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Gabriel PE, Compérat E, Cancel-Tassin G, Varinot J, Roumiguié M, Patard PM, Daniel G, Pfister C, Delcourt C, Gobet F, Larré S, Léon P, Durlach A, Bigot P, Carrouget J, Eymerit C, Bessède T, Lebacle C, Ferlicot S, Ruffion A, Seizilles de Mazancourt E, Decaussin-Petrucci M, Crouzet S, Matillon X, Mège-Lechevallier F, Robert G, Vuong NS, Philip M, Lang H, Mouracade P, Lindner V, Cussenot O, Rouprêt M, Seisen T. Assessment of the Prognostic and Predictive Values of the Deficient Mismatch Repair Phenotype in Patients Treated with Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma. Eur Urol Oncol 2025:S2588-9311(25)00092-6. [PMID: 40307090 DOI: 10.1016/j.euo.2025.03.014] [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: 01/23/2025] [Revised: 02/22/2025] [Accepted: 03/27/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND AND OBJECTIVE Given the conflicting evidence currently available in the literature, our aim was to assess the prognostic and predictive values of the deficient mismatch repair (dMMR) phenotype in a large cohort of upper tract urothelial carcinoma (UTUC) patients. METHODS Based on our national network, we performed a retrospective multicenter study including 281 UTUC patients treated with radical nephroureterectomy between 2000 and 2015 at ten French hospitals. The dMMR phenotype as well as PD-L1 and PD-1 expression were determined using immunohistochemistry analyses based on 2-mm-core tissue microarrays. Multivariable Cox regression models were fitted to assess the impact of the dMMR phenotype on recurrence-free (RFS), cancer-specific (CSS), and overall (OS) survival using interaction terms to test the heterogeneity of the treatment effect of adjuvant chemotherapy (AC). Multivariable logistic regression models were also fitted to assess the impact of the dMMR phenotype on PD-L1 and PD-1 expression. KEY FINDINGS AND LIMITATIONS Overall, 76 (27.0%) patients had a dMMR phenotype, which was an independent predictor of prolonged RFS (hazard ratio [HR] = 0.41; 95% confidence interval [CI] = [0.21-0.83]; p = 0.01), CSS (HR = 0.38; 95% CI = [0.18-0.83]; p = 0.02), and OS (HR = 0.44; 95% CI = [0.22-0.89]; p = 0.02), with a significant interaction with the use of AC in multivariable Cox regression models (all pinteraction < 0.05). Subgroup analyses showed that the use of AC was significantly associated with prolonged RFS (HR = 0.14; 95% CI = [0.06-0.30]; p < 0.001), CSS (HR = 0.10; 95% CI = [0.03-0.29]; p < 0.001), and OS (HR = 0.23; 95% CI = [0.10-0.54]; p = 0.001) in non-dMMR patients only, without any significant benefit in dMMR patients (all p > 0.05). In multivariable logistic regression analyses, the dMMR phenotype was significantly associated with inverse PD-L1 (OR = 0.20; 95% CI = [0.10-0.80]; p = 0.001) and PD-1 (OR = 0.36; 95% CI = [0.16-0.79]; p = 0.01) expression. CONCLUSIONS AND CLINICAL IMPLICATIONS We observed that the dMMR phenotype was associated with favorable pathological characteristics and prognosis in UTUC patients, despite conferring decreased sensitivity to AC and lower PD-L1 or PD-1 expression.
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Affiliation(s)
- Pierre-Etienne Gabriel
- Urology, GRC 5 Predictive Onco-Urology, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
| | - Eva Compérat
- Department of Pathology, Medical University of Vienna, Vienna, Austria; GRC 5, Predictive Onco-Urology, Sorbonne University, Paris, France; CeRePP, Tenon Hospital, Paris, France
| | - Géraldine Cancel-Tassin
- GRC 5, Predictive Onco-Urology, Sorbonne University, Paris, France; CeRePP, Tenon Hospital, Paris, France
| | - Justine Varinot
- Department of Pathology, Tenon University Hospital, AP-HP, Paris, France
| | - Mathieu Roumiguié
- Department of Urology, Toulouse University Hospital, University of Toulouse UT3, Toulouse, France
| | - Pierre-Marie Patard
- Department of Urology, Toulouse University Hospital, University of Toulouse UT3, Toulouse, France
| | - Gwendoline Daniel
- Department of Pathology, Toulouse University Hospital, University of Toulouse UT3, Toulouse, France
| | - Christian Pfister
- Urology, CIC Inserm 1404, Charles Nicolle University Hospital, Rouen Normandie University, Rouen, France
| | - Clara Delcourt
- Urology, CIC Inserm 1404, Charles Nicolle University Hospital, Rouen Normandie University, Rouen, France
| | - Françoise Gobet
- Department of Pathology, Charles Nicolle University Hospital, Rouen, France
| | - Stéphane Larré
- CeRePP, Tenon Hospital, Paris, France; Department of Urology, Reims University Hospital, Reims, France
| | - Priscilla Léon
- Department of Urology, Reims University Hospital, Reims, France
| | - Anne Durlach
- Department of Pathology, Reims University Hospital, Reims, France
| | - Pierre Bigot
- Department of Urology, Angers University Hospital, Angers, France
| | - Julie Carrouget
- Department of Urology, Angers University Hospital, Angers, France
| | - Caroline Eymerit
- Department of Pathology, Angers University Hospital, Angers, France
| | - Thomas Bessède
- Department of Urology, Bicêtre University Hospital, AP-HP, Paris-Saclay University, Le Kremlin Bicêtre, France
| | - Cédric Lebacle
- Department of Urology, Bicêtre University Hospital, AP-HP, Paris-Saclay University, Le Kremlin Bicêtre, France
| | - Sophie Ferlicot
- Department of Pathology, Bicêtre University Hospital, AP-HP, Paris-Saclay University, Le Kremlin Bicêtre, France
| | - Alain Ruffion
- Department of Urology, Lyon-Sud University Hospital, Hospices Civils de Lyon, Claude Bernard University, Lyon, France
| | | | - Myriam Decaussin-Petrucci
- Department of Pathology, Lyon-Sud University Hospital, Hospices Civils de Lyon, Claude Bernard University, Lyon, France
| | - Sébastien Crouzet
- Department of Urology, Edouard Herriot University Hospital, Lyon 1 University, Lyon, France
| | - Xavier Matillon
- Department of Urology, Edouard Herriot University Hospital, Lyon 1 University, Lyon, France
| | | | - Grégoire Robert
- Department of Urology, Bordeaux Pellegrin University Hospital, Bordeaux, France
| | - Nam-Son Vuong
- Department of Urology, Bordeaux Pellegrin University Hospital, Bordeaux, France
| | - Magali Philip
- Department of Pathology, Bordeaux Pellegrin University Hospital, Bordeaux, France
| | - Hervé Lang
- Department of Urology, Strasbourg University Hospital, Strasbourg, France
| | - Pascal Mouracade
- Department of Urology, Strasbourg University Hospital, Strasbourg, France
| | - Véronique Lindner
- Department of Pathology, Strasbourg University Hospital, Strasbourg, France
| | | | - Morgan Rouprêt
- Urology, GRC 5 Predictive Onco-Urology, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France; CeRePP, Tenon Hospital, Paris, France
| | - Thomas Seisen
- Urology, GRC 5 Predictive Onco-Urology, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
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Gabriel PE, Cancel-Tassin G, Audenet F, Masson-Lecomte A, Allory Y, Roumiguié M, Pradère B, Loriot Y, Léon P, Traxer O, Xylinas E, Rouprêt M, Neuzillet Y, Seisen T. A collaborative review of the microsatellite instability/deficient mismatch repair phenotype in patients with upper tract urothelial carcinoma. BJU Int 2024; 134:723-735. [PMID: 38813615 DOI: 10.1111/bju.16405] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
OBJECTIVE To perform a collaborative review of the literature exploring the microsatellite instability/deficient mismatch repair (MSI/dMMR) phenotype in patients with upper tract urothelial carcinoma (UTUC). METHOD A collaborative review of the literature available on Medline was conducted by the Cancer Committee of the French Association of Urology to report studies describing the genetic mechanisms, investigation, prevalence and impact of the MSI/dMMR phenotype in UTUC patients. RESULTS The predominant genetic mechanism leading to the MSI/dMMR phenotype in UTUC patients is related to the constitutional mutation of one allele of the MMR genes MLH1, MSH2, MSH6 and PMS2 within Lynch syndrome. Indications for its investigation currently remain limited to patients with a clinical suspicion for sporadic UTUC to refer only those with a positive testing for germline DNA sequencing to screen for this syndrome. With regard to technical aspects, despite the interest of MSIsensor, only PCR and immunohistochemistry are routinely used to somatically investigate the MSI and dMMR phenotypes, respectively. The prevalence of the MSI/dMMR phenotype in UTUC patients ranges from 1.7% to 57%, depending on the study population, investigation method and definition of a positive test. Younger age and a more balanced male to female ratio at initial diagnosis are the main specific clinical characteristics of UTUC patients with an MSI/dMMR phenotype. Despite the conflicting results available in the literature, these patients may have a better prognosis, potentially related to more favourable pathological features. Finally, they may also have lower sensitivity to chemotherapy but greater sensitivity to immunotherapy. CONCLUSION Our collaborative review summarises the available data from published studies exploring the MSI/dMMR phenotype in UTUC patients, the majority of which are limited by a low level of evidence.
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Affiliation(s)
- Pierre-Etienne Gabriel
- GRC 5 Predictive Onco-Uro, Sorbonne University, AP-HP, Urology, Pitie-Salpetriere Hospital, Paris, France
| | | | - François Audenet
- Department of urology, Georges Pompidou European Hospital, APHP, Centre, Université Paris Cité, Paris, France
| | | | - Yves Allory
- Department of Pathology, Institut Curie, Saint-Cloud, Paris, France
| | | | - Benjamin Pradère
- Department of Urology, La Croix Du Sud Hospital, Quint Fonsegrives, France
| | - Yohann Loriot
- Department of Oncology, Gustave Roussy, Villejuif, France
| | | | - Olivier Traxer
- Department of Urology, Tenon Hospital, AP-HP, Paris, France
| | - Evanguelos Xylinas
- Department of Urology, Bichat-Claude Bernard Hospital, AP-HP, Université de Paris, Paris, France
| | - Morgan Rouprêt
- GRC 5 Predictive Onco-Uro, Sorbonne University, AP-HP, Urology, Pitie-Salpetriere Hospital, Paris, France
| | - Yann Neuzillet
- Department of Urology, Foch Hospital, University of Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Suresnes, France
| | - Thomas Seisen
- GRC 5 Predictive Onco-Uro, Sorbonne University, AP-HP, Urology, Pitie-Salpetriere Hospital, Paris, France
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Varol A, Boulos JC, Jin C, Klauck SM, Zhitkovich A, Efferth T. Inhibition of MSH6 augments the antineoplastic efficacy of cisplatin in non-small cell lung cancer as autophagy modulator. Chem Biol Interact 2024; 402:111193. [PMID: 39168426 DOI: 10.1016/j.cbi.2024.111193] [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: 04/23/2024] [Revised: 07/18/2024] [Accepted: 08/07/2024] [Indexed: 08/23/2024]
Abstract
The altered response to chemotherapeutic agents predominantly stems from heightened single-point mutations within coding regions and dysregulated expression levels of genes implicated in drug resistance mechanisms. The identification of biomarkers based on mutation profiles and expression levels is pivotal for elucidating the underlying mechanisms of altered drug responses and for refining combinatorial therapeutic strategies in the field of oncology. Utilizing comprehensive bioinformatic analyses, we investigated the impact of eight mismatch repair (MMR) genes on overall survival across 23 cancer types, encompassing more than 7500 tumors, by integrating their mutation profiles. Among these genes, MSH6 emerged as the most predictive biomarker, characterized by a pronounced mutation frequency and elevated expression levels, which correlated with poorer patient survival outcomes. The wet lab experiments disclosed the impact of MSH6 in mediating altered drug responses. Cytotoxic assays conducted revealed that the depletion of MSH6 in H460 non-small lung cancer cells augmented the efficacy of cisplatin, carboplatin, and gemcitabine. Pathway analyses further delineated the involvement of MSH6 as a modulator, influencing the delicate equilibrium between the pro-survival and pro-death functions of autophagy. Our study elucidates the intricate interplay between MSH6, autophagy, and cisplatin efficacy, highlighting MSH6 as a potential therapeutic target to overcome cisplatin resistance. By revealing the modulation of autophagy pathways by MSH6 inhibition, our findings offer insights into novel approaches for enhancing the efficacy of cisplatin-based cancer therapy through targeted interventions.
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Affiliation(s)
- Ayşegül Varol
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, 55128, Mainz, Germany
| | - Joelle C Boulos
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, 55128, Mainz, Germany
| | - Chunmei Jin
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, 55128, Mainz, Germany
| | - Sabine M Klauck
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ) Heidelberg, National Center for Tumor Diseases (NCT), NCT Heidelberg, a Partnership Between DKFZ and University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Anatoly Zhitkovich
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, 02903, USA
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, 55128, Mainz, Germany.
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Yadav M, Vaishkiar I, Sharma A, Shukla A, Mohan A, Girdhar M, Kumar A, Malik T, Mohan A. Oestrogen receptor positive breast cancer and its embedded mechanism: breast cancer resistance to conventional drugs and related therapies, a review. Open Biol 2024; 14:230272. [PMID: 38889771 DOI: 10.1098/rsob.230272] [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: 08/10/2023] [Accepted: 03/14/2024] [Indexed: 06/20/2024] Open
Abstract
Traditional medication and alternative therapies have long been used to treat breast cancer. One of the main problems with current treatments is that there is an increase in drug resistance in the cancer cells owing to genetic differences such as mutational changes, epigenetic changes and miRNA (microRNA) alterations such as miR-1246, miR-298, miR-27b and miR-33a, along with epigenetic modifications, such as Histone3 acetylation and CCCTC-Binding Factor (CTCF) hypermethylation for drug resistance in breast cancer cell lines. Certain forms of conventional drug resistance have been linked to genetic changes in genes such as ABCB1, AKT, S100A8/A9, TAGLN2 and NPM. This review aims to explore the current approaches to counter breast cancer, the action mechanism, along with novel therapeutic methods endowing potential drug resistance. The investigation of novel therapeutic approaches sheds light on the phenomenon of drug resistance including genetic variations that impact distinct forms of oestrogen receptor (ER) cancer, genetic changes, epigenetics-reported resistance and their identification in patients. Long-term effective therapy for breast cancer includes selective oestrogen receptor modulators, selective oestrogen receptor degraders and genetic variations, such as mutations in nuclear genes, epigenetic modifications and miRNA alterations in target proteins. Novel research addressing combinational therapies including maytansine, photodynamic therapy, guajadiol, talazoparib, COX2 inhibitors and miRNA 1246 inhibitors have been developed to improve patient survival rates.
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Affiliation(s)
- Manu Yadav
- Division of Genetics, ICAR- Indian Agricultural Research Institute , Pusa, New Delhi, India
| | - Ishita Vaishkiar
- Amity Institute of Biotechnology (AIB) University, Amity University Noida , Noida, India
| | - Ananya Sharma
- Department: Botany and Microbiology, Hemwati Nandan Bahuguna Garhwal University , Srinagar, India
| | - Akanksha Shukla
- School of Bioengineering and Biosciences, Lovely Professional University , Phagwara, Punjab, India
| | - Aradhana Mohan
- Department of Biomedical Engineering, University of Michigan , Ann Arbor, MI, USA
| | - Madhuri Girdhar
- Division of Research and Development, Lovely Professional University , Phagwara, Punjab, India
| | - Anil Kumar
- Gene Regulation Laboratory, National Institute of Immunology , New Delhi, India
| | - Tabarak Malik
- Department of Biomedical Sciences, Institute of Health, Jimma University , Jimma, Oromia 378, Ethiopia
| | - Anand Mohan
- School of Bioengineering and Biosciences, Lovely Professional University , Phagwara, Punjab, India
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Gu L, Hickey RJ, Malkas LH. Therapeutic Targeting of DNA Replication Stress in Cancer. Genes (Basel) 2023; 14:1346. [PMID: 37510250 PMCID: PMC10378776 DOI: 10.3390/genes14071346] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/30/2023] Open
Abstract
This article reviews the currently used therapeutic strategies to target DNA replication stress for cancer treatment in the clinic, highlighting their effectiveness and limitations due to toxicity and drug resistance. Cancer cells experience enhanced spontaneous DNA damage due to compromised DNA replication machinery, elevated levels of reactive oxygen species, loss of tumor suppressor genes, and/or constitutive activation of oncogenes. Consequently, these cells are addicted to DNA damage response signaling pathways and repair machinery to maintain genome stability and support survival and proliferation. Chemotherapeutic drugs exploit this genetic instability by inducing additional DNA damage to overwhelm the repair system in cancer cells. However, the clinical use of DNA-damaging agents is limited by their toxicity and drug resistance often arises. To address these issues, the article discusses a potential strategy to target the cancer-associated isoform of proliferating cell nuclear antigen (caPCNA), which plays a central role in the DNA replication and damage response network. Small molecule and peptide agents that specifically target caPCNA can selectively target cancer cells without significant toxicity to normal cells or experimental animals.
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Affiliation(s)
- Long Gu
- Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Robert J Hickey
- Department of Cancer Biology & Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Linda H Malkas
- Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
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Dong L, Jiang H, Kang Z, Guan M. Biomarkers for chemotherapy and drug resistance in the mismatch repair pathway. Clin Chim Acta 2023; 544:117338. [PMID: 37060988 DOI: 10.1016/j.cca.2023.117338] [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: 09/10/2022] [Revised: 04/09/2023] [Accepted: 04/10/2023] [Indexed: 04/17/2023]
Abstract
Drugs targeting DNA repair have developed rapidly in cancer therapy, and numerous inhibitors have already been utilized in preclinical and clinical stages. To optimize the selection of patients for treatment, it is essential to discover biomarkers to anticipate chemotherapy response. The DNA mismatch repair (MMR) pathway is closely correlated with cancer susceptibility and plays an important role in the occurrence and development of cancers. Here, we give a concise introduction of the MMR genes and focus on the potential biomarkers of chemotherapeutic response and resistance. It has been clarified that the status of MMR may affect the outcome of chemotherapy. However, the specific underlying mechanisms as well as contradictory results continue to raise considerable controversy and concern. In this review, we summarize the current literature to provide a general overview.
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Affiliation(s)
- Liu Dong
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, People's Republic of China
| | - Haoqin Jiang
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, People's Republic of China
| | - Zhihua Kang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, USA.
| | - Ming Guan
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, People's Republic of China.
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Bruekner SR, Pieters W, Fish A, Liaci AM, Scheffers S, Rayner E, Kaldenbach D, Drost L, Dekker M, van Hees-Stuivenberg S, Delzenne-Goette E, de Konink C, Houlleberghs H, Dubbink H, AlSaegh A, de Wind N, Förster F, te Riele H, Sixma T. Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding. Nucleic Acids Res 2023; 51:1173-1188. [PMID: 36715327 PMCID: PMC9943660 DOI: 10.1093/nar/gkad015] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 12/30/2022] [Accepted: 01/12/2023] [Indexed: 01/31/2023] Open
Abstract
The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair lead to a predisposition to cancer. Here, we study the homozygous mutation V63E in MSH2 that was found in the germline of a patient with suspected constitutional mismatch repair deficiency syndrome who developed colorectal cancer before the age of 30. Characterization of the mutant in mouse models, as well as slippage and repair assays, shows a mildly pathogenic phenotype. Using cryogenic electron microscopy and surface plasmon resonance, we explored the mechanistic effect of this mutation on MutSα function. We discovered that V63E disrupts a previously unappreciated interface between the mismatch binding domains (MBDs) of MSH2 and MSH6 and leads to reduced DNA binding. Our research identifies this interface as a 'safety lock' that ensures high-affinity DNA binding to increase replication fidelity. Our mechanistic model explains the hypomorphic phenotype of the V63E patient mutation and other variants in the MBD interface.
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Affiliation(s)
| | | | - Alexander Fish
- Division of Biochemistry, Netherlands Cancer Institute and Oncode Institute, 1066 CX Amsterdam, The Netherlands
| | - A Manuel Liaci
- Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584CH Utrecht, The Netherlands
| | - Serge Scheffers
- Division of Biochemistry, Netherlands Cancer Institute and Oncode Institute, 1066 CX Amsterdam, The Netherlands
| | - Emily Rayner
- Department of Human Genetics, Leiden University Medical Center, PO Box 9600 2300RC Leiden, The Netherlands
| | - Daphne Kaldenbach
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
| | - Lisa Drost
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
| | - Marleen Dekker
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
| | | | - Elly Delzenne-Goette
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
| | - Charlotte de Konink
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
| | - Hellen Houlleberghs
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
| | - Hendrikus Jan Dubbink
- Department of Pathology, Erasmus Medical Center, PO Box 2040 3000CA Rotterdam, The Netherlands
| | - Abeer AlSaegh
- Sultan Qaboos Comprehensive Cancer Care and Research Center, PO Box 787, 117 Muscat, Oman
| | - Niels de Wind
- Department of Human Genetics, Leiden University Medical Center, PO Box 9600 2300RC Leiden, The Netherlands
| | - Friedrich Förster
- Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584CH Utrecht, The Netherlands
| | - Hein te Riele
- Correspondence may also be addressed to Hein te Riele. Tel: +31 20 512 2084;
| | - Titia K Sixma
- To whom correspondence should be addressed: Tel: +31 20 512 1959;
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Jin Y, Lan A, Dai Y, Jiang L, Liu S. Comparison of the pCR Rate and DFS Among Breast Cancer Patients with Different Hormone Receptor and HER2 Statuses. BREAST CANCER (DOVE MEDICAL PRESS) 2023; 15:327-335. [PMID: 37153867 PMCID: PMC10162099 DOI: 10.2147/bctt.s407896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/27/2023] [Indexed: 05/10/2023]
Abstract
Background Recent studies have investigated the features of breast cancer (BC) with low human epidermal growth factor receptor 2 (HER2) expression or HER2-0 expression. However, the results were inconsistent. In this study, we investigated the differences in the pathological complete response (pCR) rate and disease-free survival (DFS) between HER2-low and HER2-0 BC patients and between subgroups. Methods HER2-negative BC patients who received neoadjuvant chemotherapy between January 2013 and December 2019 in our hospital were retrospectively reviewed. First, the pCR rate and DFS were compared between HER2-low and HER2-0 patients and among different hormone receptor (HR) and HER2 statuses. Subsequently, DFS was compared between different HER2 status populations with or without pCR. Finally, a Cox regression model was used to identify the prognostic factors. Results Overall, 693 patients were selected: 561 were HER2-low, and 132 were HER2-0. Between the two groups, there were significant differences in N stage (P = 0.008) and HR status (P = 0.007). No significant difference in the pCR rate (12.12% vs 14.39%, P = 0.468) or DFS was observed, independent of HR status. HR+/HER2-low patients had a significantly worse pCR rate (P < 0.001) and longer DFS (P < 0.001) than HR-/HER2-low or HER2-0 patients. In addition, a longer DFS was found in HER2-low patients versus HER2-0 patients among those who did not achieve pCR. Cox regression showed that N stage and HR status were prognostic factors in the overall and HER2-low populations, while no prognostic factor was found in the HER2-0 group. Conclusion This study suggested that HER2 status is not associated with the pCR rate or DFS. Longer DFS was found only among patients who did not achieve pCR in the HER2-low versus HER2-0 population. We speculated that the interaction of HR and HER2 might have played a crucial role in this process.
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Affiliation(s)
- Yudi Jin
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Department of Pathology, Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, Chongqing, 400030, People’s Republic of China
| | - Ailin Lan
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Yuran Dai
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Linshan Jiang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Shengchun Liu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Correspondence: Shengchun Liu, Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China, Email
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The impact of HER2-low status on response to neoadjuvant chemotherapy in clinically HER2-negative breast cancer. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 25:1673-1681. [PMID: 36586066 DOI: 10.1007/s12094-022-03062-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 12/24/2022] [Indexed: 01/01/2023]
Abstract
PURPOSE Low expression of HER2 (HER2-low expression) in breast cancer (BC) has unique biological characteristics. However, whether HER2-low expression has an impact on neoadjuvant chemotherapy (NACT) in HER2-negative breast cancer remains unclear. METHODS This study reviewed the clinicopathological data of patients with BC treated with NACT at a single hospital from January 2018 to July 2022. Baseline patient characteristics, efficacy of NACT, and survival data were compared between the HER2-0 and HER2-low groups. The impact of NACT on HER2 status also was investigated. Subgroup analyses based on hormone receptor (HR) status were performed to explore the impact of HR signaling on HER2 status during chemotherapy. RESULTS The progesterone receptor-positive rate in the HER2-low group was significantly higher than that in HER2-0 group. The local treatment response of the HER2-low group was worse, but the disease-free survival rate of the HER2-low group was significantly better than that of the HER2-0 group. The proportion of patients with increased HER2 immunohistochemistry score after NACT was significantly higher in the HER2-0 group. Subgroup analysis showed that the efficacy of chemotherapy in HR + patients was significantly worse than in HR- patients, and HR + patients had a higher proportion of increased HER2 immunohistochemistry score after chemotherapy. Mechanistic studies suggested that MLH1 expression loss during chemotherapy might link HR signaling and regulation of HER2 expression. CONCLUSIONS We found that HER2-low expressing BC exhibits differential sensitivity to chemotherapy compared to HER2-0 expressing BC. The regulation of HER2 expression by HR signaling may mediate aspects of chemoresistance.
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10
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Forgie BN, Prakash R, Telleria CM. Revisiting the Anti-Cancer Toxicity of Clinically Approved Platinating Derivatives. Int J Mol Sci 2022; 23:15410. [PMID: 36499737 PMCID: PMC9793759 DOI: 10.3390/ijms232315410] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/02/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.
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Affiliation(s)
- Benjamin N. Forgie
- Experimental Pathology Unit, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Rewati Prakash
- Experimental Pathology Unit, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Carlos M. Telleria
- Experimental Pathology Unit, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
- Cancer Research Program, Research Institute, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
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11
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Daniels HG, Knicely BG, Miller AK, Thompson A, Plattner R, Goellner EM. Inhibition of ABL1 by tyrosine kinase inhibitors leads to a downregulation of MLH1 by Hsp70-mediated lysosomal protein degradation. Front Genet 2022; 13:940073. [PMID: 36338985 PMCID: PMC9631443 DOI: 10.3389/fgene.2022.940073] [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: 05/09/2022] [Accepted: 10/03/2022] [Indexed: 01/07/2023] Open
Abstract
The DNA mismatch repair (MMR) pathway and its regulation are critical for genomic stability. Mismatch repair (MMR) follows replication and repairs misincorporated bases and small insertions or deletions that are not recognized and removed by the proofreading polymerase. Cells deficient in MMR exhibit an increased overall mutation rate and increased expansion and contraction of short repeat sequences in the genome termed microsatellite instability (MSI). MSI is often a clinical measure of genome stability in tumors and is used to determine the course of treatment. MMR is also critical for inducing apoptosis after alkylation damage from environmental agents or DNA-damaging chemotherapy. MLH1 is essential for MMR, and loss or mutation of MLH1 leads to defective MMR, increased mutation frequency, and MSI. In this study, we report that tyrosine kinase inhibitors, imatinib and nilotinib, lead to decreased MLH1 protein expression but not decreased MLH1 mRNA levels. Of the seven cellular targets of Imatinib and nilotinib, we show that silencing of ABL1 also reduces MLH1 protein expression. Treatment with tyrosine kinase inhibitors or silencing of ABL1 results in decreased apoptosis after treatment with alkylating agents, suggesting the level of MLH1 reduction is sufficient to disrupt MMR function. We also report MLH1 is tyrosine phosphorylated by ABL1. We demonstrate that MLH1 downregulation by ABL1 knockdown or inhibition requires chaperone protein Hsp70 and that MLH1 degradation can be abolished with the lysosomal inhibitor bafilomycin. Taken together, we propose that ABL1 prevents MLH1 from being targeted for degradation by the chaperone Hsp70 and that in the absence of ABL1 activity at least a portion of MLH1 is degraded through the lysosome. This study represents an advance in understanding MMR pathway regulation and has important clinical implications as MMR status is used in the clinic to inform patient treatment, including the use of immunotherapy.
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Affiliation(s)
- Hannah G. Daniels
- University of Kentucky, College of Medicine Department of Toxicology and Cancer Biology, Lexington, KY, United States
| | - Breanna G. Knicely
- University of Kentucky, College of Medicine Department of Toxicology and Cancer Biology, Lexington, KY, United States
| | - Anna Kristin Miller
- University of Kentucky, College of Medicine Department of Toxicology and Cancer Biology, Lexington, KY, United States
| | - Ana Thompson
- Berea College, Berea, KY, United States,University of Kentucky Markey Cancer Center, Lexington, KY, United States
| | - Rina Plattner
- University of Kentucky Markey Cancer Center, Lexington, KY, United States,University of Kentucky, College of Medicine Department of Pharmacology and Nutritional Sciences, Lexington, KY, United States
| | - Eva M. Goellner
- University of Kentucky, College of Medicine Department of Toxicology and Cancer Biology, Lexington, KY, United States,University of Kentucky Markey Cancer Center, Lexington, KY, United States,*Correspondence: Eva M. Goellner,
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12
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Carboplatin and decitabine loaded lipid-coated albumin nanoparticles for an efficient treatment of platinum-resistant ovarian cancer. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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13
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Naves MPC, de Morais CR, de Freitas V, Ribeiro DL, Lopes DS, Antunes LMG, de Melo Rodrigues V, de Rezende AAA, Spanó MA. Mutagenic and genotoxic activities of Phospholipase A 2 Bothropstoxin-I from Bothrops jararacussu in Drosophila melanogaster and human cell lines. Int J Biol Macromol 2021; 182:1602-1610. [PMID: 34033823 DOI: 10.1016/j.ijbiomac.2021.05.114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/13/2021] [Accepted: 05/16/2021] [Indexed: 11/29/2022]
Abstract
Phospholipase A2 Bothropstoxin-I (PLA2 BthTX-I) is a myotoxic Lys49-PLA2 from Bothrops jararacussu snake venom. In order to evaluate the DNA damage caused by BthTX-I, we used the Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster and Comet assay in HUVEC and DU-145 cells. For SMART, different concentrations of BthTX-I (6.72 to 430 μg/mL) were used and no significant changes in the survival rate were observed. Significant frequency of mutant spots was observed for the ST cross at the highest concentration of BthTX-I due to recombinogenic activity. In the HB cross, BthTX-I increased the number of mutant spots at intermediate concentrations, being 53.75 μg/mL highly mutagenic and 107.5 μg/mL predominantly recombinogenic. The highest concentrations were neither mutagenic nor recombinogenic, which could indicate cytotoxicity in the wing cells of D. melanogaster. In vitro, all BthTX-I concentrations (1 to 50 μg/mL) induced decrease in HUVEC cell viability, as well as in DU-145 cells at concentrations of 10, 25, and 50 μg/mL. The comet assay showed that in HUVEC and DU-145 cells, all BthTX-I concentrations promoted increase of DNA damage. Further studies should be performed to elucidate the mechanism of action of PLA2 BthTX-I and its possible use in therapeutic strategies against cancer.
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Affiliation(s)
| | - Cássio Resende de Morais
- Institute of Biotechnology, Federal University of Uberlândia, Campus Umuarama, Uberlândia, MG, Brazil
| | - Vitor de Freitas
- Institute of Biotechnology, Federal University of Uberlândia, Campus Umuarama, Uberlândia, MG, Brazil
| | - Diego Luis Ribeiro
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Daiana Silva Lopes
- Multidisciplinary Institute in Health, Federal University of Bahia, Vitória da Conquista, BA, Brazil
| | - Lusânia Maria Greggi Antunes
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | | | | | - Mário Antônio Spanó
- Institute of Biotechnology, Federal University of Uberlândia, Campus Umuarama, Uberlândia, MG, Brazil.
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Köberle B, Schoch S. Platinum Complexes in Colorectal Cancer and Other Solid Tumors. Cancers (Basel) 2021; 13:cancers13092073. [PMID: 33922989 PMCID: PMC8123298 DOI: 10.3390/cancers13092073] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary Cisplatin is successfully used for the treatment of various solid cancers. Unfortunately, it shows no activity in colorectal cancer. The resistance phenotype of colorectal cancer cells is mainly caused by alterations in p53-controlled DNA damage signaling and/or defects in the cellular mismatch repair pathway. Improvement of platinum-based chemotherapy in cisplatin-unresponsive cancers, such as colorectal cancer, might be achieved by newly designed cisplatin analogues, which retain activity in unresponsive tumor cells. Moreover, a combination of cisplatin with biochemical modulators of DNA damage signaling might sensitize cisplatin-resistant tumor cells to the drug, thus providing another strategy to improve cancer therapy. Abstract Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.
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Affiliation(s)
- Beate Köberle
- Department of Food Chemistry and Toxicology, Karlsruhe Institute of Technology, Adenauerring 20a, 76131 Karlsruhe, Germany
| | - Sarah Schoch
- Department of Laboratory Medicine, Lund University, Scheelevägen 2, 223 81 Lund, Sweden
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15
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Huang Z, Huang L, Liu L, Wang L, Lin W, Zhu X, Su W, Lv C. Knockdown of microRNA-203 reduces cisplatin chemo-sensitivity to osteosarcoma cell lines MG63 and U2OS in vitro by targeting RUNX2. J Chemother 2021; 33:328-341. [PMID: 33764270 DOI: 10.1080/1120009x.2021.1899441] [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] [Indexed: 01/24/2023]
Abstract
Clinical studies have reported that miRNAs abnormal expression are associated with the generation of cisplatin-resistant to osteosarcoma. Our previous research found that miR-203 is downregulated in osteosarcoma cells and overexpressed miR-203 exerts antitumor properties on osteosarcoma cells. However, the role and mechanism of miR-203 in regulating the sensitivity of cisplatin in osteosarcoma cells remains unclear. This study aimed to investigate the effects of miR-203 in cisplatin therapy for osteosarcoma cells in vitro and determined the underlying mechanism. In this study, we found that miR-203 was significantly upregulated in osteosarcoma cells after exposure to cisplatin. miR-203 knockdown reduced the sensitivity of osteosarcoma cells to cisplatin by suppressing cell apoptosis, cell cycle arrest, and inducing invasion. Meanwhile, we found that miR-203 knockdown reduces the therapeutic sensitivity of osteosarcoma cells by upregulating RUNX2. Moreover, we found that RUNX2 silencing sensitizes osteosarcoma cells to chemotherapy treatment of cisplatin. In summary, our findings demonstrated that miR-203 knockdown reduces cisplatin chemo-sensitivity to osteosarcoma cells in vitro by targeting RUNX2, and speculated that miR-203 may be a target for drug resistance of osteosarcoma to cisplatin.
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Affiliation(s)
- Zhengxiang Huang
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lintuo Huang
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lue Liu
- Department of Orthopedics, the Third Affiliated Hospital of Wenzhou Medical University, Ruian, Zhejiang, China
| | - Lu Wang
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenjun Lin
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiongbai Zhu
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wei Su
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chen Lv
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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16
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Schneider B, Glass Ä, Jagdmann S, Hühns M, Claus J, Zettl H, Dräger DL, Maruschke M, Hakenberg OW, Erbersdobler A, Zimpfer A. Loss of Mismatch-repair Protein Expression and Microsatellite Instability in Upper Tract Urothelial Carcinoma and Clinicopathologic Implications. Clin Genitourin Cancer 2020; 18:e563-e572. [PMID: 32340874 DOI: 10.1016/j.clgc.2020.03.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 02/28/2020] [Accepted: 03/03/2020] [Indexed: 01/23/2023]
Abstract
BACKGROUND Upper tract urothelial carcinoma (UTUC) may arise in the setting of hereditary non-polyposis colorectal cancer (Lynch syndrome [LS]) or sporadically. Variable frequencies of microsatellite instability (MSI) were found in UTUC. For advanced solid MSI tumors, targeted therapy with programmed death-ligand 1 inhibitors is available. Therefore, we aimed to determine the prevalence of mismatch repair (MMR) protein loss and MSI in UTUC using a tissue microarray approach and further molecular and correlation analysis. MATERIALS AND METHODS We studied the immunohistochemical expression of MLH1, MSH2, MSH6, and PMS2 on tissue microarrays containing formalin-fixed, paraffin-embedded samples of 128 patients with UTUC. MSI analysis was performed in 79 cases with deficient MMR protein expression, and/or in patients aged 60 years and below, and/or other tumors possibly related to LS. RESULTS Loss of MMR protein expression was seen in 24 (18.8%) of 128 cases. MSI analysis revealed MSI-high in 29, MSI-low in 7 cases. The Fisher exact test demonstrated significant differences between MSI and loss of MMR protein expression, clinically possible LS, tumor growth pattern, inverted growth pattern, and death (P < .001, P < .001, P = .002, P = .003, and P = .033, respectively). MSI does not appear to influence survival (overall and progression-free), but there was a significant shorter progression-free survival in MSI-high versus MSS patients who had received chemotherapy. CONCLUSION The frequency of MSI in UTUC was 36 (28.1%) of 128 patients with a good accuracy of immunohistochemistry. In daily practice, MSI screening especially is recommended in patients with advanced UTUC and inverted papillary tumor growth pattern with the aim of screening patients for possible targeted therapy.
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Affiliation(s)
- Björn Schneider
- Institute of Pathology, University Medicine Rostock, Rostock, Germany.
| | - Änne Glass
- Institute for Biostatistics and Informatics in Medicine, University Medicine Rostock, Rostock, Germany
| | - Sandra Jagdmann
- Institute for Medical Immunology, Charité University Medicine, Berlin, Germany
| | - Maja Hühns
- Institute of Pathology, University Medicine Rostock, Rostock, Germany
| | - Jessica Claus
- Institute of Pathology, University Medicine Rostock, Rostock, Germany
| | - Heike Zettl
- Rostock Cancer Registry, University Medicine Rostock, Rostock, Germany
| | | | - Matthias Maruschke
- Department of Urology, University Medicine Rostock, Rostock, Germany; Department of Urology, HELIOS Hanseklinikum Stralsund, Stralsund, Germany
| | - Oliver W Hakenberg
- Department of Urology, University Medicine Rostock, Rostock, Germany; Department of Urology, HELIOS Hanseklinikum Stralsund, Stralsund, Germany
| | | | - Annette Zimpfer
- Institute of Pathology, University Medicine Rostock, Rostock, Germany
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Metabolic Remodelling: An Accomplice for New Therapeutic Strategies to Fight Lung Cancer. Antioxidants (Basel) 2019; 8:antiox8120603. [PMID: 31795465 PMCID: PMC6943435 DOI: 10.3390/antiox8120603] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/22/2019] [Accepted: 11/27/2019] [Indexed: 12/12/2022] Open
Abstract
Metabolic remodelling is a hallmark of cancer, however little has been unravelled in its role in chemoresistance, which is a major hurdle to cancer control. Lung cancer is a leading cause of death by cancer, mainly due to the diagnosis at an advanced stage and to the development of resistance to therapy. Targeted therapeutic agents combined with comprehensive drugs are commonly used to treat lung cancer. However, resistance mechanisms are difficult to avoid. In this review, we will address some of those therapeutic regimens, resistance mechanisms that are eventually developed by lung cancer cells, metabolic alterations that have already been described in lung cancer and putative new therapeutic strategies, and the integration of conventional drugs and genetic and metabolic-targeted therapies. The oxidative stress is pivotal in this whole network. A better understanding of cancer cell metabolism and molecular adaptations underlying resistance mechanisms will provide clues to design new therapeutic strategies, including the combination of chemotherapeutic and targeted agents, considering metabolic intervenients. As cancer cells undergo a constant metabolic adaptive drift, therapeutic regimens must constantly adapt.
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Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance. BMC Cancer 2019; 19:1039. [PMID: 31684899 PMCID: PMC6829976 DOI: 10.1186/s12885-019-6278-9] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 10/21/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. METHODS In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. RESULTS We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. CONCLUSIONS We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.
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Ponnusamy L, Mahalingaiah PKS, Singh KP. Epigenetic reprogramming and potential application of epigenetic-modifying drugs in acquired chemotherapeutic resistance. Adv Clin Chem 2019; 94:219-259. [PMID: 31952572 DOI: 10.1016/bs.acc.2019.07.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chemotherapy is the most common clinical choice of treatment for cancer, however, acquired chemoresistance is a major challenge that limits the successful outcome of this option. Systematic review of in vitro, in vivo, preclinical and clinical studies suggests that acquired chemoresistance is polygenic, progressive, and involve both genetic and epigenetic heterogeneities and perturbations. Various mechanisms that confer resistance to chemotherapy are tightly controlled by epigenetic regulations. Poised epigenetic plasticity and temporal increase in epigenetic alterations upon chemotherapy make chemoresistance likely an epigenetic-driven process. The transient and reversible nature of epigenetic modulations enable ways to intervene the epigenetic re-programing associated with acquired chemoresistance via application of epigenetic modifying drugs. This review discusses recent understandings behind the various mechanisms of acquired chemoresistance that are under the control of epigenetic drivers, potential application of epigenetic-based drugs in resensitizing refractory cancers to chemotherapy, the limitations and future scope for clinical application of epigenetic therapeutics in successfully addressing chemoresistance.
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Affiliation(s)
- Logeswari Ponnusamy
- Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX, United States
| | - Prathap Kumar S Mahalingaiah
- Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX, United States
| | - Kamaleshwar P Singh
- Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX, United States.
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20
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Noordhuis P, Laan AC, van de Born K, Honeywell RJ, Peters GJ. Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines. Int J Mol Sci 2019; 20:3619. [PMID: 31344863 PMCID: PMC6696456 DOI: 10.3390/ijms20153619] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/05/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Oxaliplatin (OHP) treatment of colorectal cancer (CRC) frequently leads to resistance. OHP resistance was induced in CRC cell lines LoVo-92 and LoVo-Li and a platinum-sensitive ovarian cancer cell line, A2780, and related to cellular platinum accumulation, platinum-DNA adducts, transporter expression, DNA repair genes, gene expression arrays, and array-CGH profiling. Pulse (4 h, 4OHP) and continuous exposure (72 h, cOHP) resulted in 4.0 to 7.9-fold and 5.0 to 11.8-fold drug resistance, respectively. Cellular oxaliplatin accumulation and DNA-adduct formation were decreased and related to OCT1-3 and ATP7A expression. Gene expression profiling and pathway analysis showed significantly altered p53 signaling, xenobiotic metabolism, role of BRCA1 in DNA damage response, and aryl hydrocarbon receptor signaling pathways, were related to decreased ALDH1L2, Bax, and BBC3 (PUMA) and increased aldo-keto reductases C1 and C3. The array-CGH profiles showed focal aberrations. In conclusion, OHP resistance was correlated with total platinum accumulation and OCT1-3 expression, decreased proapoptotic, and increased anti-apoptosis and homologous repair genes.
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Affiliation(s)
- Paul Noordhuis
- Department of 1Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Adrianus C Laan
- Department of 1Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Kasper van de Born
- Department of 1Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Richard J Honeywell
- Department of 1Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Godefridus J Peters
- Department of 1Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
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EBV infection is associated with histone bivalent switch modifications in squamous epithelial cells. Proc Natl Acad Sci U S A 2019; 116:14144-14153. [PMID: 31235597 DOI: 10.1073/pnas.1821752116] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) induces histone modifications to regulate signaling pathways involved in EBV-driven tumorigenesis. To date, the regulatory mechanisms involved are poorly understood. In this study, we show that EBV infection of epithelial cells is associated with aberrant histone modification; specifically, aberrant histone bivalent switches by reducing the transcriptional activation histone mark (H3K4me3) and enhancing the suppressive mark (H3K27me3) at the promoter regions of a panel of DNA damage repair members in immortalized nasopharyngeal epithelial (NPE) cells. Sixteen DNA damage repair family members in base excision repair (BER), homologous recombination, nonhomologous end-joining, and mismatch repair (MMR) pathways showed aberrant histone bivalent switches. Among this panel of DNA repair members, MLH1, involved in MMR, was significantly down-regulated in EBV-infected NPE cells through aberrant histone bivalent switches in a promoter hypermethylation-independent manner. Functionally, expression of MLH1 correlated closely with cisplatin sensitivity both in vitro and in vivo. Moreover, seven BER members with aberrant histone bivalent switches in the EBV-positive NPE cell lines were significantly enriched in pathway analysis in a promoter hypermethylation-independent manner. This observation is further validated by their down-regulation in EBV-infected NPE cells. The in vitro comet and apurinic/apyrimidinic site assays further confirmed that EBV-infected NPE cells showed reduced DNA damage repair responsiveness. These findings suggest the importance of EBV-associated aberrant histone bivalent switch in host cells in subsequent suppression of DNA damage repair genes in a methylation-independent manner.
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Ponnusamy L, Mahalingaiah PKS, Chang YW, Singh KP. Reversal of epigenetic aberrations associated with the acquisition of doxorubicin resistance restores drug sensitivity in breast cancer cells. Eur J Pharm Sci 2018; 123:56-69. [DOI: 10.1016/j.ejps.2018.07.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 06/04/2018] [Accepted: 07/12/2018] [Indexed: 12/20/2022]
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23
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Malik SS, Masood N, Asif M, Ahmed P, Shah ZU, Khan JS. Expressional analysis of MLH1 and MSH2 in breast cancer. Curr Probl Cancer 2018; 43:97-105. [PMID: 30149959 DOI: 10.1016/j.currproblcancer.2018.08.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 07/05/2018] [Accepted: 08/01/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Mismatch repair proteins are ubiquitous keys in diverse cellular functions and protects the genome by correcting mismatch as post replication error correction machinery. Mismatch repair deficiency was associated with tumor development and progression therefore, current study was aimed to investigate MLH1 and MSH2 expression in breast cancer and correlate patients' clinicopathological factors with status of mismatch repair genes. MATERIAL AND METHODS Breast cancer tissues with adjacent normal tissue along with clinical details were collected during surgery from 80 cases. Immunohistochemistry was performed with primary and secondary antibodies for expressional analysis. Results were analyzed using SPSS version 24. RESULTS Immunohistochemical analysis revealed that both MLH1 and MSH2 were crucial in maintaining DNA repair system and loss of these 2 mismatch repair proteins may lead to adverse outcomes in breast cancer. Statistically significant association was found between loss of MLH1 (P = 0.0004; odds ratio 13.8; 95% confidence interval 4.6-41.1), MSH2 (P = 0.0002; odds ratio 14.0; 95% confidence interval 4.7-42.2) and breast cancer. Statistical analysis demonstrated that MLH1 and MSH2 deficiency may lead breast cancer progression to advanced stage, correlated with tumor focality (MLH1 P = 0.001; MSH2 P = 0.002) and chemotherapy (MLH1 P = 0.01; MSH2 P = 0.04). Presence of CK7, GATA 3, and E cadherin tends to increase in mismatch repair deficient breast cancer. Whereas, no association of mismatch repair deficiency was observed with age, tumor grade, positive lymph nodes, menopause, and ER and/or PR status. CONCLUSION Loss of mismatch repair proteins in breast cancer highlights its potential role in DNA repair mechanisms and helps tumor cells to become resistant against chemotherapeutic drugs. Therefore, mismatch repair deficiency may contribute to breast cancer progression.
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Affiliation(s)
- Saima Shakil Malik
- Microbiology and Biotechnology Research Lab, Fatima Jinnah Women University, Rawalpindi, Pakistan; Armed Forces Institute of Pathology, Rawalpindi, Pakistan.
| | - Nosheen Masood
- Microbiology and Biotechnology Research Lab, Fatima Jinnah Women University, Rawalpindi, Pakistan
| | - Muhammad Asif
- Armed Forces Institute of Pathology, Rawalpindi, Pakistan
| | - Parvez Ahmed
- Armed Forces Institute of Pathology, Rawalpindi, Pakistan
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24
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Melvin RL, Xiao J, Godwin RC, Berenhaut KS, Salsbury FR. Visualizing correlated motion with HDBSCAN clustering. Protein Sci 2018; 27:62-75. [PMID: 28799290 PMCID: PMC5734272 DOI: 10.1002/pro.3268] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 07/31/2017] [Accepted: 08/02/2017] [Indexed: 12/22/2022]
Abstract
Correlated motion analysis provides a method for understanding communication between and dynamic similarities of biopolymer residues and domains. The typical equal-time correlation matrices-frequently visualized with pseudo-colorings or heat maps-quickly convey large regions of highly correlated motion but hide more subtle similarities of motion. Here we propose a complementary method for visualizing correlations within proteins (or general biopolymers) that quickly conveys intuition about which residues have a similar dynamic behavior. For grouping residues, we use the recently developed non-parametric clustering algorithm HDBSCAN. Although the method we propose here can be used to group residues using correlation as a similarity matrix-the most straightforward and intuitive method-it can also be used to more generally determine groups of residues which have similar dynamic properties. We term these latter groups "Dynamic Domains", as they are based not on spatial closeness but rather closeness in the column space of a correlation matrix. We provide examples of this method across three human proteins of varying size and function-the Nf-Kappa-Beta essential modulator, the clotting promoter Thrombin and the mismatch repair protein (dimer) complex MutS-alpha. Although the examples presented here are from all-atom molecular dynamics simulations, this visualization technique can also be used on correlations matrices built from any ensembles of conformations from experiment or computation.
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Affiliation(s)
- Ryan L. Melvin
- Department of PhysicsWake Forest UniversityWinston SalemNorth Carolina
- Department of Mathematics and StatisticsWake Forest UniversityWinston‐SalemNorth Carolina27109
| | - Jiajie Xiao
- Department of PhysicsWake Forest UniversityWinston SalemNorth Carolina
- Department of Computer ScienceWake Forest UniversityWinston‐SalemNorth Carolina27109
| | - Ryan C. Godwin
- Department of PhysicsWake Forest UniversityWinston SalemNorth Carolina
| | - Kenneth S. Berenhaut
- Department of Mathematics and StatisticsWake Forest UniversityWinston‐SalemNorth Carolina27109
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25
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Jin P, Wang DZ, Lyu CX, Wang YT, He YQ, Sheng JQ, Li X. Mismatch Repair Protein hMLH1, but not hMSH2, Enhances Estrogen-Induced Apoptosis of Colon Cancer Cells. J Cancer 2017; 8:3232-3241. [PMID: 29158795 PMCID: PMC5665039 DOI: 10.7150/jca.20833] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 08/25/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Epidemiological studies suggest a protective role of estrogen against colon carcinogenesis; this effect appears to be dependent on mismatch repair (MMR) status. However, the underlying mechanism remains unclear. This study investigated the role of MMR proteins in apoptosis of colon cancer cells in the presence or absence of estrogen. METHODS Two major MMR proteins, human mutL homolog 1 (hMLH1) and mutS homolog 2 (hMSH2), as well as estrogen receptor-β (ERβ), were transiently expressed in either hMLH1-deficient HCT116 cells or hMSH2-deficient LoVo cells. Effects of estradiol on cell viability and apoptosis were assessed. Furthermore, we examined the apoptotic status of epithelial cells in colonic mucosa taken from previous healthy female subjects with menopausal syndrome before and after 6-month hormone replacement therapy (HRT). RESULTS In hMLH1-deficient HCT116 cells, re-expression of hMLH1 led to a significantly decreased cell viability and increased apoptosis, which were further enhanced by estradiol, including marked increase of activated caspase-3 and caspase-9, as well as Bax and P53. The effect of hMLH1 overexpression in LoVo cells resulted in a similar increase in apoptosis that was greatly stimulated by estradiol. The enhanced apoptosis by hMLH1 and estradiol was further validated by FACS analyses of Annexin V expression. Re-expression of hMSH2 or overexpression of ERβ in HCT116 cells also enhanced apoptosis; however, the effects were independent of estradiol. Furthermore, studies on healthy menopausal women before and after 6-month HRT demonstrated a significant HRT-mediated upregulation of the hMLH1 expression, with concomitant elevation of caspase-3 and caspase-9 activation in the colonic mucosa. CONCLUSION We present the first evidence that hMLH1 and hMSH2 have similar but distinct roles in the apoptosis of colon cancer cells: an increased expression of either one can promote apoptosis, while only the effect of hMLH1 but not hMSH2 is estradiol-dependent. Our data suggest that MMR status should be assessed before hormone replacement therapy or future application of estrogen-based chemoprevention.
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Affiliation(s)
- Peng Jin
- Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China
| | - De-Zhi Wang
- Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China.,Johns Hopkins University School of Medicine, Department of Medicine/GI Division, Baltimore, MD21205, USA
| | - Chen-Xi Lyu
- Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China
| | - Ya-Ting Wang
- Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China
| | - Yu-Qi He
- Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China
| | - Jian-Qiu Sheng
- Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China
| | - Xuhang Li
- Johns Hopkins University School of Medicine, Department of Medicine/GI Division, Baltimore, MD21205, USA
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26
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Kritsch D, Hoffmann F, Steinbach D, Jansen L, Mary Photini S, Gajda M, Mosig AS, Sonnemann J, Peters S, Melnikova M, Thomale J, Dürst M, Runnebaum IB, Häfner N. Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer. Int J Cancer 2017; 141:1600-1614. [PMID: 28670762 DOI: 10.1002/ijc.30860] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 06/06/2017] [Accepted: 06/16/2017] [Indexed: 12/20/2022]
Abstract
Aim was to identify methylated genes with functional involvement in cisplatin-resistance development of epithelial ovarian cancer (EOC). Genome-wide analyses of hypermethylated CpG-islands in resistant cell lines in combination with qRT-PCR analyses were used to identify epigenetically silenced genes. EOC-Type-II tumors were analyzed for gene methylation and expression and TCGA data were interrogated in-silico. Experiments revealed 37 commonly hypermethylated genes in resistant cells of which Tribbles 2 (TRIB2) showed the most pronounced downregulation on mRNA level and was characterized further. TRIB2 showed a reactivation after 5'-Aza-Cytidine treatment in resistant cells but a cisplatin-dependent, prominent upregulation on mRNA level in sensitive cells, only. Re-expression in resistant A2780 cells increased the sensitivity to cisplatin and other DNA-damaging agents, but not taxanes. Contrary, knockdown of TRIB2 increased resistance to cisplatin in sensitive cells. TRIB2 was involved in the induction of a cisplatin-dependent cell cycle arrest and apoptosis by influencing p21 and survivin expression. An increased Pt-DNA-adduct formation in TRIB2 re-expressing cells did not translate in higher levels of dsDNA damage (yH2AX-foci). Thus, TRIB2 is potentially involved in the signal transduction from nucleotide excision repair of intrastrand cross links. Importantly, patient stratification of two homogenous cohorts of EOC-Type-II patients from Jena (n = 38) and the TCGA (n = 149) by TRIB2 mRNA expression consistently revealed a significantly decreased PFS for patients with low TRIB2 levels (log-rank p < 0.05). Tumors from resistant patients expressed the lowest levels of TRIB2. Downregulation of TRIB2 contributes to platin-resistance and TRIB2 expression should be validated as prognostic and predictive marker for EOC.
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Affiliation(s)
- Daniel Kritsch
- Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Franziska Hoffmann
- Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Daniel Steinbach
- Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Lars Jansen
- Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Stella Mary Photini
- Department of Obstetrics, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Mieczyslaw Gajda
- Institute of Pathology, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Alexander S Mosig
- Department of Biochemistry II, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Jürgen Sonnemann
- Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Sven Peters
- Experimental Ophthalmology, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Margarita Melnikova
- DNA Repair Lab, Institute for Cell Biology, University Hospital Duisburg-Essen, Essen, Germany
| | - Jürgen Thomale
- DNA Repair Lab, Institute for Cell Biology, University Hospital Duisburg-Essen, Essen, Germany
| | - Matthias Dürst
- Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Ingo B Runnebaum
- Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Norman Häfner
- Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
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27
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Bailis JM, Weidmann AG, Mariano NF, Barton JK. Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells. Proc Natl Acad Sci U S A 2017; 114:6948-6953. [PMID: 28634291 PMCID: PMC5502648 DOI: 10.1073/pnas.1706665114] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)]2+ (Rh-PPO). We find that Rh-PPO binding induces a lesion that triggers the DNA damage response (DDR). DDR activation results in cell-cycle blockade and inhibition of DNA replication and transcription. Significantly, the lesion induced by Rh-PPO is not repaired in MMR-deficient cells, resulting in selective cytotoxicity. The Rh-PPO mechanism is reminiscent of DNA repair enzymes that displace mismatched bases, and is differentiated from other DNA-targeted chemotherapeutics such as cisplatin by its potency, cellular mechanism, and selectivity for MMR-deficient cells.
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Affiliation(s)
- Julie M Bailis
- Department of Oncology Research, Amgen, Inc., South San Francisco, CA 94080;
| | - Alyson G Weidmann
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
| | - Natalie F Mariano
- Department of Oncology Research, Amgen, Inc., South San Francisco, CA 94080
| | - Jacqueline K Barton
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
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28
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Rudolph C, Melau C, Nielsen JE, Vile Jensen K, Liu D, Pena-Diaz J, Rajpert-De Meyts E, Rasmussen LJ, Jørgensen A. Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours. Cell Oncol (Dordr) 2017; 40:341-355. [PMID: 28536927 DOI: 10.1007/s13402-017-0326-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Testicular germ cell tumours (TGCT) are highly sensitive to cisplatin-based chemotherapy, but patients with tumours containing differentiated teratoma components are less responsive to this treatment. The cisplatin sensitivity in TGCT has previously been linked to the embryonic phenotype in the majority of tumours, although the underlying mechanism largely remains to be elucidated. The aim of this study was to investigate the role of the DNA mismatch repair (MMR) system in the cisplatin sensitivity of TGCT. METHODS The expression pattern of key MMR proteins, including MSH2, MSH6, MLH1 and PMS2, were investigated during testis development and in the pathogenesis of TGCT, including germ cell neoplasia in situ (GCNIS). The TGCT-derived cell line NTera2 was differentiated using retinoic acid (10 μM, 6 days) after which MMR protein expression and activity, as well as cisplatin sensitivity, were investigated in both undifferentiated and differentiated cells. Finally, the expression of MSH2 was knocked down by siRNA in NTera2 cells after which the effect on cisplatin sensitivity was examined. RESULTS MMR proteins were expressed in proliferating cells in the testes, while in malignant germ cells MMR protein expression was found to coincide with the expression of the pluripotency factor OCT4, with no or low expression in the more differentiated yolk sac tumours, choriocarcinomas and teratomas. In differentiated NTera2 cells we found a significantly (p < 0.05) lower expression of the MMR and pluripotency factors, as well as a reduced MMR activity and cisplatin sensitivity, compared to undifferentiated NTera2 cells. Also, we found that partial knockdown of MSH2 expression in undifferentiated NTera2 cells resulted in a significantly (p < 0.001) reduced cisplatin sensitivity. CONCLUSION This study reports, for the first time, expression of the MMR system in fetal gonocytes, from which GCNIS cells are derived. Our findings in primary TGCT specimens and TGCT-derived cells suggest that a reduced sensitivity to cisplatin in differentiated TGCT components could result from a reduced expression of MMR proteins, in particular MSH2 and MLH1, which are involved in the recognition of cisplatin adducts and in activation of the DNA damage response pathway to initiate apoptosis.
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Affiliation(s)
- Christiane Rudolph
- University Department of Growth and Reproduction (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen, Denmark.,Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Cecilie Melau
- University Department of Growth and Reproduction (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - John E Nielsen
- University Department of Growth and Reproduction (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Kristina Vile Jensen
- University Department of Growth and Reproduction (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen, Denmark.,Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Dekang Liu
- Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Javier Pena-Diaz
- Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Ewa Rajpert-De Meyts
- University Department of Growth and Reproduction (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Lene Juel Rasmussen
- Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Anne Jørgensen
- University Department of Growth and Reproduction (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen, Denmark.
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29
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Arai A, Chano T, Ikebuchi K, Hama Y, Ochi Y, Tameno H, Shimada T. p62/SQSTM1 levels predicts radiotherapy resistance in hypopharyngeal carcinomas. Am J Cancer Res 2017; 7:881-891. [PMID: 28469960 PMCID: PMC5411795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 03/27/2017] [Indexed: 06/07/2023] Open
Abstract
Hypopharyngeal carcinoma is one of the worst prognostic malignancies among head and neck carcinomas. Therefore, a good biomarker should be identified to predict the best therapeutic option before starting the treatment. In cell models, p62/SQSTM1 levels affected the Nrf2-Keap1 pathway, ROS levels, GSH/GSSG ratios and cell growth, especially under irradiation rather than under CDDP exposure, which was toxic despite p62/SQSTM1 status. In a clinical cohort of hypopharyngeal carcinomas, high levels of p62/SQSTM1 significantly predicted poor prognosis (log-rank test, Chi-square value = 6.750, P = 0.0094) and maximum critical risk (Cox proportional hazard ratio = 4.405, P = 0.0086), especially in the radiotherapy group. Therefore, when p62/SQSTM1 is elevated in the biopsy section, hypopharyngeal carcinoma should be treated with surgical and/or chemotherapeutic options.
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Affiliation(s)
- Akihito Arai
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of MedicineKajiicho 465, Kamigyo-ku, Kyoto, Kyoto 602-8566, Japan
| | - Tokuhiro Chano
- Department of Clinical Laboratory Medicine, Shiga University of Medical ScienceTsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan
| | - Kaichiro Ikebuchi
- Ikebuchi ClinicHachino-tsubo 122, Terado-cho, Muko, Kyoto 617-0002, Japan
| | - Yusuke Hama
- Department of Clinical Laboratory Medicine, Shiga University of Medical ScienceTsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan
| | - Yasuko Ochi
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of MedicineKajiicho 465, Kamigyo-ku, Kyoto, Kyoto 602-8566, Japan
| | - Hitosuke Tameno
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of MedicineKajiicho 465, Kamigyo-ku, Kyoto, Kyoto 602-8566, Japan
| | - Taketoshi Shimada
- Shimada Clinic for OtolaryngologyTomo-oka 4-21-13, Nagaoka-kyo, Kyoto 617-0843, Japan
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30
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Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2017; 771:32-58. [DOI: 10.1016/j.mrrev.2016.11.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 11/16/2016] [Indexed: 11/20/2022]
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31
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Melvin RL, Godwin RC, Xiao J, Thompson WG, Berenhaut KS, Salsbury FR. Uncovering Large-Scale Conformational Change in Molecular Dynamics without Prior Knowledge. J Chem Theory Comput 2016; 12:6130-6146. [PMID: 27802394 PMCID: PMC5719493 DOI: 10.1021/acs.jctc.6b00757] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
As the length of molecular dynamics (MD) trajectories grows with increasing computational power, so does the importance of clustering methods for partitioning trajectories into conformational bins. Of the methods available, the vast majority require users to either have some a priori knowledge about the system to be clustered or to tune clustering parameters through trial and error. Here we present non-parametric uses of two modern clustering techniques suitable for first-pass investigation of an MD trajectory. Being non-parametric, these methods require neither prior knowledge nor parameter tuning. The first method, HDBSCAN, is fast-relative to other popular clustering methods-and is able to group unstructured or intrinsically disordered systems (such as intrinsically disordered proteins, or IDPs) into bins that represent global conformational shifts. HDBSCAN is also useful for determining the overall stability of a system-as it tends to group stable systems into one or two bins-and identifying transition events between metastable states. The second method, iMWK-Means, with explicit rescaling followed by K-Means, while slower than HDBSCAN, performs well with stable, structured systems such as folded proteins and is able to identify higher resolution details such as changes in relative position of secondary structural elements. Used in conjunction, these clustering methods allow a user to discern quickly and without prior knowledge the stability of a simulated system and identify both local and global conformational changes.
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Affiliation(s)
- Ryan L. Melvin
- Department of Physics, Wake Forest University, Winston-Salem, North Carolina 27109, United States
| | - Ryan C. Godwin
- Department of Physics, Wake Forest University, Winston-Salem, North Carolina 27109, United States
| | - Jiajie Xiao
- Department of Physics, Wake Forest University, Winston-Salem, North Carolina 27109, United States
| | - William G. Thompson
- Department of Physics, Wake Forest University, Winston-Salem, North Carolina 27109, United States
| | - Kenneth S. Berenhaut
- Department of Mathematics & Statistics, Wake Forest University, Winston-Salem, North Carolina 27109, United States
| | - Freddie R. Salsbury
- Department of Physics, Wake Forest University, Winston-Salem, North Carolina 27109, United States
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32
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Gerratana L, Fanotto V, Pelizzari G, Agostinetto E, Puglisi F. Do platinum salts fit all triple negative breast cancers? Cancer Treat Rev 2016; 48:34-41. [PMID: 27343437 DOI: 10.1016/j.ctrv.2016.06.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 06/02/2016] [Accepted: 06/06/2016] [Indexed: 12/27/2022]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options and poor prognosis once metastatic. Pre-clinical and clinical data suggest that TNBC could be more sensitive to platinum-based chemotherapy, especially among BRCA1/2-mutated patients. In recent years, several randomised trials have been conducted to evaluate platinum efficacy in both early-stage and advanced TNBC, with conflicting results especially for long-term outcomes. Experimental studies are now focusing on identifying biomarkers of response to help selecting patients who may benefit most from platinum-based therapies, including BRCA1/2 mutational status and genomic instability signatures (such as HRD-LOH or HRD-LST scores). A standard therapy for TNBC is still missing and platinum-based regimens represent an emerging therapeutic option for selected patients with a defect in the homologous recombination repair system. The identification of these patients through validated biomarker assays will be crucial to optimize the use of currently approved agents in TNBC.
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Affiliation(s)
- L Gerratana
- Department of Medical and Biological Sciences, University of Udine, Udine, Italy; Department of Medical Oncology, University Hospital of Udine, Udine, Italy
| | - V Fanotto
- Department of Medical and Biological Sciences, University of Udine, Udine, Italy; Department of Medical Oncology, University Hospital of Udine, Udine, Italy
| | - G Pelizzari
- Department of Medical and Biological Sciences, University of Udine, Udine, Italy; Department of Medical Oncology, University Hospital of Udine, Udine, Italy
| | - E Agostinetto
- Department of Medical Oncology, University Hospital of Udine, Udine, Italy
| | - F Puglisi
- Department of Medical and Biological Sciences, University of Udine, Udine, Italy; Department of Medical Oncology, University Hospital of Udine, Udine, Italy.
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33
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Pan J, Sinclair E, Xuan Z, Dyba M, Fu Y, Sen S, Berry D, Creswell K, Hu J, Roy R, Chung FL. Nucleotide excision repair deficiency increases levels of acrolein-derived cyclic DNA adduct and sensitizes cells to apoptosis induced by docosahexaenoic acid and acrolein. Mutat Res 2016; 789:33-8. [PMID: 27036235 DOI: 10.1016/j.mrfmmm.2016.02.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 02/23/2016] [Accepted: 02/28/2016] [Indexed: 12/24/2022]
Abstract
The acrolein derived cyclic 1,N(2)-propanodeoxyguanosine adduct (Acr-dG), formed primarily from ω-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) under oxidative conditions, while proven to be mutagenic, is potentially involved in DHA-induced apoptosis. The latter may contribute to the chemopreventive effects of DHA. Previous studies have shown that the levels of Acr-dG are correlated with apoptosis induction in HT29 cells treated with DHA. Because Acr-dG is shown to be repaired by the nucleotide excision repair (NER) pathway, to further investigate the role of Acr-dG in apoptosis, in this study, NER-deficient XPA and its isogenic NER-proficient XAN1 cells were treated with DHA. The Acr-dG levels and apoptosis were sharply increased in XPA cells, but not in XAN1 cells when treated with 125μM of DHA. Because DHA can induce formation of various DNA damage, to specifically investigate the role of Acr-dG in apoptosis induction, we treated XPA knockdown HCT116+ch3 cells with acrolein. The levels of both Acr-dG and apoptosis induction increased significantly in the XPA knockdown cells. These results clearly demonstrate that NER deficiency induces higher levels of Acr-dG in cells treated with DHA or acrolein and sensitizes cells to undergo apoptosis in a correlative manner. Collectively, these results support that Acr-dG, a ubiquitously formed mutagenic oxidative DNA adduct, plays a role in DHA-induced apoptosis and suggest that it could serve as a biomarker for the cancer preventive effects of DHA.
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Affiliation(s)
- Jishen Pan
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Elizabeth Sinclair
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Zhuoli Xuan
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Marcin Dyba
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Ying Fu
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Supti Sen
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Deborah Berry
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Karen Creswell
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Jiaxi Hu
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Rabindra Roy
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - Fung-Lung Chung
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
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Li Z, Pearlman AH, Hsieh P. DNA mismatch repair and the DNA damage response. DNA Repair (Amst) 2016; 38:94-101. [PMID: 26704428 PMCID: PMC4740233 DOI: 10.1016/j.dnarep.2015.11.019] [Citation(s) in RCA: 221] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 09/17/2015] [Accepted: 11/30/2015] [Indexed: 12/12/2022]
Abstract
This review discusses the role of DNA mismatch repair (MMR) in the DNA damage response (DDR) that triggers cell cycle arrest and, in some cases, apoptosis. Although the focus is on findings from mammalian cells, much has been learned from studies in other organisms including bacteria and yeast [1,2]. MMR promotes a DDR mediated by a key signaling kinase, ATM and Rad3-related (ATR), in response to various types of DNA damage including some encountered in widely used chemotherapy regimes. An introduction to the DDR mediated by ATR reveals its immense complexity and highlights the many biological and mechanistic questions that remain. Recent findings and future directions are highlighted.
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Affiliation(s)
- Zhongdao Li
- Genetics & Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 5 Rm. 324, 5 Memorial Dr. MSC 0538, Bethesda, MD 20892-0538, USA
| | - Alexander H Pearlman
- Genetics & Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 5 Rm. 324, 5 Memorial Dr. MSC 0538, Bethesda, MD 20892-0538, USA
| | - Peggy Hsieh
- Genetics & Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 5 Rm. 324, 5 Memorial Dr. MSC 0538, Bethesda, MD 20892-0538, USA.
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Ferreira JA, Peixoto A, Neves M, Gaiteiro C, Reis CA, Assaraf YG, Santos LL. Mechanisms of cisplatin resistance and targeting of cancer stem cells: Adding glycosylation to the equation. Drug Resist Updat 2016; 24:34-54. [DOI: 10.1016/j.drup.2015.11.003] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 11/09/2015] [Accepted: 11/18/2015] [Indexed: 02/06/2023]
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Zhu S, Pabla N, Tang C, He L, Dong Z. DNA damage response in cisplatin-induced nephrotoxicity. Arch Toxicol 2015; 89:2197-205. [PMID: 26564230 DOI: 10.1007/s00204-015-1633-3] [Citation(s) in RCA: 146] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 10/29/2015] [Indexed: 01/17/2023]
Abstract
Cisplatin and its derivatives are widely used chemotherapeutic drugs for cancer treatment. However, they have debilitating side effects in normal tissues and induce ototoxicity, neurotoxicity, and nephrotoxicity. In kidneys, cisplatin preferentially accumulates in renal tubular cells causing tubular cell injury and death, resulting in acute kidney injury (AKI). Recent studies have suggested that DNA damage and the associated DNA damage response (DDR) are an important pathogenic mechanism of AKI following cisplatin treatment. Activation of DDR may lead to cell cycle arrest and DNA repair for cell survival or, in the presence of severe injury, kidney cell death. Modulation of DDR may provide novel renoprotective strategies for cancer patients undergoing cisplatin chemotherapy.
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Affiliation(s)
- Shiyao Zhu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Navjotsingh Pabla
- Departments of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Chengyuan Tang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liyu He
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zheng Dong
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd, Augusta, GA, 30912, USA.
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Sawant A, Kothandapani A, Zhitkovich A, Sobol RW, Patrick SM. Role of mismatch repair proteins in the processing of cisplatin interstrand cross-links. DNA Repair (Amst) 2015; 35:126-36. [PMID: 26519826 DOI: 10.1016/j.dnarep.2015.10.003] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 10/09/2015] [Accepted: 10/10/2015] [Indexed: 12/13/2022]
Abstract
Mismatch repair (MMR) deficiency gives rise to cisplatin resistance and can lead to poor prognosis in cancers. Various models have been proposed to explain this low level of resistance caused due to loss of MMR proteins. We have shown that MMR proteins are required to maintain cisplatin interstrand cross-links (ICLs) on the DNA leading to increased cellular sensitivity. In our previous studies, we have shown that BER processing of the cisplatin ICLs is mutagenic. Polymerase β (Polβ) can generate mismatches which leads to the activation and the recruitment of mismatch repair proteins. In this paper, we distinguished between the requirement of different downstream MMR proteins for maintaining cisplatin sensitivity. We show that the MutSα (MSH2-MSH6) heterocomplex is required to maintain cisplatin sensitivity, whereas the Mutsβ complex has no effect. These results can be correlated with the increased repair of cisplatin ICLs and ICL induced DNA double strand breaks (DSBs) in the resistant cells. Moreover, we show that MLH1 proficient cells displayed a cisplatin sensitive phenotype when compared with the MLH1 deficient cells and the ATPase activity of MLH1 is essential to mediate this effect. Based on these results, we propose that MutSα as well as the downstream MMR pathway proteins are essential to maintain a cisplatin sensitive phenotype as a consequence of processing Polβ induced mismatches at sites flanking cisplatin ICLs.
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Affiliation(s)
- Akshada Sawant
- Department of Biochemistry and Cancer Biology, University of Toledo-Health Science Campus, Toledo, OH 43614, USA
| | - Anbarasi Kothandapani
- Department of Biochemistry and Cancer Biology, University of Toledo-Health Science Campus, Toledo, OH 43614, USA
| | - Anatoly Zhitkovich
- Department of Pathology and Laboratory Medicine, Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Robert W Sobol
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA; Department of Oncologic Sciences, Molecular & Metabolic Oncology Program, University of South Alabama Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL 36604, USA
| | - Steve M Patrick
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
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Torgovnick A, Schumacher B. DNA repair mechanisms in cancer development and therapy. Front Genet 2015; 6:157. [PMID: 25954303 PMCID: PMC4407582 DOI: 10.3389/fgene.2015.00157] [Citation(s) in RCA: 260] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 04/07/2015] [Indexed: 01/18/2023] Open
Abstract
DNA damage has been long recognized as causal factor for cancer development. When erroneous DNA repair leads to mutations or chromosomal aberrations affecting oncogenes and tumor suppressor genes, cells undergo malignant transformation resulting in cancerous growth. Genetic defects can predispose to cancer: mutations in distinct DNA repair systems elevate the susceptibility to various cancer types. However, DNA damage not only comprises a root cause for cancer development but also continues to provide an important avenue for chemo- and radiotherapy. Since the beginning of cancer therapy, genotoxic agents that trigger DNA damage checkpoints have been applied to halt the growth and trigger the apoptotic demise of cancer cells. We provide an overview about the involvement of DNA repair systems in cancer prevention and the classes of genotoxins that are commonly used for the treatment of cancer. A better understanding of the roles and interactions of the highly complex DNA repair machineries will lead to important improvements in cancer therapy.
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Affiliation(s)
- Alessandro Torgovnick
- Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases Research Center, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany
| | - Björn Schumacher
- Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases Research Center, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany
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Kamat N, Khidhir MA, Hussain S, Alashari MM, Rannug U. Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients. Cancer Cell Int 2014; 14:118. [PMID: 25493073 PMCID: PMC4260186 DOI: 10.1186/s12935-014-0118-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 10/27/2014] [Indexed: 01/05/2023] Open
Abstract
Background The inevitable side effects of the currently used chemotherapy are associated with serious syndromes. Genotoxic effects and consequent genetic instability may play an important role in these syndromes. The aim of the study was to evaluate chemotherapy-related microsatellite instability (MSI), loss of heterozygosity (LOH), and loss of mismatch repair (MMR) expression in solid tumor patients. Methods Samples were collected from 117 de novo patients with solid tumors of different origins. Specimens, taken pre- and post-treatment, were screened for MSI and LOH in 10 microsatellite sequences in blood, and expression of five MMR proteins were analyzed in cancer tissues using immunohistochemistry. Statistical analysis included the use of; Fisher’s exact test, Chi Square, and an inter-rater reliability test using Cohen’s kappa coefficient. Results Microsatellite analysis showed that 66.7% of the patients had MSI, including 23.1% high-positive MSI and 43.6% low-positive MSI. A large portion (41%) of the patients exhibited LOH in addition to MSI. MSI and LOH were detected in seven loci in which incidence rates ranged from 3.8% positive for Bat-26 to 34.6% positive for Tp53-Alu. Immunohistochemistry revealed that human mutL homolog 1 (hMLH1) expression was deficient in 29.1% of the patients, whereas 18.8%, 23.9%, 13.4%, and 9.7% were deficient for human mutS homolog 2 (hMSH2), P53, human mutS homolog 6 (hMSH6) and human post-meiotic segregation increased 2 (hPMS2), respectively. There was a significant correlation between MSI and LOH incidence in Tp53-Alu, Mfd41, and APC with low or deficient expression of hMLH1, hMSH2, and P53. A significant association between MSI and LOH, and incidence of secondary tumors was also evident. Conclusions The negative correlation between MMR expression, MSI, and LOH and increased resistance to anti-cancer drugs and development of secondary cancers demonstrates a useful aid in early detection of potential chemotherapy-related side-effects. The diagnostic value demonstrated in our earlier study on breast cancer patients was confirmed for other solid tumors. Electronic supplementary material The online version of this article (doi:10.1186/s12935-014-0118-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nasir Kamat
- Department of Molecular Biosciences, the Wenner-Gren Institute (MBW), Stockholm University, SE-106 91 Stockholm, Sweden
| | - Mohammed A Khidhir
- Department of Genetics Research, Management of Natural Conservations, AlAin City, UAE
| | - Sabir Hussain
- Department of Oncology and Hematology, Tawam Hospital, AlAin City, UAE
| | - Mouied M Alashari
- Department of Pathology, University of Utah, Salt Lake City, Utah 84112 USA
| | - Ulf Rannug
- Department of Molecular Biosciences, the Wenner-Gren Institute (MBW), Stockholm University, SE-106 91 Stockholm, Sweden
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Liu L, Zhou W, Cheng CT, Ren X, Somlo G, Fong MY, Chin AR, Li H, Yu Y, Xu Y, O'Connor STF, O'Connor TR, Ann DK, Stark JM, Wang SE. TGFβ induces "BRCAness" and sensitivity to PARP inhibition in breast cancer by regulating DNA-repair genes. Mol Cancer Res 2014; 12:1597-609. [PMID: 25103497 DOI: 10.1158/1541-7786.mcr-14-0201] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
UNLABELLED Transforming growth factor beta (TGFβ) proteins are multitasking cytokines, in which high levels at tumor sites generally correlate with poor prognosis in human patients with cancer. Previously, it was reported that TGFβ downregulates the expression of ataxia telangiectasia-mutated (ATM) and mutS homolog 2 (MSH2) in breast cancer cells through an miRNA-mediated mechanism. In this study, expression of a panel of DNA-repair genes was examined, identifying breast cancer 1, early onset (BRCA1) as a target downregulated by TGFβ through the miR181 family. Correlations between the expression levels of TGFβ1 and the miR181/BRCA1 axis were observed in primary breast tumor specimens. By downregulating BRCA1, ATM, and MSH2, TGFβ orchestrates DNA damage response in certain breast cancer cells to induce a "BRCAness" phenotype, including impaired DNA-repair efficiency and synthetic lethality to the inhibition of poly (ADP-ribose) polymerase (PARP). Xenograft tumors with active TGFβ signaling exhibited resistance to the DNA-damaging agent doxorubicin but increased sensitivity to the PARP inhibitor ABT-888. Combination of doxorubicin with ABT-888 significantly improved the treatment efficacy in TGFβ-active tumors. Thus, TGFβ can induce "BRCAness" in certain breast cancers carrying wild-type BRCA genes and enhance the responsiveness to PARP inhibition, and the molecular mechanism behind this is characterized. IMPLICATIONS These findings enable better selection of patients with sporadic breast cancer for PARP interventions, which have exhibited beneficial effects in patients carrying BRCA mutations.
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Affiliation(s)
- Liang Liu
- Department of Cancer Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Biotherapy and Key Laboratory of Cancer Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Weiying Zhou
- Department of Cancer Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing, China
| | - Chun-Ting Cheng
- Department of Molecular Pharmacology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. City of Hope Irell and Manella Graduate School of Biological Sciences, Duarte, California
| | - Xiubao Ren
- Department of Biotherapy and Key Laboratory of Cancer Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - George Somlo
- Department of Medical Oncology, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Miranda Y Fong
- Department of Cancer Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Andrew R Chin
- Department of Cancer Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. City of Hope Irell and Manella Graduate School of Biological Sciences, Duarte, California
| | - Hui Li
- Department of Biotherapy and Key Laboratory of Cancer Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yang Yu
- Department of Biotherapy and Key Laboratory of Cancer Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yang Xu
- Department of Cancer Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | | | - Timothy R O'Connor
- Department of Cancer Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - David K Ann
- Department of Molecular Pharmacology, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Jeremy M Stark
- Department of Radiation Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Shizhen Emily Wang
- Department of Cancer Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Biotherapy and Key Laboratory of Cancer Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
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Sui L, Yang T, Gao P, Meng A, Wang P, Wu Z, Wang J. Incorporation of cisplatin into PEG-wrapped ultrapurified large-inner-diameter MWCNTs for enhanced loading efficiency and release profile. Int J Pharm 2014; 471:157-65. [DOI: 10.1016/j.ijpharm.2014.05.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 05/09/2014] [Accepted: 05/16/2014] [Indexed: 12/21/2022]
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Treas J, Tyagi T, Singh KP. Chronic exposure to arsenic, estrogen, and their combination causes increased growth and transformation in human prostate epithelial cells potentially by hypermethylation-mediated silencing of MLH1. Prostate 2013; 73:1660-72. [PMID: 23804311 DOI: 10.1002/pros.22701] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 05/29/2013] [Indexed: 11/07/2022]
Abstract
BACKGROUND Chronic exposure to arsenic and estrogen is associated with risk of prostate cancer, but their mechanism is not fully understood. Additionally, the carcinogenic effects of their co-exposure are not known. Therefore, the objective of this study was to evaluate the effects of chronic exposure to arsenic, estrogen, and their combination, on cell growth and transformation, and identify the mechanism behind these effects. METHODS RWPE-1 human prostate epithelial cells were chronically exposed to arsenic and estrogen alone and in combination. Cell growth was measured by cell count and cell cycle, whereas cell transformation was evaluated by colony formation assay. Gene expression was measured by quantitative real-time PCR and confirmed at protein level by Western blot analysis. MLH1 promoter methylation was determined by pyrosequencing method. RESULTS Exposure to arsenic, estrogen, and their combinations increases cell growth and transformation in RWPE-1 cells. Increased expression of Cyclin D1 and Bcl2, whereas decreased expression of mismatch repair genes MSH4, MSH6, and MLH1 was also observed. Hypermethylation of MLH1 promoter further suggested the epigenetic inactivation of MLH1 expression in arsenic and estrogen treated cells. Arsenic and estrogen combination caused greater changes than their individual treatments. CONCLUSIONS Findings of this study for the first time suggest that arsenic and estrogen exposures cause increased cell growth and survival potentially through epigenetic inactivation of MLH1 resulting in decreased MLH1-mediated apoptotic response, and consequently increased cellular transformation.
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Affiliation(s)
- Justin Treas
- Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, Texas
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Abstract
Normal cell function requires strict control over the repair of DNA damage, which prevents excessive mutagenesis. An enhanced accumulation of mutations results in the multistep process generally known as carcinogenesis. Defects in repair pathways fuel such mutagenesis by allowing reiterative cycles of mutation, selection, and clonal expansion that drive cancer progression. The repair of mismatches is an important mechanism in the prevention of such genetic instability. In addition, proteins of this pathway have the unique ability to function in DNA damage response by inducing apoptosis when irreparable damage is encountered. Though originally identified primarily in association with a predisposition to hereditary colon cancer, mismatch repair defects have been identified in many other cancer types, including prostate cancer. From the first discovery of microsatellite instability in prostate cancer cell lines and tumor samples, variations in protein levels and a possible association with recurrence and aggression of disease have been described. Current results suggest that the involvement of mismatch repair proteins in prostate cancer may differ from that found in colorectal cancer, in the type of proteins and protein defects involved and the type of causative mutations. Additional work is clearly needed to investigate this involvement and the possibility that such defects may affect treatment response and androgen independence.
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Affiliation(s)
- John Jarzen
- Department of Biology, College of Science and Technology, Georgia Southern University, Statesboro, Georgia, USA
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Sedletska Y, Culard F, Midoux P, Malinge JM. Interaction studies of muts and mutl with DNA containing the major cisplatin lesion and its mismatched counterpart under equilibrium and nonequilibrium conditions. Biopolymers 2013; 99:636-47. [DOI: 10.1002/bip.22232] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Revised: 02/04/2013] [Accepted: 03/05/2013] [Indexed: 11/12/2022]
Affiliation(s)
| | - Françoise Culard
- Centre de Biophysique Moléculaire; CNRS UPR 4301; affiliated to the University of Orléans and INSERM; rue Charles Sadron, 45071 Orléans Cedex 02; France
| | - Patrick Midoux
- Centre de Biophysique Moléculaire; CNRS UPR 4301; affiliated to the University of Orléans and INSERM; rue Charles Sadron, 45071 Orléans Cedex 02; France
| | - Jean-Marc Malinge
- Centre de Biophysique Moléculaire; CNRS UPR 4301; affiliated to the University of Orléans and INSERM; rue Charles Sadron, 45071 Orléans Cedex 02; France
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Zhu G, Song L, Lippard SJ. Visualizing inhibition of nucleosome mobility and transcription by cisplatin-DNA interstrand crosslinks in live mammalian cells. Cancer Res 2013; 73:4451-60. [PMID: 23695549 DOI: 10.1158/0008-5472.can-13-0198] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cisplatin is a widely used anticancer drug that acts by binding DNA and causing the formation of intrastrand and interstrand (ICL) crosslinks, but the precise downstream effects of the latter damage are not well understood. In this study, we investigated the influence of cisplatin ICLs on synthetic nucleosomes that were platinated in a site-specific manner in vitro and on gene transcription in live mammalian cells. Nucleosome core particles that we constructed contained site-specific cisplatin 5'-d(G*pC)/5'-d(G*pC) ICLs, where the asterisk denotes the platinated nucleoside, to examine the influence of platinum lesions on the dynamic behavior of nucleosomes in solution. A cisplatin ICL, but not a 1,2-d(GpG) crosslink, significantly inhibited ATP-independent histone octamer-DNA sliding. We also used a novel linearization-recircularization strategy described here to synthesize mammalian expression vectors containing site-specific cisplatin ICLs. Plasmid vectors were tested in live mammalian cells to study the transcription inhibition effects of cisplatin ICLs in the context of two different repair backgrounds. Cisplatin ICLs inhibit transcription as effectively as 1,2-d(GpG) crosslinks. We determined that nucleotide excision repair plays a key role in the removal of cisplatin ICLs, acting in a replication-independent fashion. We also found that loss of mismatch repair function dramatically attenuates the transcription inhibition effects by cisplatin ICLs but not 1,2-d(GpG) intrastrand crosslinks. Our results revealed the unique properties of cisplatin ICLs on nucleosome mobility and on transcription, and they defined how these adducts act in a manner completely different from that used for cisplatin 1,2-d(GpG) crosslinks. These new findings provide direct support for a role of ICLs in the pharmacologic activities of cisplatin, despite the lower frequency of their formation.
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Affiliation(s)
- Guangyu Zhu
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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AbdelHafez EMN, Diamanduros A, Negureanu L, Luy Y, Bean JH, Zielke K, Crowe B, Vasilyeva A, Clodfelter JE, Aly OM, Abuo-Rahma GEDAA, Scarpinato KD, Salsbury FR, King SB. Computational and synthetic studies towards improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment. MOLECULAR CANCER BIOLOGY 2013; 1:44. [PMID: 25485184 PMCID: PMC4254817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
We, and others, have previously shown that mismatch repair proteins, in addition to their repair function, contribute to cell death initiation. In response to some drugs, this cell death activity is independent of the repair function of the proteins. Rescinnamine, a derivative of the indole alkaloid reserpine, a drug used to treat hypertension several decades ago, was shown to target the cell death-initiating activity of mismatch repair proteins. When used in animals, the hypotensive action of this drug prevents applying appropriate concentrations for statistically significant tumor reduction. Using a combination of computational modeling, chemical synthesis and cell assays, we determine how rescinnamine can be structurally modified and what effect these modifications have on cell survival. These results inform further computational modeling to suggest new synthetic lead molecules to move toward further biological testing.
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Affiliation(s)
| | | | | | - Yan Luy
- Department of Physics, Wake Forest University, Winston-Salem, NC
| | - J. Hayley Bean
- Department of Biology, Georgia Southern University, Statesboro, GA
| | - Katherine Zielke
- Department of Biology, Georgia Southern University, Statesboro, GA
| | - Brittany Crowe
- Department of Biology, Georgia Southern University, Statesboro, GA
| | - Aksana Vasilyeva
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC; now: St. Jude Hospital, Memphis, TN
| | - Jill E. Clodfelter
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC
| | - Omar M. Aly
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia , Egypt
| | | | | | | | - S. Bruce King
- Department of Chemistry, Wake Forest University, Winston-Salem, NC
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Hassen S, Ali N, Chowdhury P. Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer. World J Gastrointest Pathophysiol 2012; 3:71-9. [PMID: 22737591 PMCID: PMC3382705 DOI: 10.4291/wjgp.v3.i3.71] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Revised: 05/31/2012] [Accepted: 06/12/2012] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the second most leading cause of cancer related deaths in the western countries. One of the forms of colorectal cancer is hereditary non-polyposis colorectal cancer (HNPCC), also known as “Lynch syndrome”. It is the most common hereditary form of cancer accounting for 5%-10% of all colon cancers. HNPCC is a dominant autosomal genetic disorder caused by germ line mutations in mismatch repair genes. Human mismatch repair genes play a crucial role in genetic stability of DNA, the inactivation of which results in an increased rate of mutation and often a loss of mismatch repair function. Recent studies have shown that certain mismatch repair genes are involved in the regulation of key cellular processes including apoptosis. Thus, differential expression of mismatch repair genes particularly the contributions of MLH1 and MSH2 play important roles in therapeutic resistance to certain cytotoxic drugs such as cisplatin that is used normally as chemoprevention. An understanding of the role of mismatch repair genes in molecular signaling mechanism of apoptosis and its involvement in HNPCC needs attention for further work into this important area of cancer research, and this review article is intended to accomplish that goal of linkage of apoptosis with HNPCC. The current review was not intended to provide a comprehensive enumeration of the entire body of literature in the area of HNPCC or mismatch repair system or apoptosis; it is rather intended to focus primarily on the current state of knowledge of the role of mismatch repair proteins in molecular signaling mechanism of apoptosis as it relates to understanding of HNPCC.
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Legolvan MP, Taliano RJ, Resnick MB. Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach. Hum Pathol 2012; 43:1157-68. [PMID: 22658275 DOI: 10.1016/j.humpath.2012.03.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 02/29/2012] [Accepted: 03/02/2012] [Indexed: 12/13/2022]
Abstract
There has been an increasing role for molecular diagnostics in the diagnosis and management of cancer, and colorectal carcinoma is no exception. Recent molecular advances have elucidated 3 broad molecular subtypes of colorectal cancer, including chromosomal instability, microsatellite instability, and cytosine-phosphoguanine island methylator phenotype, which will be discussed. Also, the common syndromes associated with colorectal carcinoma will be reviewed with a focus on the differentiation between Lynch syndrome and microsatellite unstable tumors. Molecular biomarkers for predictive and prognostic markers are also becoming widely used, and due to the clinical use of monoclonal antibodies to the epidermal growth factor receptor, an emphasis is placed on that pathway.
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Affiliation(s)
- Mark P Legolvan
- Department of Pathology, Rhode Island Hospital, and the Alpert Medical School of Brown University, Providence, RI 02908, USA
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Zhu G, Myint M, Ang WH, Song L, Lippard SJ. Monofunctional platinum-DNA adducts are strong inhibitors of transcription and substrates for nucleotide excision repair in live mammalian cells. Cancer Res 2011; 72:790-800. [PMID: 22180496 DOI: 10.1158/0008-5472.can-11-3151] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
To overcome drug resistance and reduce the side effects of cisplatin, a widely used antineoplastic agent, major efforts have been made to develop next generation platinum-based anticancer drugs. Because cisplatin-DNA adducts block RNA polymerase II unless removed by transcription-coupled excision repair, compounds that react similarly but elude repair are desirable. The monofunctional platinum agent pyriplatin displays antitumor activity in mice, a cytotoxicity profile in cell cultures distinct from that of cisplatin, and a unique in vitro transcription inhibition mechanism. In this study, we incorporated pyriplatin globally or site specifically into luciferase reporter vectors to examine its transcription inhibition profiles in live mammalian cells. Monofunctional pyriplatin reacted with plasmid DNA as efficiently as bifunctional cisplatin and inhibited transcription as strongly as cisplatin in various mammalian cells. Using repair-defective nucleotide excision repair (NER)-, mismatch repair-, and single-strand break repair-deficient cells, we show that NER is mainly responsible for removal of pyriplatin-DNA adducts. These findings reveal that the mechanism by which pyriplatin generates its antitumor activity is very similar to that of cisplatin, despite the chemically different nature of their DNA adducts, further supporting a role for monofunctional platinum anticancer agents in human cancer therapy. This information also provides support for the validity of the proposed mechanism of action of cisplatin and provides a rational basis for the design of more potent platinum anticancer drug candidates using a monofunctional DNA-damaging strategy.
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Affiliation(s)
- Guangyu Zhu
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
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The awakening of an advanced malignant cancer: an insult to the mitochondrial genome. Biochim Biophys Acta Gen Subj 2011; 1820:652-62. [PMID: 21920409 DOI: 10.1016/j.bbagen.2011.08.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 08/26/2011] [Accepted: 08/29/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND In only months-to-years a primary cancer can progress to an advanced phenotype that is metastatic and resistant to clinical treatments. As early as the 1900s, it was discovered that the progression of a cancer to the advanced phenotype is often associated with a shift in the metabolic profile of the disease from a state of respiration to anaerobic fermentation - a phenomenon denoted as the Warburg Effect. SCOPE OF REVIEW Reports in the literature strongly suggest that the Warburg Effect is generated as a response to a loss in the integrity of the sequence and/or copy number of the mitochondrial genome content within a cancer. MAJOR CONCLUSIONS Multiple studies regarding the progression of cancer indicate that mutation, and/or, a flux in the copy number, of the mitochondrial genome content can support the early development of a cancer, until; the mutational load and/or the reduction-to-depletion of the copy number of the mitochondrial genome content induces the progression of the disease to an advanced phenotype. GENERAL SIGNIFICANCE Collectively, evidence has revealed that the human cell has incorporated the mitochondrial genome content into a cellular mechanism that, when pathologically actuated, can de(un)differentiate a cancer from the parental tissue of origin into an autonomous disease that disrupts the hierarchical structure-and-function of the human body. This article is part of a Special Issue entitled: Biochemistry of Mitochondria.
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