2 gene and protein levels. Co-incubation with Tx and U-359 further decreased the mRNA and protein expression of these transporters. The MDR test indicated that U-359 increased MDR dye retention, suggesting its potential as an MDR inhibitor. U-359 and Tx, either individually or combined, modulated NF-κBp65 protein levels. CONCLUSION The development of a Taxol-resistant MCF-7 cell line provided valuable insights. U-359 demonstrated effectiveness in reducing the expression of ABC transporters and NF-κB, suggesting a potential solution for overcoming multidrug resistance in breast cancer cells. The study recommends a strategy to enhance the sensitivity of cancer cells to chemotherapy by integrating U-359 with traditional drugs.
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MESH Headings
- Humans
- Paclitaxel/pharmacology
- Drug Resistance, Neoplasm/drug effects
- NF-kappa B/metabolism
- MCF-7 Cells
- Female
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/metabolism
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Antineoplastic Agents, Phytogenic/pharmacology
- Drug Resistance, Multiple/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
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Affiliation(s)
- Angelika Długosz-Pokorska
- Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
| | - Tomasz Janecki
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Lodz, Poland
| | - Anna Janecka
- Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Katarzyna Gach-Janczak
- Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
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16
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Chiang JY, Wei ST, Chang HJ, Chen DC, Wang HL, Lei FJ, Wei KY, Huang YC, Wang CC, Hsieh CH. ABCC4 suppresses glioblastoma progression and recurrence by restraining cGMP-PKG signalling. Br J Cancer 2024; 130:1324-1336. [PMID: 38347095 PMCID: PMC11014854 DOI: 10.1038/s41416-024-02581-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND Cyclic nucleotides are critical mediators of cellular signalling in glioblastoma. However, the clinical relevance and mechanisms of regulating cyclic nucleotides in glioblastoma progression and recurrence have yet to be thoroughly explored. METHODS In silico, mRNA, and protein level analyses identified the primary regulator of cyclic nucleotides in recurrent human glioblastoma. Lentiviral and pharmacological manipulations examined the functional impact of cyclic nucleotide signalling in human glioma cell lines and primary glioblastoma cells. An orthotopic xenograft mice model coupled with aspirin hydrogels verified the in vivo outcome of targeting cyclic nucleotide signalling. RESULTS Elevated intracellular levels of cGMP, instead of cAMP, due to a lower substrate efflux from ATP-binding cassette sub-family C member 4 (ABCC4) is engaged in the recurrence of glioblastoma. ABCC4 gene expression is negatively associated with recurrence and overall survival outcomes in glioblastoma specimens. ABCC4 loss-of-function activates cGMP-PKG signalling, promoting malignancy in glioblastoma cells and xenografts. Hydrogels loaded with aspirin, inhibiting glioblastoma progression partly by upregulating ABCC4 expressions, augment the efficacy of standard-of-care therapies in orthotopic glioblastoma xenografts. CONCLUSION ABCC4, repressing the cGMP-PKG signalling pathway, is a tumour suppressor in glioblastoma progression and recurrence. Aspirin hydrogels impede glioblastoma progression through ABCC4 restoration and constitute a viable translational approach.
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Affiliation(s)
- Jung-Ying Chiang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Neurosurgery, China Medical University Hsinchu Hospital, Hsinchu, Taiwan
| | - Sung-Tai Wei
- Division of Neurosurgery, Asia University Hospital, Taichung, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
| | - Huan-Jui Chang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Der-Cherng Chen
- Department of Neurosurgery, China Medical University and Hospital, Taichung, Taiwan
| | - Hwai-Lee Wang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Fu-Ju Lei
- Graduate Institute of Clinical Medical Sciences, China Medical University, Taichung, Taiwan
| | - Kai-Yu Wei
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Mingdao High School, Taichung, Taiwan
| | - Yen-Chih Huang
- Department of Medical Imaging, China Medical University and Hospital, Taichung, Taiwan
| | - Chi-Chung Wang
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei, Taiwan
| | - Chia-Hung Hsieh
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
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17
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Azizan S, Cheng KJ, Mejia Mohamed EH, Ibrahim K, Faruqu FN, Vellasamy KM, Khong TL, Syafruddin SE, Ibrahim ZA. Insights into the molecular mechanisms and signalling pathways of epithelial to mesenchymal transition (EMT) in colorectal cancer: A systematic review and bioinformatic analysis of gene expression. Gene 2024; 896:148057. [PMID: 38043836 DOI: 10.1016/j.gene.2023.148057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 11/19/2023] [Accepted: 11/29/2023] [Indexed: 12/05/2023]
Abstract
Colorectal cancer (CRC) is ranked as the second leading cause of mortality worldwide, mainly due to metastasis. Epithelial to mesenchymal transition (EMT) is a complex cellular process that drives CRC metastasis, regulated by changes in EMT-associated gene expression. However, while numerous genes have been identified as EMT regulators through various in vivo and in vitro studies, little is known about the genes that are differentially expressed in CRC tumour tissue and their signalling pathway in regulating EMT. Using an integration of systematic search and bioinformatic analysis, gene expression profiles of CRC tumour tissues were compared to non-tumour adjacent tissues to identify differentially expressed genes (DEGs), followed by performing systematic review on common identified DEGs. Fifty-eight common DEGs were identified from the analysis of 82 tumour tissue samples obtained from four gene expression datasets (NCBI GEO). These DEGS were then systematically searched for their roles in modulating EMT in CRC based on previously published studies. Following this, 10 common DEGs (CXCL1, CXCL8, MMP1, MMP3, MMP7, TACSTD2, VIP, HPGD, ABCG2, CLCA4) were included in this study and subsequently subjected to further bioinformatic analysis. Their roles and functions in modulating EMT in CRC were discussed in this review. This study enhances our understanding of the molecular mechanisms underlying EMT and uncovers potential candidate genes and pathways that could be targeted in CRC.
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Affiliation(s)
- Suha Azizan
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Kim Jun Cheng
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | | | - Kamariah Ibrahim
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Farid Nazer Faruqu
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Kumutha Malar Vellasamy
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Tak Loon Khong
- Department of Surgery, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Saiful Effendi Syafruddin
- UKM Medical Molecular Biology Institute (UMBI), UKM Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Zaridatul Aini Ibrahim
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
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18
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Moon DO. Exploring the Role of Surface and Mitochondrial ATP-Sensitive Potassium Channels in Cancer: From Cellular Functions to Therapeutic Potentials. Int J Mol Sci 2024; 25:2129. [PMID: 38396807 PMCID: PMC10888650 DOI: 10.3390/ijms25042129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/08/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
ATP-sensitive potassium (KATP) channels are found in plasma membranes and mitochondria. These channels are a type of ion channel that is regulated by the intracellular concentration of adenosine triphosphate (ATP) and other nucleotides. In cell membranes, they play a crucial role in linking metabolic activity to electrical activity, especially in tissues like the heart and pancreas. In mitochondria, KATP channels are involved in protecting cells against ischemic damage and regulating mitochondrial function. This review delves into the role of KATP channels in cancer biology, underscoring their critical function. Notably responsive to changes in cellular metabolism, KATP channels link metabolic states to electrical activity, a feature that becomes particularly significant in cancer cells. These cells, characterized by uncontrolled growth, necessitate unique metabolic and signaling pathways, differing fundamentally from normal cells. Our review explores the intricate roles of KATP channels in influencing the metabolic and ionic balance within cancerous cells, detailing their structural and operational mechanisms. We highlight the channels' impact on cancer cell survival, proliferation, and the potential of KATP channels as therapeutic targets in oncology. This includes the challenges in targeting these channels due to their widespread presence in various tissues and the need for personalized treatment strategies. By integrating molecular biology, physiology, and pharmacology perspectives, the review aims to enhance the understanding of cancer as a complex metabolic disease and to open new research and treatment avenues by focusing on KATP channels. This comprehensive approach provides valuable insights into the potential of KATP channels in developing innovative cancer treatments.
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Affiliation(s)
- Dong-Oh Moon
- Department of Biology Education, Daegu University, 201, Daegudae-ro, Gyeongsan-si 38453, Gyeongsangbuk-do, Republic of Korea
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19
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Cervenkova L, Palek R, Moulisova V, Liska V, Daum O, Mohelnikova-Duchonova B, Soucek P. Protein expression and localization of ABC transporters in pancreatic adenocarcinoma: Prognostic role of ABCC8. Pancreatology 2023; 23:978-987. [PMID: 37839922 DOI: 10.1016/j.pan.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/03/2023] [Accepted: 10/08/2023] [Indexed: 10/17/2023]
Abstract
BACKGROUND ATP-binding cassette (ABC) transporters translocate various substances across cellular membranes. Their deregulation may cause cancer drug resistance or perturbations in the supply of building blocks for cancer cells and modify patients' prognosis. This study investigated protein expression and cellular localization of the previously suggested putative prognostic biomarkers - ABCB2/TAP1, ABCC7/CFTR, ABCC8/SUR1, and ABCD4 in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS Protein expression and localization were assessed by immunohistochemistry in formalin-fixed paraffin-embedded primary tumor tissue blocks of 61 PDAC patients and associated with clinical data and the survival of patients. RESULTS No CFTR protein expression was observed in PDAC, while TAP1 and ABCC8 were expressed predominantly in the cytoplasm of tumor cells. Most samples (81 %) had detectable both membranous and cytoplasmic ABCD4 staining and 42 % had ABCD4 expressed in the apical orientation. Negative membranous ABCD4 staining was significantly more frequent in advanced stage III or IV tumors (p = 0.022). Small or medium counts of individual ABCC8-positive cells in the stroma surrounding tumor tubules were also more often found in stage III or IV (p = 0.044). Patients with moderate or strong ABCC8 cytoplasmic staining intensity in tumor cells had a 3.5-fold higher risk of disease progression than those with weak staining (p = 0.002). CONCLUSIONS The study shows for the first time that the cytoplasmic ABCC8 protein expression has prognostic value in PDAC.
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Affiliation(s)
- Lenka Cervenkova
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; Third Faculty of Medicine, Charles University, Prague, Czech Republic.
| | - Richard Palek
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; Department of Surgery, Faculty Hospital and Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
| | - Vladimira Moulisova
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
| | - Vaclav Liska
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; Department of Surgery, Faculty Hospital and Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
| | - Ondrej Daum
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; Department of Pathology, Faculty Hospital and Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
| | - Beatrice Mohelnikova-Duchonova
- Department of Oncology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
| | - Pavel Soucek
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
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20
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Matera I, Miglionico R, Abruzzese V, Marchese G, Ventola GM, Castiglione Morelli MA, Bisaccia F, Ostuni A. A Regulator Role for the ATP-Binding Cassette Subfamily C Member 6 Transporter in HepG2 Cells: Effect on the Dynamics of Cell-Cell and Cell-Matrix Interactions. Int J Mol Sci 2023; 24:16391. [PMID: 38003580 PMCID: PMC10670978 DOI: 10.3390/ijms242216391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/12/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
There is growing evidence that various ATP-binding cassette (ABC) transporters contribute to the growth and development of tumors, but relatively little is known about how the ABC transporter family behaves in hepatocellular carcinoma (HCC), one of the most common cancers worldwide. Cellular model studies have shown that ABCC6, which belongs to the ABC subfamily C (ABCC), plays a role in the cytoskeleton rearrangement and migration of HepG2 hepatocarcinoma cells, thus highlighting its role in cancer biology. Deep knowledge on the molecular mechanisms underlying the observed results could provide therapeutic insights into the tumors in which ABCC6 is modulated. In this study, differential expression levels of mRNA transcripts between ABCC6-silenced HepG2 and control groups were measured, and subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Real-Time PCR and Western blot analyses confirmed bioinformatics; functional studies support the molecular mechanisms underlying the observed effects. The results provide valuable information on the dysregulation of fundamental cellular processes, such as the focal adhesion pathway, which allowed us to obtain detailed information on the active role that the down-regulation of ABCC6 could play in the biology of liver tumors, as it is involved not only in cell migration but also in cell adhesion and invasion.
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Affiliation(s)
- Ilenia Matera
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (I.M.); (R.M.); (V.A.); (M.A.C.M.)
| | - Rocchina Miglionico
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (I.M.); (R.M.); (V.A.); (M.A.C.M.)
| | - Vittorio Abruzzese
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (I.M.); (R.M.); (V.A.); (M.A.C.M.)
| | - Giovanna Marchese
- Genomix4Life Srl, 84081 Baronissi, Italy; (G.M.); (G.M.V.)
- Genome Research Center for Health—CRGS, 84081 Baronissi, Italy
| | | | | | - Faustino Bisaccia
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (I.M.); (R.M.); (V.A.); (M.A.C.M.)
| | - Angela Ostuni
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (I.M.); (R.M.); (V.A.); (M.A.C.M.)
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21
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Galati L, Gupta P, Tufaro A, Marinaro M, Saponaro C, Escobar Marcillo DI, Loisi D, Sen R, Robitaille A, Brancaccio RN, Cuenin C, McKay-Chopin S, Paradiso AV, Liška V, Souček P, Zito FA, Hughes DJ, Tommasino M, Gheit T. Evaluation of human papillomavirus DNA in colorectal cancer and adjacent mucosal tissue samples. Infect Agent Cancer 2023; 18:71. [PMID: 37941001 PMCID: PMC10634082 DOI: 10.1186/s13027-023-00552-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 11/02/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND Although the role of viral agents, such as human papillomavirus (e.g. HPV16, HPV18) in colorectal cancer (CRC) has been previously investigated, results remain inconclusive. METHODS To further evaluate the involvement of oncogenic HPV types in CRC, 40 frozen neoplastic and 40 adjacent colonic tissues collected from Italian patients were analyzed by Luminex-based assays that detect a broad spectrum of HPV types, i.e. Alpha (n = 21), Beta (n = 46) and Gamma HPVs (n = 52). In addition, 125 frozen CRC samples and 70 surrounding mucosal tissues were collected from Czech patients and analyzed by broad spectrum PCR protocols: (i) FAP59/64, (ii) FAPM1 and (iii) CUT combined with Next Generation Sequencing (NGS). RESULTS Using Luminex-basedassays, DNA from HPV16 was detected in 5% (2/40) CRC tissues from Italian patients. One HPV16 DNA-positive CRC case was subsequently confirmed positive for E6*I mRNA. Cutaneous beta HPV types were detected in 10% (4/40) adjacent tissues only, namely HPV111 (n = 3) and HPV120 (n = 1), while gamma HPV168 (n = 1) and HPV199 (n = 1) types were detected in adjacent and in tumor tissues, respectively. The NGS analysis of the CRC Czech samples identified HPV sequences from mucosal alpha-3 (HPV89), alpha-7 (HPV18, 39, 68 and 70) and alpha-10 species (HPV11), as well as cutaneous beta-1 (HPV20, 24, 93, 98, 105,124) beta-2 (HPV23), beta-3 (HPV49) and gamma-1 species (HPV205). CONCLUSIONS Our findings indicate that HPV types belonging to the mucosal alpha, and the 'cutaneous' beta and gamma genera can be detected in the colonic mucosal samples with a low prevalence rate and a low number of HPV reads by Luminex and NGS, respectively. However, additional studies are required to corroborate these findings.
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Affiliation(s)
- Luisa Galati
- International Agency for Research on Cancer (IARC), 25 Avenue Tony Garnier, CS 90627, 69366, Lyon Cedex 07, France
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Purnima Gupta
- International Agency for Research on Cancer (IARC), 25 Avenue Tony Garnier, CS 90627, 69366, Lyon Cedex 07, France
| | - Antonio Tufaro
- Institutional BioBank, Istituto Tumori "Giovanni Paolo II", IRCCS, Bari, Italy
| | - Mariarosaria Marinaro
- Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy
| | - Concetta Saponaro
- Pathology Department, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | | | - Donato Loisi
- Pathology Department, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Rajdip Sen
- International Agency for Research on Cancer (IARC), 25 Avenue Tony Garnier, CS 90627, 69366, Lyon Cedex 07, France
| | - Alexis Robitaille
- International Agency for Research on Cancer (IARC), 25 Avenue Tony Garnier, CS 90627, 69366, Lyon Cedex 07, France
- Leibniz Institute of Virology, Hamburg, Germany
| | - Rosario N Brancaccio
- International Agency for Research on Cancer (IARC), 25 Avenue Tony Garnier, CS 90627, 69366, Lyon Cedex 07, France
| | - Cyrille Cuenin
- International Agency for Research on Cancer (IARC), 25 Avenue Tony Garnier, CS 90627, 69366, Lyon Cedex 07, France
| | - Sandrine McKay-Chopin
- International Agency for Research on Cancer (IARC), 25 Avenue Tony Garnier, CS 90627, 69366, Lyon Cedex 07, France
| | | | - Václav Liška
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
- Department of Surgery, Faculty Hospital and Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Pavel Souček
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | | | - David J Hughes
- Cancer Biology and Therapeutics Group, School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
| | - Massimo Tommasino
- International Agency for Research on Cancer (IARC), 25 Avenue Tony Garnier, CS 90627, 69366, Lyon Cedex 07, France
| | - Tarik Gheit
- International Agency for Research on Cancer (IARC), 25 Avenue Tony Garnier, CS 90627, 69366, Lyon Cedex 07, France.
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22
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Sałagacka-Kubiak A, Zawada D, Saed L, Kordek R, Jeleń A, Balcerczak E. ABCG2 Gene and ABCG2 Protein Expression in Colorectal Cancer-In Silico and Wet Analysis. Int J Mol Sci 2023; 24:10539. [PMID: 37445716 DOI: 10.3390/ijms241310539] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/13/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
ABCG2 (ATP-binding cassette superfamily G member 2) is a cell membrane pump encoded by the ABCG2 gene. ABCG2 can protect cells against compounds initiating and/or intensifying neoplasia and is considered a marker of stem cells responsible for cancer growth, drug resistance and recurrence. Expression of the ABCG2 gene or its protein has been shown to be a negative prognostic factor in various malignancies. However, its prognostic significance in colorectal cancer remains unclear. Using publicly available data, ABCG2 was shown to be underexpressed in colon and rectum adenocarcinomas, with lower expression compared to both the adjacent nonmalignant lung tissues and non-tumour lung tissues of healthy individuals. This downregulation could result from the methylation level of some sites of the ABCG2 gene. This was connected with microsatellite instability, weight and age among patients with colon adenocarcinoma, and with tumour localization, population type and age of patients for rectum adenocarcinoma. No association was found between ABCG2 expression level and survival of colorectal cancer patients. In wet analysis of colorectal cancer samples, neither ABCG2 gene expression, analysed by RT-PCR, nor ABCG2 protein level, assessed by immunohistochemistry, was associated with any clinicopathological factors or overall survival. An ABCG2-centered protein-protein interaction network build by STRING showed proteins were found to be involved in leukotriene, organic anion and xenobiotic transport, endodermal cell fate specification, and histone methylation and ubiquitination. Hence, ABCG2 underexpression could be an indicator of the activity of certain signalling pathways or protein interactors essential for colorectal carcinogenesis.
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Affiliation(s)
- Aleksandra Sałagacka-Kubiak
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, 92-213 Lodz, Poland
| | - Dawid Zawada
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, 92-213 Lodz, Poland
| | - Lias Saed
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, 92-213 Lodz, Poland
| | - Radzisław Kordek
- Department of Pathology, Medical University of Lodz, 92-213 Lodz, Poland
| | - Agnieszka Jeleń
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, 92-213 Lodz, Poland
| | - Ewa Balcerczak
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, 92-213 Lodz, Poland
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23
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Ousalem F, Singh S, Bailey NA, Wong KH, Zhu L, Neky MJ, Sibindi C, Fei J, Gonzalez RL, Boël G, Hunt JF. Comparative genetic, biochemical, and biophysical analyses of the four E. coli ABCF paralogs support distinct functions related to mRNA translation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.11.543863. [PMID: 37398404 PMCID: PMC10312648 DOI: 10.1101/2023.06.11.543863] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Multiple paralogous ABCF ATPases are encoded in most genomes, but the physiological functions remain unknown for most of them. We herein compare the four Escherichia coli K12 ABCFs - EttA, Uup, YbiT, and YheS - using assays previously employed to demonstrate EttA gates the first step of polypeptide elongation on the ribosome dependent on ATP/ADP ratio. A Δ uup knockout, like Δ ettA , exhibits strongly reduced fitness when growth is restarted from long-term stationary phase, but neither Δ ybiT nor Δ yheS exhibits this phenotype. All four proteins nonetheless functionally interact with ribosomes based on in vitro translation and single-molecule fluorescence resonance energy transfer experiments employing variants harboring glutamate-to-glutamine active-site mutations (EQ 2 ) that trap them in the ATP-bound conformation. These variants all strongly stabilize the same global conformational state of a ribosomal elongation complex harboring deacylated tRNA Val in the P site. However, EQ 2 -Uup uniquely exchanges on/off the ribosome on a second timescale, while EQ 2 -YheS-bound ribosomes uniquely sample alternative global conformations. At sub-micromolar concentrations, EQ 2 -EttA and EQ 2 -YbiT fully inhibit in vitro translation of an mRNA encoding luciferase, while EQ 2 -Uup and EQ 2 -YheS only partially inhibit it at ~10-fold higher concentrations. Moreover, tripeptide synthesis reactions are not inhibited by EQ 2 -Uup or EQ 2 -YheS, while EQ 2 -YbiT inhibits synthesis of both peptide bonds and EQ 2 -EttA specifically traps ribosomes after synthesis of the first peptide bond. These results support the four E. coli ABCF paralogs all having different activities on translating ribosomes, and they suggest that there remains a substantial amount of functionally uncharacterized "dark matter" involved in mRNA translation.
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24
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R I A, Vatsyayan A, Damodaran D, Sivadas A, Van der Speeten K. Multi-omics Analysis Classifies Colorectal Cancer into Distinct Methylated Immunogenic and Angiogenic Subtypes Based on Anatomical Laterality. Indian J Surg Oncol 2023; 14:209-219. [PMID: 37359923 PMCID: PMC10284779 DOI: 10.1007/s13193-023-01760-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 04/25/2023] [Indexed: 06/28/2023] Open
Abstract
We employed supervised machine learning algorithms to a cohort of colorectal cancer patients from the NCI to differentiate and classify the heterogenous disease based on anatomical laterality and multi-omics stratification, in a first of its kind. Multi-omics integrative analysis shows distinct clustering of left and right colorectal cancer with disentangled representation of methylome and delineation of transcriptome and genome. We present novel multi-omics findings consistent with augmented hypermethylation of genes in right CRC, epigenomic biomarkers on the right in conjunction with immune-mediated pathway signatures, and lymphocytic invasion which unlocks unique therapeutic avenues. Contrarily, left CRC multi-omics signature is found to be marked by angiogenesis, cadherins, and epithelial-mesenchymal transition (EMT). An integrated multi-omics molecular signature of RNF217-AS1, hsa-miR-10b, and panel of FBX02, FBX06, FBX044, MAD2L2, and MIIP copy number altered genes have been found by the study. Overall survival analysis reveals genomic biomarkers ABCA13 and TTN in 852 LCRC cases, and SOX11 in 170 RCRC cases that predicts a significant survival benefit. Our study exemplifies the translational competence and robustness of machine learning in effective translational bridging of research and clinic. Supplementary Information The online version contains supplementary material available at 10.1007/s13193-023-01760-6.
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Affiliation(s)
- Anu R I
- Department of Cancer Biology and Therapeutics, MVR Cancer Center and Research Institute, Calicut, Kerala India
- Department of Clinical Biochemistry, MVR Cancer Center and Research Institute, Calicut, Kerala India
| | - Aastha Vatsyayan
- CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Dileep Damodaran
- Department of Surgical Oncology, MVR Cancer Center and Research Institute, Calicut, Kerala India
| | - Ambily Sivadas
- Division of Nutrition, St. John’s Research Institute, Bangalore, India
| | - Kurt Van der Speeten
- Department of Surgical Oncology, Ziekenhuis Oost-Limburg, Genk, Belgium
- Faculty of Medicine and Life Sciences, BIOMED Research Institute, University Hasselt, Hasselt, Belgium
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25
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Zappe K, Kopic A, Scheichel A, Schier AK, Schmidt LE, Borutzki Y, Miedl H, Schreiber M, Mendrina T, Pirker C, Pfeiler G, Hacker S, Haslik W, Pils D, Bileck A, Gerner C, Meier-Menches S, Heffeter P, Cichna-Markl M. Aberrant DNA Methylation, Expression, and Occurrence of Transcript Variants of the ABC Transporter ABCA7 in Breast Cancer. Cells 2023; 12:1462. [PMID: 37296582 PMCID: PMC10252461 DOI: 10.3390/cells12111462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/09/2023] [Accepted: 05/16/2023] [Indexed: 06/12/2023] Open
Abstract
The ABC transporter ABCA7 has been found to be aberrantly expressed in a variety of cancer types, including breast cancer. We searched for specific epigenetic and genetic alterations and alternative splicing variants of ABCA7 in breast cancer and investigated whether these alterations are associated with ABCA7 expression. By analyzing tumor tissues from breast cancer patients, we found CpGs at the exon 5-intron 5 boundary aberrantly methylated in a molecular subtype-specific manner. The detection of altered DNA methylation in tumor-adjacent tissues suggests epigenetic field cancerization. In breast cancer cell lines, DNA methylation levels of CpGs in promoter-exon 1, intron 1, and at the exon 5-intron 5 boundary were not correlated with ABCA7 mRNA levels. By qPCR involving intron-specific and intron-flanking primers, we identified intron-containing ABCA7 mRNA transcripts. The occurrence of intron-containing transcripts was neither molecular subtype-specific nor directly correlated with DNA methylation at the respective exon-intron boundaries. Treatment of breast cancer cell lines MCF-7, BT-474, SK-BR3, and MDA-MB-231 with doxorubicin or paclitaxel for 72 h resulted in altered ABCA7 intron levels. Shotgun proteomics revealed that an increase in intron-containing transcripts was associated with significant dysregulation of splicing factors linked to alternative splicing.
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Affiliation(s)
- Katja Zappe
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Antonio Kopic
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Alexandra Scheichel
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Ann-Katrin Schier
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Lukas Emanuel Schmidt
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Yasmin Borutzki
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
- Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Heidi Miedl
- Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Martin Schreiber
- Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Theresa Mendrina
- Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Christine Pirker
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Georg Pfeiler
- Division of Gynecology and Gynecological Oncology, Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria
| | - Stefan Hacker
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Werner Haslik
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Dietmar Pils
- Division of Visceral Surgery, Department of General Surgery and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Andrea Bileck
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
- Joint Metabolome Facility, University of Vienna and Medical University of Vienna, 1090 Vienna, Austria
| | - Christopher Gerner
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
- Joint Metabolome Facility, University of Vienna and Medical University of Vienna, 1090 Vienna, Austria
| | - Samuel Meier-Menches
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
- Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
- Joint Metabolome Facility, University of Vienna and Medical University of Vienna, 1090 Vienna, Austria
| | - Petra Heffeter
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Margit Cichna-Markl
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
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26
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Maqoud F, Zizzo N, Attimonelli M, Tinelli A, Passantino G, Antonacci M, Ranieri G, Tricarico D. Immunohistochemical, pharmacovigilance, and omics analyses reveal the involvement of ATP-sensitive K + channel subunits in cancers: role in drug-disease interactions. Front Pharmacol 2023; 14:1115543. [PMID: 37180726 PMCID: PMC10167295 DOI: 10.3389/fphar.2023.1115543] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 04/10/2023] [Indexed: 05/16/2023] Open
Abstract
Background: ATP-sensitive-K+ channels (KATP) are involved in diseases, but their role in cancer is poorly described. Pituitary macroadenoma has been observed in Cantu' syndrome (C.S.), which is associated with the gain-of-function mutations of the ABCC9 and KCNJ8 genes. We tested the role of the ABCC8/Sur1, ABCC9/Sur2A/B, KCNJ11/Kir6.2, and KCNJ8/Kir6.1 genes experimentally in a minoxidil-induced renal tumor in male rats and in the female canine breast cancer, a spontaneous animal model of disease, and in the pharmacovigilance and omics databases. Methods: We performed biopsies from renal tissues of male rats (N = 5) following a sub-chronic high dosing topical administration of minoxidil (0.777-77.7 mg/kg/day) and from breast tissues of female dogs for diagnosis (N = 23) that were analyzed by immunohistochemistry. Pharmacovigilance and omics data were extracted from EudraVigilance and omics databases, respectively. Results: An elevated immunohistochemical reactivity to Sur2A-mAb was detected in the cytosol of the Ki67+/G3 cells other than in the surface membrane in the minoxidil-induced renal tumor and the breast tumor samples. KCNJ11, KCNJ8, and ABCC9 genes are upregulated in cancers but ABCC8 is downregulated. The Kir6.2-Sur2A/B-channel opener minoxidil showed 23 case reports of breast cancer and one case of ovarian cancer in line with omics data reporting, respectively, and the negative and positive prognostic roles of the ABCC9 gene in these cancers. Sulfonylureas and glinides blocking the pancreatic Kir6.2-Sur1 subunits showed a higher risk for pancreatic cancer in line with the positive prognostic role of the ABCC8 gene but low risks for common cancers. Glibenclamide, repaglinide, and glimepiride show a lower cancer risk within the KATP channel blockers. The Kir6.2-Sur1 opener diazoxide shows no cancer reactions. Conclusion: An elevated expression of the Sur2A subunit was found in proliferating cells in two animal models of cancer. Immunohistochemistry/omics/pharmacovigilance data reveal the role of the Kir6.1/2-Sur2A/B subunits as a drug target in breast/renal cancers and in C.S.
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Affiliation(s)
- Fatima Maqoud
- Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology Saverio de Bellis, I.R.C.C.S. Research Hospital, Milan, Italy
- Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", Bari, Italy
| | - Nicola Zizzo
- Section of Veterinary Pathology and Comparative Oncology, Department of Veterinary Medicine, University of Bari "Aldo Moro", Valenzano, Italy
| | - Marcella Attimonelli
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University "Aldo Moro" Bari, Bari, Italy
| | - Antonella Tinelli
- Section of Veterinary Pathology and Comparative Oncology, Department of Veterinary Medicine, University of Bari "Aldo Moro", Valenzano, Italy
| | - Giuseppe Passantino
- Section of Veterinary Pathology and Comparative Oncology, Department of Veterinary Medicine, University of Bari "Aldo Moro", Valenzano, Italy
| | - Marina Antonacci
- Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", Bari, Italy
| | - Girolamo Ranieri
- Department of Interventional Radiology and Integrated Medical Oncology, I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Domenico Tricarico
- Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", Bari, Italy
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27
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Lee J, Jang CH, Kim Y, Oh J, Kim JS. Quercetin-Induced Glutathione Depletion Sensitizes Colorectal Cancer Cells to Oxaliplatin. Foods 2023; 12:foods12081733. [PMID: 37107528 PMCID: PMC10138196 DOI: 10.3390/foods12081733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/07/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Quercetin is an antioxidant phytochemical which belongs to the natural flavonoids group. Recently, the compound has been reported to inhibit glutathione reductase responsible for replenishing reduced forms of glutathione and thus leads to glutathione depletion, triggering cell death. In this study, we examined if quercetin sensitizes tumors to oxaliplatin by inhibiting glutathione reductase activity in human colorectal cancer cells, and thereby facilitates apoptotic cell death. A combined treatment with quercetin and oxaliplatin was found to synergistically inhibit glutathione reductase activity, lower intracellular glutathione level, increase reactive oxygen species production, and reduce cell viability, compared to treatment with oxaliplatin alone in human colorectal HCT116 cancer cells. Furthermore, the incorporation of sulforaphane, recognized for its ability to scavenge glutathione, in combination with quercetin and oxaliplatin, substantially suppressed tumor growth in an HCT116 xenograft mouse model. These findings suggest that the depletion of intracellular glutathione by quercetin and sulforaphane could strengthen the anti-cancer efficacy of oxaliplatin.
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Affiliation(s)
- Jinkyung Lee
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Chan Ho Jang
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea
- Institute of Agricultural Science and Technology, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Yoonsu Kim
- Department of Integrative Biology, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jisun Oh
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
| | - Jong-Sang Kim
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea
- Institute of Agricultural Science and Technology, Kyungpook National University, Daegu 41566, Republic of Korea
- Department of Integrative Biology, Kyungpook National University, Daegu 41566, Republic of Korea
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28
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Al Bitar S, El-Sabban M, Doughan S, Abou-Kheir W. Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond. World J Gastroenterol 2023; 29:1395-1426. [PMID: 36998426 PMCID: PMC10044855 DOI: 10.3748/wjg.v29.i9.1395] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/12/2022] [Accepted: 11/17/2022] [Indexed: 03/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and a major leading cause of cancer-related deaths worldwide. Despite advances in therapeutic regimens, the number of patients presenting with metastatic CRC (mCRC) is increasing due to resistance to therapy, conferred by a small population of cancer cells, known as cancer stem cells. Targeted therapies have been highly successful in prolonging the overall survival of patients with mCRC. Agents are being developed to target key molecules involved in drug-resistance and metastasis of CRC, and these include vascular endothelial growth factor, epidermal growth factor receptor, human epidermal growth factor receptor-2, mitogen-activated extracellular signal-regulated kinase, in addition to immune checkpoints. Currently, there are several ongoing clinical trials of newly developed targeted agents, which have shown considerable clinical efficacy and have improved the prognosis of patients who do not benefit from conventional chemotherapy. In this review, we highlight recent developments in the use of existing and novel targeted agents against drug-resistant CRC and mCRC. Furthermore, we discuss limitations and challenges associated with targeted therapy and strategies to combat intrinsic and acquired resistance to these therapies, in addition to the importance of implementing better preclinical models and the application of personalized therapy based on predictive biomarkers for treatment selection.
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Affiliation(s)
- Samar Al Bitar
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Marwan El-Sabban
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Samer Doughan
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
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29
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Xu C, Jin X, Wei S, Wang P, Luo M, Xu Z, Yang W, Cai Y, Xiao L, Lin X, Liu H, Cheng R, Pang F, Chen R, Su X, Hu Y, Wang G, Jiang Q. DeepST: identifying spatial domains in spatial transcriptomics by deep learning. Nucleic Acids Res 2022; 50:e131. [PMID: 36250636 PMCID: PMC9825193 DOI: 10.1093/nar/gkac901] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 09/20/2022] [Accepted: 10/04/2022] [Indexed: 01/29/2023] Open
Abstract
Recent advances in spatial transcriptomics (ST) have brought unprecedented opportunities to understand tissue organization and function in spatial context. However, it is still challenging to precisely dissect spatial domains with similar gene expression and histology in situ. Here, we present DeepST, an accurate and universal deep learning framework to identify spatial domains, which performs better than the existing state-of-the-art methods on benchmarking datasets of the human dorsolateral prefrontal cortex. Further testing on a breast cancer ST dataset, we showed that DeepST can dissect spatial domains in cancer tissue at a finer scale. Moreover, DeepST can achieve not only effective batch integration of ST data generated from multiple batches or different technologies, but also expandable capabilities for processing other spatial omics data. Together, our results demonstrate that DeepST has the exceptional capacity for identifying spatial domains, making it a desirable tool to gain novel insights from ST studies.
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Affiliation(s)
- Chang Xu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Xiyun Jin
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Songren Wei
- Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangdong 523335, China
| | - Pingping Wang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Meng Luo
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Zhaochun Xu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Wenyi Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Yideng Cai
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Lixing Xiao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Xiaoyu Lin
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Hongxin Liu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Rui Cheng
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Fenglan Pang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Rui Chen
- Department of Forensic Medicine, Guangdong Medical University, Dongguan 523808, China
| | - Xi Su
- ChinaFoshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan 528000, China
| | - Ying Hu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Guohua Wang
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin 150000, China
| | - Qinghua Jiang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150000, China
- School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin 150076, China
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Encorafenib Acts as a Dual-Activity Chemosensitizer through Its Inhibitory Effect on ABCC1 Transporter In Vitro and Ex Vivo. Pharmaceutics 2022; 14:pharmaceutics14122595. [PMID: 36559089 PMCID: PMC9785850 DOI: 10.3390/pharmaceutics14122595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/26/2022] Open
Abstract
Encorafenib (LGX818, trade name Braftovi), a novel BRAF inhibitor, has been approved for the treatment of melanoma and colorectal cancer. In the present work, we evaluated encorafenib's possible antagonistic effects on the pharmacokinetic mechanisms of multidrug resistance (MDR), as well as its perpetrator role in drug interactions. Firstly, encorafenib potently inhibited the efflux function of the ABCC1 transporter in drug accumulation assays, while moderate and null interaction levels were recorded for ABCB1 and ABCG2, respectively. In contrast, the mRNA expression levels of all the tested transporters were not altered by encorafenib. In the drug combination studies, we found that daunorubicin and topotecan resistances were synergistically attenuated by the encorafenib-mediated interaction in A431-ABCC1 cells. Notably, further experiments in ex vivo patient-derived explants confirmed the MDR-modulating ability of encorafenib. Advantageously, the overexpression of tested drug efflux transporters failed to hinder the antiproliferative activity of encorafenib. In addition, no significant modulation of the CYP3A4 enzyme's activity by encorafenib was observed. In conclusion, our work indicated that encorafenib can act as an effective chemosensitizer targeting the ABCC1-induced MDR. Our in vitro and ex vivo data might provide valuable information for designing the novel effective scheme applicable in the clinical pharmacotherapy of BRAF-mutated/ABCC1-expressing tumors.
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Wada M. Role of ABC Transporters in Cancer Development and Malignant Alteration. YAKUGAKU ZASSHI 2022; 142:1201-1225. [DOI: 10.1248/yakushi.22-00108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Pilotto Heming C, Muriithi W, Wanjiku Macharia L, Niemeyer Filho P, Moura-Neto V, Aran V. P-glycoprotein and cancer: what do we currently know? Heliyon 2022; 8:e11171. [PMID: 36325145 PMCID: PMC9618987 DOI: 10.1016/j.heliyon.2022.e11171] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
Abstract
Acquired resistance during cancer treatment is unfortunately a frequent event. There are several reasons for this, including the ability of the ATP-binding cassette transporters (ABC transporters), which are integral membrane proteins, to export chemotherapeutic molecules from the interior of the tumor cells. One important member of this family is the protein known as Permeability Glycoprotein (P-Glycoprotein, P-gp or ABCB1). Its clinical relevance relies mainly on the fact that the inhibition of P-gp and other ABC transporters could result in the reversal of the multidrug resistance (MDR) phenotype in some patients. Recently, other roles apart from being a key player in MDR, have emerged for P-gp. Therefore, this review discusses the relationship between P-gp and MDR, in addition to the possible role of this protein as a biomarker in cancer.
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Performance of the Use of Genetic Information to Assess the Risk of Colorectal Cancer in the Basque Population. Cancers (Basel) 2022; 14:cancers14174193. [PMID: 36077729 PMCID: PMC9454881 DOI: 10.3390/cancers14174193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/18/2022] [Accepted: 08/26/2022] [Indexed: 01/14/2023] Open
Abstract
Although the genetic contribution to colorectal cancer (CRC) has been studied in various populations, studies on the applicability of available genetic information in the Basque population are scarce. In total, 835 CRC cases and 940 controls from the Basque population were genotyped and genome-wide association studies were carried out. Mendelian Randomization analyses were used to discover the effect of modifiable risk factors and microbiota on CRC. In total, 25 polygenic risk score models were evaluated to assess their performance in CRC risk calculation. Moreover, 492 inflammatory bowel disease cases were used to assess whether that genetic information would not confuse both conditions. Five suggestive (p < 5 × 10−6) loci were associated with CRC risk, where genes previously associated with CRC were located (e.g., ABCA12, ATIC or ERBB4). Moreover, the analyses of CRC locations detected additional genes consistent with the biology of CRC. The possible contribution of cholesterol, BMI, Firmicutes and Cyanobacteria to CRC risk was detected by Mendelian Randomization. Finally, although polygenic risk score models showed variable performance, the best model performed correctly regardless of the location and did not misclassify inflammatory bowel disease cases. Our results are consistent with CRC biology and genetic risk models and could be applied to assess CRC risk in the Basque population.
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Wang L, Sun X, He J, Liu Z. Identification and Validation of Prognostic Related Hallmark ATP-Binding Cassette Transporters Associated With Immune Cell Infiltration Patterns in Thyroid Carcinoma. Front Oncol 2022; 12:781686. [PMID: 35837087 PMCID: PMC9273952 DOI: 10.3389/fonc.2022.781686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
ATP-binding cassette (ABC) transporters are a large superfamily of membrane proteins that facilitate the translocation of heterogeneous substrates. Studies indicate that ABC transporters may play important roles in various carcinomas. However, the correlation between ABC transporters and immunomodulation in thyroid carcinoma (TC), as well as the prognoses for this disease, is poorly understood.TC data from The Cancer Genome Atlas (TCGA) database were used to identify prognostic hallmark ABC transporters associated with immune cell infiltration patterns via multiple bioinformatic analyses. Thereafter, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the expression of these selected hallmark ABC transporters in both TC and para-cancerous thyroid tissues. Of a total of 49 ABC transporters, five (ABCA8, ABCA12, ABCB6, ABCB8, and ABCC10) were identified as hallmark ABC transporters. All five were differentially expressed in TC and associated with the relapse-free survival rates of patients with TC. Immunoregulation by these five hallmark ABC transporters involved the modulation of various aspects of immune cell infiltration, such as hot or cold tumor subsets and the abundances of infiltrating immune cells, as well as specific immunomodulators and chemokines. Besides the diverse significantly correlated factors, the five hallmark ABC transporters and correlated genes were most highly enriched in plasma membrane, transporter activity, and transmembrane transport of small molecules. In addition, many chemicals, namely bisphenol A and vincristine, affected the expression of these five transporters. The qRT-PCR results of collected TC and para-cancerous thyroid tissues were consistent with those of TCGA. The findings in this study may reveal the role played by these five hallmark ABC transporters in regulating immune cell infiltration patterns in TC as well as the molecular mechanisms underlying their functions, leading to a better understanding of their potential prognostic and immunotherapeutic values.
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Affiliation(s)
- Lidong Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaodan Sun
- Postdoctoral Research Workstation, Jilin Cancer Hospital, Changchun, China
- Department of 1st Gynecologic Oncology Surgery, Jilin Cancer Hospital, Changchun, China
| | - Jingni He
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhen Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Zhen Liu,
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Xiang L, Wang Y, Lan J, Na F, Wu S, Gong Y, Du H, Shao B, Xie G. HIF-1-dependent heme synthesis promotes gemcitabine resistance in human non-small cell lung cancers via enhanced ABCB6 expression. Cell Mol Life Sci 2022; 79:343. [PMID: 35661930 PMCID: PMC11072486 DOI: 10.1007/s00018-022-04360-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 04/16/2022] [Accepted: 05/10/2022] [Indexed: 12/12/2022]
Abstract
Gemcitabine is commonly used to treat various cancer types, including human non-small cell lung cancer (NSCLC). However, even cases that initially respond rapidly commonly develop acquired resistance, limiting our ability to effectively treat advanced NSCLC. To gain insight for developing a strategy to overcome gemcitabine resistance, the present study investigated the mechanism of gemcitabine resistance in NSCLC according to the involvement of ATP-binding cassette subfamily B member 6 (ABCB6) and heme biosynthesis. First, an analysis of ABCB6 expression in human NSCLCs was found to be associated with poor prognosis and gemcitabine resistance in a hypoxia-inducible factor (HIF)-1-dependent manner. Further experiments showed that activation of HIF-1α/ABCB6 signaling led to intracellular heme metabolic reprogramming and a corresponding increase in heme biosynthesis to enhance the activation and accumulation of catalase. Increased catalase levels diminished the effective levels of reactive oxygen species, thereby promoting gemcitabine-based resistance. In a mouse NSCLC model, inhibition of HIF-1α or ABCB6, in combination with gemcitabine, strongly restrained tumor proliferation, increased tumor cell apoptosis, and prolonged animal survival. These results suggest that, in combination with gemcitabine-based chemotherapy, targeting HIF-1α/ABCB6 signaling could result in enhanced tumor chemosensitivity and, thus, may improve outcomes in NSCLC patients.
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Affiliation(s)
- Lisha Xiang
- Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Thoracic Oncology, Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yongsheng Wang
- Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Thoracic Oncology, Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jie Lan
- Department of Thoracic Oncology, Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Feifei Na
- Department of Thoracic Oncology, Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Shuang Wu
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Chongqing, 400038, China
| | - Yuzhu Gong
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Chongqing, 400038, China
| | - Hanjian Du
- Department of Neurosurgery, Chongqing University Cancer Hospital, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing, 400030, China
| | - Bin Shao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Renmin south road 3 section, Chengdu, 610041, China.
| | - Ganfeng Xie
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Chongqing, 400038, China.
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Abruzzese V, Sukowati CHC, Tiribelli C, Matera I, Ostuni A, Bisaccia F. The Expression Level of ABCC6 Transporter in Colon Cancer Cells Correlates with the Activation of Different Intracellular Signaling Pathways. PATHOPHYSIOLOGY 2022; 29:173-186. [PMID: 35645325 PMCID: PMC9149812 DOI: 10.3390/pathophysiology29020015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/04/2022] [Accepted: 05/09/2022] [Indexed: 11/16/2022] Open
Abstract
The ATP-binding cassette sub-family C member 6 transporter (ABCC6) is mainly found in the basolateral plasma membrane of hepatic and kidney cells. In hepatocarcinoma HepG2 cells, ABCC6 was involved in cell migration. In the present study, we investigated the role of ABCC6 in colon cancer evaluating the effect of Quercetin and Probenecid, inhibitors of the ectonucleotidase NT5E and ABCC6, respectively, on migration rate of Caco2 and HT29 cell lines. Both drugs reduced cell migration analyzed by scratch test. Gene and protein expression were evaluated by quantitative reverse-transcription PCR (RT-qPCR) and Western blot, respectively. In Caco2 cells, in which ABCC6 is significantly expressed, the addition of ATP restored motility, suggesting the involvement of P2 receptors. Contrary to HT29 cells, where the expression of ABCC6 is negligible but remarkable to the level of NT5E, no effect of ATP addition was detected, suggesting a main role on their migration by the phosphatidylinositol 3′-kinase (PI3K)/Akt system. Therefore, in some colon cancers in which ABCC6 is overexpressed, it may have a primary role in controlling the extracellular purinergic system by feeding it with ATP, thus representing a potential target for a therapy aimed at mitigating invasiveness of those type of cancers.
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Affiliation(s)
- Vittorio Abruzzese
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (V.A.); (I.M.)
| | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (C.H.C.S.); (C.T.)
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (C.H.C.S.); (C.T.)
| | - Ilenia Matera
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (V.A.); (I.M.)
| | - Angela Ostuni
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (V.A.); (I.M.)
- Correspondence: (A.O.); (F.B.)
| | - Faustino Bisaccia
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (V.A.); (I.M.)
- Correspondence: (A.O.); (F.B.)
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DNA Copy Number Aberrations and Expression of ABC Transporter Genes in Breast Tumour: Correlation with the Effect of Neoadjuvant Chemotherapy and Prognosis of the Disease. Pharmaceutics 2022; 14:pharmaceutics14050948. [PMID: 35631534 PMCID: PMC9146568 DOI: 10.3390/pharmaceutics14050948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 11/17/2022] Open
Abstract
One of the important reasons for the ineffectiveness of chemotherapy in breast cancer (BC) is considered to be the formation of a multidrug resistance phenotype in tumour cells, which is caused by the expression of energy-dependent ABC transporters. The aim of this work was to assess chromosomal aberrations and the level of transcripts of all 49 known ABC transporter genes in breast tumours. Materials and Methods. The study included 129 patients with breast cancer. A microarray study of all tumour samples was carried out on microchips. Results. This study established that the presence of a deletion in genes ABCB1, ABCB4, ABCB8, ABCC7, ABCC11, ABCC12, ABCF2, and ABCG4 is associated with an objective response to treatment (p ≤ 0.05). A decrease in the expression of genes was associated with a good response to chemotherapy, whereas an increase in expression caused the progression and stabilization of the tumour. Analysis of metastatic-free survival rates showed that the presence of ABCB1/4 and ABCC1/6 deletions was associated with 100% survival (log-rank test p = 0.01 and p = 0.03). Conclusions. The study showed that the aberrant state of ABC transporter genes, as well as a decrease in the expression of these genes, is a predictor of the effectiveness of therapeutic treatment and a potential prognostic marker of metastatic survival.
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Blanco-Vázquez C, Alonso-Hearn M, Iglesias N, Vázquez P, Juste RA, Garrido JM, Balseiro A, Canive M, Amado J, Queipo MA, Iglesias T, Casais R. Use of ATP-Binding Cassette Subfamily A Member 13 (ABCA13) for Sensitive Detection of Focal Pathological Forms of Subclinical Bovine Paratuberculosis. Front Vet Sci 2022; 9:816135. [PMID: 35359676 PMCID: PMC8960928 DOI: 10.3389/fvets.2022.816135] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/24/2022] [Indexed: 12/20/2022] Open
Abstract
Bovine paratuberculosis (PTB) is a chronic enteritis caused by Mycobacterium avium subspecies paratuberculosis (Map) that causes a heavy economic impact worldwide. Map infected animals can remain asymptomatic for years while transmitting the mycobacteria to other members of the herd. Therefore, accurate detection of subclinically infected animals is crucial for disease control. In a previous RNA-Seq study, we identified several mRNAs that were overexpressed in whole blood of cows with different PTB-associated histological lesions compared with control animals without detected lesions. The proteins encoded by two of these mRNAs, ATP binding cassette subfamily A member 13 (ABCA13) and Matrix Metallopeptidase 8 (MMP8) were significantly overexpressed in whole blood of animals with focal histological lesions, the most frequent pathological form in the subclinical stages of the disease. In the current study, the potential of sensitive early diagnostic tools of commercial ELISAs, based on the detection of these two biomarkers, was evaluated in serum samples of 704 Holstein Friesian cows (566 infected animals and 138 control animals from PTB-free farms). For this evaluation, infected animals were classified into three groups, according to the type of histological lesions present in their gut tissues: focal (n = 447), multifocal (n = 59), and diffuse (n = 60). The ELISA based on the detection of ABCA13 was successfully validated showing good discriminatory power between animals with focal lesions and control animals (sensitivity 82.99% and specificity 80.43%). Conversely, the MMP8-based ELISA showed a poor discriminatory power between the different histological groups and non-infected controls. The ABCA13-based ELISA showed a higher diagnostic value (0.822) than the IDEXX ELISA (0.517), the fecal bacterial isolation (0.523) and the real-time PCR (0.531) for the detection of animals with focal lesions. Overall, our results indicate that this ABCA13 ELISA greatly improves the identification of subclinically infected animals with focal lesions that are undetectable using current diagnostic methods.
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Affiliation(s)
- Cristina Blanco-Vázquez
- Centro de Biotecnología Animal, Servicio Regional de Investigación y Desarrollo Agroalimentario (SERIDA), Deva, Spain
| | - Marta Alonso-Hearn
- Department of Animal Health, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Natalia Iglesias
- Centro de Biotecnología Animal, Servicio Regional de Investigación y Desarrollo Agroalimentario (SERIDA), Deva, Spain
| | - Patricia Vázquez
- Department of Animal Health, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Ramón A. Juste
- Department of Animal Health, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Joseba M. Garrido
- Department of Animal Health, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Ana Balseiro
- Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad de León, León, Spain
- Instituto de Ganadería de Montaña, Centro Superior de Investigaciones Científicas (CSIC-Universidad de León), León, Spain
| | - María Canive
- Department of Animal Health, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Javier Amado
- Laboratorio Regional de Sanidad Animal del Principado de Asturias, Gijón, Spain
| | - Manuel A. Queipo
- Servicio de Sanidad y Producción Animal del Principado de Asturias, Oviedo, Spain
| | - Tania Iglesias
- Unidad de Consultoría Estadística, Servicios científico-técnicos, Universidad de Oviedo, Gijón, Spain
| | - Rosa Casais
- Centro de Biotecnología Animal, Servicio Regional de Investigación y Desarrollo Agroalimentario (SERIDA), Deva, Spain
- *Correspondence: Rosa Casais
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Pavlíková L, Šereš M, Breier A, Sulová Z. The Roles of microRNAs in Cancer Multidrug Resistance. Cancers (Basel) 2022; 14:cancers14041090. [PMID: 35205839 PMCID: PMC8870231 DOI: 10.3390/cancers14041090] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/16/2022] [Accepted: 02/20/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary The resistance of neoplastic cells to multiple drugs is a serious problem in cancer chemotherapy. The molecular causes of multidrug resistance in cancer are largely known, but less is known about the mechanisms by which cells deliver phenotypic changes that resist the attack of anticancer drugs. The findings of RNA interference based on microRNAs represented a breakthrough in biology and pointed to the possibility of sensitive and targeted regulation of gene expression at the post-transcriptional level. Such regulation is also involved in the development of multidrug resistance in cancer. The aim of the current paper is to summarize the available knowledge on the role of microRNAs in resistance to multiple cancer drugs. Abstract Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes in cell cycle checkpoints; elevated DNA repair mechanisms. Although these mechanisms of MDR are well described, information on their molecular interaction in overall multidrug resistance is still lacking. MicroRNA (miRNA) expression and subsequent RNA interference are candidates that could be important players in the interplay of MDR mechanisms. The regulation of post-transcriptional processes in the proteosynthetic pathway is considered to be a major function of miRNAs. Due to their complementarity, they are able to bind to target mRNAs, which prevents the mRNAs from interacting effectively with the ribosome, and subsequent degradation of the mRNAs can occur. The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to MDR. The possibility of considering miRNAs as either specific effectors or interesting targets for cancer therapy is also analyzed.
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Affiliation(s)
- Lucia Pavlíková
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
| | - Mário Šereš
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Albert Breier
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Zdena Sulová
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
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Kong J, Yu G, Si W, Li G, Chai J, Liu Y, Liu J. Identification of a glycolysis-related gene signature for predicting prognosis in patients with hepatocellular carcinoma. BMC Cancer 2022; 22:142. [PMID: 35123420 PMCID: PMC8817563 DOI: 10.1186/s12885-022-09209-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 01/06/2022] [Indexed: 12/24/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common primary liver cancer in the world. Although great advances in HCC diagnosis and treatment have been achieved, due to the complicated mechanisms in tumor development and progression, the prognosis of HCC is still dismal. Recent studies have revealed that the Warburg effect is related to the development, progression and treatment of various cancers; however, there have been a few explorations of the relationship between glycolysis and HCC prognosis. Methods mRNA expression profiling was downloaded from public databases. Gene set enrichment analysis (GSEA) was used to explore glycolysis-related genes (GRGs), and the LASSO method and Cox regression analysis were used to identify GRGs related to HCC prognosis and to construct predictive models associated with overall survival (OS) and disease-free survival (DFS). The relationship between the predictive model and the tumor mutation burden (TMB) and tumor immune microenvironment (TIME) was explored. Finally, real-time PCR was used to validate the expression levels of the GRGs in clinical samples and different cell lines. Results Five GRGs (ABCB6, ANKZF1, B3GAT3, KIF20A and STC2) were identified and used to construct gene signatures to predict HCC OS and DFS. Using the median value, HCC patients were divided into low- and high-risk groups. Patients in the high-risk group had worse OS/DFS than those in the low-risk group, were related to higher TMB and were associated with a higher rate of CD4+ memory T cells resting and CD4+ memory T cells activated. Finally, real-time PCR suggested that the five GRGs were all dysregulated in HCC samples compared to adjacent normal samples. Conclusions We identified five GRGs associated with HCC prognosis and constructed two GRGs-related gene signatures to predict HCC OS and DFS. The findings in this study may contribute to the prediction of prognosis and promote HCC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09209-9.
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Huang PJ, Huang CY, Li YX, Liu YC, Chu LJ, Yeh YM, Cheng WH, Chen RM, Lee CC, Chen LC, Lin HC, Chiu SF, Lin WN, Lyu PC, Tang P, Huang KY. Dissecting the Transcriptomes of Multiple Metronidazole-Resistant and Sensitive Trichomonas vaginalis Strains Identified Distinct Genes and Pathways Associated with Drug Resistance and Cell Death. Biomedicines 2021; 9:biomedicines9121817. [PMID: 34944632 PMCID: PMC8698965 DOI: 10.3390/biomedicines9121817] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/25/2021] [Accepted: 11/30/2021] [Indexed: 12/20/2022] Open
Abstract
Trichomonas vaginalis is the causative agent of trichomoniasis, the most prevalent non-viral sexually transmitted infection worldwide. Metronidazole (MTZ) is the mainstay of anti-trichomonal chemotherapy; however, drug resistance has become an increasingly worrying issue. Additionally, the molecular events of MTZ-induced cell death in T. vaginalis remain elusive. To gain insight into the differential expression of genes related to MTZ resistance and cell death, we conducted RNA-sequencing of three paired MTZ-resistant (MTZ-R) and MTZ-sensitive (MTZ-S) T. vaginalis strains treated with or without MTZ. Comparative transcriptomes analysis identified that several putative drug-resistant genes were exclusively upregulated in different MTZ-R strains, such as ATP-binding cassette (ABC) transporters and multidrug resistance pumps. Additionally, several shared upregulated genes among all the MTZ-R transcriptomes were not previously identified in T. vaginalis, such as 5′-nucleotidase surE and Na+-driven multidrug efflux pump, which are a potential stress response protein and a multidrug and toxic compound extrusion (MATE)-like protein, respectively. Functional enrichment analysis revealed that purine and pyrimidine metabolisms were suppressed in MTZ-S parasites upon drug treatment, whereas the endoplasmic reticulum-associated degradation (ERAD) pathway, proteasome, and ubiquitin-mediated proteolysis were strikingly activated, highlighting the novel pathways responsible for drug-induced stress. Our work presents the most detailed analysis of the transcriptional changes and the regulatory networks associated with MTZ resistance and MTZ-induced signaling, providing insights into MTZ resistance and cell death mechanisms in trichomonads.
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Affiliation(s)
- Po-Jung Huang
- Department of Biomedical Sciences, Chang Gung University, Taoyuan City 333, Taiwan;
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taoyuan City 333, Taiwan; (Y.-M.Y.); (C.-C.L.)
| | - Ching-Yun Huang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City 114, Taiwan; (C.-Y.H.); (S.-F.C.)
- Host-Parasite Interactions Laboratory, National Defense Medical Center, Taipei City 114, Taiwan
| | - Yu-Xuan Li
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan; (Y.-X.L.); (L.-J.C.); (P.T.)
| | - Yi-Chung Liu
- Institute of Bioinformatics and Structural Biology, Department of Life Science, National Tsing Hua University, Hsinchu 300, Taiwan; (Y.-C.L.); (P.-C.L.)
| | - Lichieh-Julie Chu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan; (Y.-X.L.); (L.-J.C.); (P.T.)
- Molecular Medicine Research Center, Chang Gung University, Taoyuan City 333, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan City 333, Taiwan
| | - Yuan-Ming Yeh
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taoyuan City 333, Taiwan; (Y.-M.Y.); (C.-C.L.)
| | - Wei-Hung Cheng
- Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung City 824, Taiwan;
| | - Ruei-Ming Chen
- Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan; (R.-M.C.); (H.-C.L.)
| | - Chi-Ching Lee
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taoyuan City 333, Taiwan; (Y.-M.Y.); (C.-C.L.)
- Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan City 333, Taiwan
| | - Lih-Chyang Chen
- Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan;
| | - Hsin-Chung Lin
- Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan; (R.-M.C.); (H.-C.L.)
- Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei City 114, Taiwan
| | - Shu-Fang Chiu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City 114, Taiwan; (C.-Y.H.); (S.-F.C.)
- Host-Parasite Interactions Laboratory, National Defense Medical Center, Taipei City 114, Taiwan
- Department of Inspection, Taipei City Hospital, Renai Branch, Taipei City 114, Taiwan
| | - Wei-Ning Lin
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan;
| | - Ping-Chiang Lyu
- Institute of Bioinformatics and Structural Biology, Department of Life Science, National Tsing Hua University, Hsinchu 300, Taiwan; (Y.-C.L.); (P.-C.L.)
| | - Petrus Tang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan; (Y.-X.L.); (L.-J.C.); (P.T.)
| | - Kuo-Yang Huang
- Host-Parasite Interactions Laboratory, National Defense Medical Center, Taipei City 114, Taiwan
- Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei City 114, Taiwan
- Correspondence: ; Tel.: +886-2-87923100 (ext. 18564)
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Hadanny A, Forer R, Volodarsky D, Daniel-Kotovsky M, Catalogna M, Zemel Y, Bechor Y, Efrati S. Hyperbaric oxygen therapy induces transcriptome changes in elderly: a prospective trial. Aging (Albany NY) 2021; 13:24511-24523. [PMID: 34818212 PMCID: PMC8660606 DOI: 10.18632/aging.203709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 11/11/2021] [Indexed: 12/14/2022]
Abstract
Introduction: Aging is characterized by the progressive loss of physiological capacity. Changes in gene expression can alter activity in defined age-related molecular pathways leading to cellular aging and increased aging disease susceptibility. The aim of the current study was to evaluate whether hyperbaric oxygen therapy (HBOT) affects gene expression in normal, non-pathological, aging adults. Methods: Thirty-five healthy independently living adults, aged 64 and older, were enrolled to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30th and 60th HBOT session, and 1–2 weeks following the last session. Differential gene expression analysis was performed. Results: Following 60 sessions of HBOT, 1342 genes and 570 genes were differently up- and downregulated (1912 total), respectively (p < 0.01 FDR), compared to baseline. Out of which, five genes were downregulated with a >1.5-fold change: ABCA13 (FC = −2.28), DNAJ6 (FC = −2.16), HBG2 (FC = −1.56), PDXDC1 (FC = −1.53), RANBP17 (FC = −1.75). Two weeks post-HBOT, ABCA13 expression was significantly downregulated with a >1.5fold change (FC = −1.54, p = 0.008). In conclusion, for the first time in humans, the study provides direct evidence of HBOT is associated with transcriptome changes in whole-blood samples. Our results demonstrate significant changes in gene expression of normal aging population.
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Affiliation(s)
- Amir Hadanny
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Bar Ilan University, Ramat-Gan, Israel.,Aviv Scientific LTD, Bnei-Brak, Israel
| | | | | | - Malka Daniel-Kotovsky
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin, Israel
| | - Merav Catalogna
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin, Israel
| | - Yonatan Zemel
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin, Israel.,Aviv Scientific LTD, Bnei-Brak, Israel
| | - Yair Bechor
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin, Israel.,Aviv Scientific LTD, Bnei-Brak, Israel
| | - Shai Efrati
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Aviv Scientific LTD, Bnei-Brak, Israel.,Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
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Wang JQ, Wu ZX, Yang Y, Teng QX, Li YD, Lei ZN, Jani KA, Kaushal N, Chen ZS. ATP-binding cassette (ABC) transporters in cancer: A review of recent updates. J Evid Based Med 2021; 14:232-256. [PMID: 34388310 DOI: 10.1111/jebm.12434] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023]
Abstract
The ATP-binding cassette (ABC) transporter superfamily is one of the largest membrane protein families existing in wide spectrum of organisms from prokaryotes to human. ABC transporters are also known as efflux pumps because they mediate the cross-membrane transportation of various endo- and xenobiotic molecules energized by ATP hydrolysis. Therefore, ABC transporters have been considered closely to multidrug resistance (MDR) in cancer, where the efflux of structurally distinct chemotherapeutic drugs causes reduced itherapeutic efficacy. Besides, ABC transporters also play other critical biological roles in cancer such as signal transduction. During the past decades, extensive efforts have been made in understanding the structure-function relationship, transportation profile of ABC transporters, as well as the possibility to overcome MDR via targeting these transporters. In this review, we discuss the most recent knowledge regarding ABC transporters and cancer drug resistance in order to provide insights for the development of more effective therapies.
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Affiliation(s)
- Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Zhuo-Xun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Yuqi Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Yi-Dong Li
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Zi-Ning Lei
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
- School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Khushboo A Jani
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Neeraj Kaushal
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
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Silva J, Nina P, Romão L. Translation of ABCE1 Is Tightly Regulated by Upstream Open Reading Frames in Human Colorectal Cells. Biomedicines 2021; 9:biomedicines9080911. [PMID: 34440115 PMCID: PMC8389594 DOI: 10.3390/biomedicines9080911] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 07/26/2021] [Indexed: 11/29/2022] Open
Abstract
ATP-binding cassette subfamily E member 1 (ABCE1) belongs to the ABC protein family of transporters; however, it does not behave as a drug transporter. Instead, ABCE1 actively participates in different stages of translation and is also associated with oncogenic functions. Ribosome profiling analysis in colorectal cancer cells has revealed a high ribosome occupancy in the human ABCE1 mRNA 5′-leader sequence, indicating the presence of translatable upstream open reading frames (uORFs). These cis-acting translational regulatory elements usually act as repressors of translation of the main coding sequence. In the present study, we dissect the regulatory function of the five AUG and five non-AUG uORFs identified in the human ABCE1 mRNA 5′-leader sequence. We show that the expression of the main coding sequence is tightly regulated by the ABCE1 AUG uORFs in colorectal cells. Our results are consistent with a model wherein uORF1 is efficiently translated, behaving as a barrier to downstream uORF translation. The few ribosomes that can bypass uORF1 (and/or uORF2) must probably initiate at the inhibitory uORF3 or uORF5 that efficiently repress translation of the main ORF. This inhibitory property is slightly overcome in conditions of endoplasmic reticulum stress. In addition, we observed that these potent translation-inhibitory AUG uORFs function equally in cancer and in non-tumorigenic colorectal cells, which is consistent with a lack of oncogenic function. In conclusion, we establish human ABCE1 as an additional example of uORF-mediated translational regulation and that this tight regulation contributes to control ABCE1 protein levels in different cell environments.
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Affiliation(s)
- Joana Silva
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal; (J.S.); (P.N.)
- Instituto de Biossistemas e Ciências Integrativas (BioISI), Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Pedro Nina
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal; (J.S.); (P.N.)
| | - Luísa Romão
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal; (J.S.); (P.N.)
- Instituto de Biossistemas e Ciências Integrativas (BioISI), Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Correspondence: ; Tel.: +351-21-750-8155
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Bendova P, Pardini B, Susova S, Rosendorf J, Levy M, Skrobanek P, Buchler T, Kral J, Liska V, Vodickova L, Landi S, Soucek P, Naccarati A, Vodicka P, Vymetalkova V. Genetic variations in microRNA-binding sites of solute carrier transporter genes as predictors of clinical outcome in colorectal cancer. Carcinogenesis 2021; 42:378-394. [PMID: 33319241 DOI: 10.1093/carcin/bgaa136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/01/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors, such as colorectal cancer (CRC), is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single-nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent inter-individual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient's survival. Using an in silico approach for functional predictions, we analyzed 26 miRSNPs in 9 SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient's survival. SNPs in SLCO3A1, SLC22A2 and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient's prognosis.
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Affiliation(s)
- Petra Bendova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska, Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov, Prague, Czech Republic.,Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Barbara Pardini
- IIGM Italian Institute for Genomic Medicine, Candiolo, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Simona Susova
- Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic.,Toxicogenomics Unit, National Institute of Public Health, Srobarova, Prague, Czech Republic
| | - Jachym Rosendorf
- Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Miloslav Levy
- Department of Surgery, Thomayer University Hospital, Videnska, Prague, Czech Republic
| | - Pavel Skrobanek
- Department of Oncology, Thomayer Hospital, Videnska, Prague, Czech Republic
| | - Tomas Buchler
- Department of Oncology, Thomayer Hospital, Videnska, Prague, Czech Republic
| | - Jan Kral
- Institute for Clinical and Experimental Medicine, IKEM, Prague, Czech Republic
| | - Vaclav Liska
- Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska, Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov, Prague, Czech Republic.,Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Stefano Landi
- Department of Biology, University of Pisa, Via Derna, Pisa, Italy
| | - Pavel Soucek
- Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic.,Toxicogenomics Unit, National Institute of Public Health, Srobarova, Prague, Czech Republic
| | - Alessio Naccarati
- IIGM Italian Institute for Genomic Medicine, Candiolo, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska, Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov, Prague, Czech Republic.,Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska, Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov, Prague, Czech Republic.,Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
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Kotlyarov S, Kotlyarova A. The Role of ABC Transporters in Lipid Metabolism and the Comorbid Course of Chronic Obstructive Pulmonary Disease and Atherosclerosis. Int J Mol Sci 2021; 22:6711. [PMID: 34201488 PMCID: PMC8269124 DOI: 10.3390/ijms22136711] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/12/2021] [Accepted: 06/18/2021] [Indexed: 12/11/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) ranks among the leading causes of morbidity and mortality worldwide. COPD rarely occurs in isolation and is often combined with various diseases. It is considered that systemic inflammation underlies the comorbid course of COPD. The data obtained in recent years have shown the importance of violations of the cross-links of lipid metabolism and the immune response, which are links in the pathogenesis of both COPD and atherosclerosis. The role of lipid metabolism disorders in the pathogenesis of the comorbid course of COPD and atherosclerosis and the participation of ATP-binding cassette (ABC) transporters in these processes is discussed in this article. It is known that about 20 representatives of a large family of ABC transporters provide lipid homeostasis of cells by moving lipids inside the cell and in its plasma membrane, as well as removing lipids from the cell. It was shown that some representatives of the ABC-transporter family are involved in various links of the pathogenesis of COPD and atherosclerosis, which can determine their comorbid course.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia
| | - Anna Kotlyarova
- Department of Pharmacology and Pharmacy, Ryazan State Medical University, 390026 Ryazan, Russia;
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Hanicinec V, Brynychova V, Rosendorf J, Palek R, Liska V, Oliverius M, Kala Z, Mohelnikova-Duchonova B, Krus I, Soucek P. Gene expression of cytokinesis regulators PRC1, KIF14 and CIT has no prognostic role in colorectal and pancreatic cancer. Oncol Lett 2021; 22:598. [PMID: 34188700 PMCID: PMC8228381 DOI: 10.3892/ol.2021.12859] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 05/12/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is one of the most common cancers and pancreatic cancer is among the most fatal and difficult to treat. New prognostic biomarkers are urgently needed to improve the treatment of colorectal and pancreatic cancer. Protein regulating cytokinesis 1 (PRC1), kinesin family member 14 (KIF14) and citron Rho-interacting serine/threonine kinase (CIT) serve important roles in cytokinesis, are strongly associated with cancer progression and have prognostic potential. The present study aimed to investigate the prognostic relevance of the PRC1, KIF14 and CIT genes in colorectal and pancreatic cancer. PRC1, KIF14 and CIT transcript expression was assessed by reverse transcription-quantitative PCR in tumors and paired distant unaffected mucosa from 67 patients with colorectal cancer and tumors and paired non-neoplastic control tissues from 48 patients with pancreatic cancer. The extent of transcript dysregulation between tumor and control tissues and between groups of patients divided by main clinical characteristics, namely patients' age and sex, disease stage, localization and grade, was determined. Finally, the associations of transcript levels in tumors with disease-free interval and overall survival time were evaluated. PRC1, KIF14 and CIT transcripts were upregulated in tumors compared with control tissues. PRC1, KIF14 and CIT levels strongly correlated to each other in both colorectal and pancreatic tumor and control tissues after correction for multiple testing. However, no significant associations were found among the transcript levels of PRC1, KIF14 and CIT and disease-free interval or overall survival time. In summary, the present study demonstrated mutual correlation of PRC1, KIF14 and CIT cytokinesis regulators with no clear prognostic value in pancreatic and colorectal cancers. Hence, according to the results of the present study, transcript levels of these genes cannot be clinically exploited as prognostic biomarkers in colorectal or pancreatic cancer patients.
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Affiliation(s)
- Vojtech Hanicinec
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic
| | - Veronika Brynychova
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic
| | - Jachym Rosendorf
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic.,Deparment of Surgery, Teaching Hospital and Faculty of Medicine in Pilsen, Charles University, 30460 Pilsen, Czech Republic
| | - Richard Palek
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic.,Deparment of Surgery, Teaching Hospital and Faculty of Medicine in Pilsen, Charles University, 30460 Pilsen, Czech Republic
| | - Vaclav Liska
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic.,Deparment of Surgery, Teaching Hospital and Faculty of Medicine in Pilsen, Charles University, 30460 Pilsen, Czech Republic
| | - Martin Oliverius
- Department of Surgery, Faculty Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
| | - Zdenek Kala
- Department of Surgery, University Hospital Brno and Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
| | - Beatrice Mohelnikova-Duchonova
- Department of Oncology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic
| | - Ivona Krus
- Department of Toxicogenomics, National Institute of Public Health, Prague 10042, Czech Republic
| | - Pavel Soucek
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic.,Department of Toxicogenomics, National Institute of Public Health, Prague 10042, Czech Republic
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Wang Y, Wei Q, Chen Y, Long S, Yao Y, Fu K. Identification of Hub Genes Associated With Sensitivity of 5-Fluorouracil Based Chemotherapy for Colorectal Cancer by Integrated Bioinformatics Analysis. Front Oncol 2021; 11:604315. [PMID: 33912443 PMCID: PMC8071956 DOI: 10.3389/fonc.2021.604315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 03/16/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors. 5-fluorouracil (5-FU) has been used for the standard first-line treatment for CRC patients for several decades. Although 5-FU based chemotherapy has increased overall survival (OS) of CRC patients, the resistance of CRC to 5-FU based chemotherapy is the principal cause for treatment failure. Thus, identifying novel biomarkers to predict response to 5-FU based chemotherapy is urgently needed. In the present study, the gene expression profile of GSE3964 from the Gene Expression Omnibus database was used to explore the potential genes related to intrinsic resistance to 5-FU. A gene module containing 81 genes was found to have the highest correlation with chemotherapy response using Weighted Gene Co-expression Network Analysis (WGCNA). Then a protein-protein interaction (PPI) network was constructed and ten hub genes (TGFBI, NID, LEPREL2, COL11A1, CYR61, PCOLCE, IGFBP7, COL4A2, CSPG2, and VTN) were identified using the CytoHubba plugin of Cytoscape. Seven of these hub genes showed significant differences in expression between chemotherapy-sensitive and chemotherapy-resistant samples. The prognostic value of these seven genes was evaluated using TCGA COAD (Colorectal Adenocarcinoma) data. The results showed that TGFBI was highly expressed in chemotherapy-sensitive patients, and patients with high TGFBI expression have better survival.
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Affiliation(s)
- Ya Wang
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Qunhui Wei
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China
| | - Yuqiao Chen
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Shichao Long
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yuanbing Yao
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Kai Fu
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.,Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China.,Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
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49
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Revealing the Role of High-Density Lipoprotein in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22073352. [PMID: 33805921 PMCID: PMC8037642 DOI: 10.3390/ijms22073352] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a highly prevalent malignancy with multifactorial etiology, which includes metabolic alterations as contributors to disease development. Studies have shown that lipid status disorders are involved in colorectal carcinogenesis. In line with this, previous studies have also suggested that the serum high-density lipoprotein cholesterol (HDL-C) level decreases in patients with CRC, but more recently, the focus of investigations has shifted toward the exploration of qualitative properties of HDL in this malignancy. Herein, a comprehensive overview of available evidences regarding the putative role of HDL in CRC will be presented. We will analyze existing findings regarding alterations of HDL-C levels but also HDL particle structure and distribution in CRC. In addition, changes in HDL functionality in this malignancy will be discussed. Moreover, we will focus on the genetic regulation of HDL metabolism, as well as the involvement of HDL in disturbances of cholesterol trafficking in CRC. Finally, possible therapeutic implications related to HDL will be presented. Given the available evidence, future studies are needed to resolve all raised issues concerning the suggested protective role of HDL in CRC, its presumed function as a biomarker, and eventual therapeutic approaches based on HDL.
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50
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Asif M, Usman M, Ayub S, Farhat S, Huma Z, Ahmed J, Kamal MA, Hussein D, Javed A, Khan I. Role of ATP-Binding Cassette Transporter Proteins in CNS Tumors: Resistance- Based Perspectives and Clinical Updates. Curr Pharm Des 2021; 26:4747-4763. [PMID: 32091329 DOI: 10.2174/1381612826666200224112141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/22/2020] [Indexed: 12/24/2022]
Abstract
Despite gigantic advances in medical research and development, chemotherapeutic resistance remains a major challenge in complete remission of CNS tumors. The failure of complete eradication of CNS tumors has been correlated with the existence of several factors including overexpression of transporter proteins. To date, 49 ABC-transporter proteins (ABC-TPs) have been reported in humans, and the evidence of their strong association with chemotherapeutics' influx, dissemination, and efflux in CNS tumors, is growing. Research studies on CNS tumors are implicating ABC-TPs as diagnostic, prognostic and therapeutic biomarkers that may be utilised in preclinical and clinical studies. With the current advancements in cell biology, molecular analysis of genomic and transcriptomic interplay, and protein homology-based drug-transporters interaction, our research approaches are streamlining the roles of ABC-TPs in cancer and multidrug resistance. Potential inhibitors of ABC-TP for better clinical outcomes in CNS tumors have emerged. Elacridar has shown to enhance the chemo-sensitivity of Dasatanib and Imatinib in various glioma models. Tariquidar has improved the effectiveness of Temozolomide's in CNS tumors. Although these inhibitors have been effective in preclinical settings, their clinical outcomes have not been as significant in clinical trials. Thus, to have a better understanding of the molecular evaluations of ABC-TPs, as well as drug-interactions, further research is being pursued in research labs. Our lab aims to better comprehend the biological mechanisms involved in drug resistance and to explore novel strategies to increase the clinical effectiveness of anticancer chemotherapeutics, which will ultimately improve clinical outcomes.
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Affiliation(s)
- M Asif
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - M Usman
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Shahid Ayub
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan,Department of Neurosurgery, Hayatabad Medical Complex, KPK Medical Teaching Institute, Peshawar, Pakistan
| | - Sahar Farhat
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Zilli Huma
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Jawad Ahmed
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Mohammad A Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia,4Enzymoics; Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW 2770, Australia
| | - Deema Hussein
- Neurooncology Translational Group, Medical Technology, College of Applied Medical Sciences, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Aneela Javed
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology,
Islamabad 44000, Pakistan,Department of Infectious diseases, Brigham and Women Hospital, Harvard Medical School, Cambridge, Boston, MA 02139, USA
| | - Ishaq Khan
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
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