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1
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Hertel A, Storchová Z. The Role of p53 Mutations in Early and Late Response to Mitotic Aberrations. Biomolecules 2025; 15:244. [PMID: 40001547 PMCID: PMC11852650 DOI: 10.3390/biom15020244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/30/2025] [Accepted: 02/01/2025] [Indexed: 02/27/2025] Open
Abstract
Mutations in the TP53 gene and chromosomal instability (CIN) are two of the most common alterations in cancer. CIN, marked by changes in chromosome numbers and structure, drives tumor development, but is poorly tolerated in healthy cells, where developmental and tissue homeostasis mechanisms typically eliminate cells with chromosomal abnormalities. Mechanisms that allow cancer cells to acquire and adapt to CIN remain largely unknown. Tumor suppressor protein p53, often referred to as the "guardian of the genome", plays a critical role in maintaining genomic stability. In cancer, CIN strongly correlates with TP53 mutations, and recent studies suggest that p53 prevents the propagation of cells with abnormal karyotypes arising from mitotic errors. Furthermore, p53 dysfunction is frequent in cells that underwent whole-genome doubling (WGD), a process that facilitates CIN onset, promotes aneuploidy tolerance, and is associated with poor patient prognosis across multiple cancer types. This review summarizes current insights into p53's role in protecting cells from chromosome copy number alterations and discusses the implications of its dysfunction for the adaption and propagation of cancer cells.
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Affiliation(s)
| | - Zuzana Storchová
- Group Molecular Genetics, Faculty of Biology, RPTU Kaiserslautern-Landau, Paul Ehrlich Str. 24, 67663 Kaiserslautern, Germany
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2
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Pilotto Heming C, de Souza Barbosa I, Lyra Miranda R, Nogueira Ugarte O, Santório de São José V, Moura Neto V, Aran V. P-Glycoprotein Drives Glioblastoma Survival and Chemotherapy Resistance: Potential as a Promising Liquid Biopsy Biomarker. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(24)00476-0. [PMID: 39788485 DOI: 10.1016/j.ajpath.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/21/2024] [Accepted: 12/03/2024] [Indexed: 01/12/2025]
Abstract
Drug resistance is a major challenge in cancer therapy, and the expression of efflux pumps such as P-glycoprotein (P-gp, ABCB1) often correlates with poor prognosis in various tumors, including glioblastoma (GB). Considering that different roles for these proteins have been established in the biology of various tumors, this study aimed to investigate the functions of P-gp in GB-derived cells by evaluating its survival, migratory, and apoptosis-regulating capabilities, as well as its potential as a liquid biopsy biomarker. P-gp expression was diminished via siRNA to determine its exact role in GB biology. The P-gp mRNA levels were evaluated by using quantitative real-time RT-PCR. With respect to liquid biopsy, circulating cell-free RNA was extracted from plasma belonging to patients diagnosed with GB, and P-gp levels were compared with matching tumor tissues using digital PCR. P-gp silencing significantly decreased viability, increased apoptosis, and enhanced chemotherapy sensitivity in GB cells, although it did not affect migratory patterns. Finally, P-gp expression levels in circulating cell-free RNA from patients with GB matched tumor tissue, whereas healthy volunteers appeared to bear no circulating P-gp. Taken together, the results indicate that P-gp affects GB tumor biology beyond its known role in drug resistance and could integrate a broader molecular signature for future diagnosis via liquid biopsy.
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Affiliation(s)
- Carlos Pilotto Heming
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil; Post-Graduate Program in Anatomic Pathology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Isabel de Souza Barbosa
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil; Post-Graduate Program in Anatomic Pathology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Renan Lyra Miranda
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil
| | | | | | - Vivaldo Moura Neto
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil
| | - Veronica Aran
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil; Post-Graduate Program in Anatomic Pathology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
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3
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Hernández-Velázquez ED, Granados-López AJ, López JA, Solorio-Alvarado CR. Multidrug Resistance Reversed by Maleimide Interactions. A Biological and Synthetic Overview for an Emerging Field. Chembiochem 2025; 26:e202400640. [PMID: 39383297 DOI: 10.1002/cbic.202400640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/08/2024] [Accepted: 10/09/2024] [Indexed: 10/11/2024]
Abstract
Multidrug Resistance (MDR) can be considered one of the most frightening adaptation types in bacteria, fungi, protozoa, and eukaryotic cells. It allows the organisms to survive the attack of many drugs used in the daily basis. This forces the development of new and more complex, highly specific drugs to fight diseases. Given the high usage of medicaments, poor variation in active chemical cores, and self-medication, the appearance of MDR is more frequent each time, and has been established as a serious medical and social problem. Over the years it has been possible the identification of several genes and proteins responsible for MDR and with that the development of blockers of them to reach MDR reversion and try to avoid a global problem. These mechanisms also have been observed in cancer cells, and several calcium channel blockers have been successful in MDR reversion, and the maleimide can be found included in them. In this review, we explore particularly the tree main proteins involved in cancer chemoresistance, MRP1 (encoded by ABCC1), BCRP (encoded by ABCG2) and P-gp (encoded by ABCB1). The participation of P-gp is remarkably important, and several aspects of its regulations are discussed. Additionally, we address the history, mechanisms, reversion efforts, and we specifically focused on the maleimide synthesis as MDR-reversers in co-administration, as well as on how their biological applications are imperative to expand the available information and explore a very plausible MDR reversion source.
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Affiliation(s)
- Edson D Hernández-Velázquez
- Campus Guanajuato, División de Ciencias Naturales y Exactas, Departamento de Química, Universidad de Guanajuato, Noria Alta S/N, 36050, Guanajuato, Gto., México
| | | | - Jesús Adrián López
- Laboratorio de MicroRNAs y Cáncer, Universidad Autónoma de Zacatecas, 98066, Zacatecas, México
| | - César R Solorio-Alvarado
- Campus Guanajuato, División de Ciencias Naturales y Exactas, Departamento de Química, Universidad de Guanajuato, Noria Alta S/N, 36050, Guanajuato, Gto., México
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4
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Ahmadi SE, Rahimian E, Rahimi S, Zarandi B, Bahraini M, Soleymani M, Safdari SM, Shabannezhad A, Jaafari N, Safa M. From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy. Biomark Res 2024; 12:137. [PMID: 39538363 PMCID: PMC11565275 DOI: 10.1186/s40364-024-00676-9] [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: 07/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
The p53 protein, encoded by the TP53 gene, serves as a critical tumor suppressor, playing a vital role in maintaining genomic stability and regulating cellular responses to stress. Dysregulation of p53 is frequently observed in hematological malignancies, significantly impacting disease progression and patient outcomes. This review aims to examine the regulatory mechanisms of p53, the implications of TP53 mutations in various hematological cancers, and emerging therapeutic strategies targeting p53. We conducted a comprehensive literature review to synthesize recent findings related to p53's multifaceted role in hematologic cancers, focusing on its regulatory pathways and therapeutic potential. TP53 mutations in hematological malignancies often lead to treatment resistance and poor prognosis. Current therapeutic strategies, including p53 reactivation and gene therapy, show promise in improving treatment outcomes. Understanding the intricacies of p53 regulation and the consequences of its mutations is essential for developing effective diagnostic and therapeutic strategies in hematological malignancies, ultimately enhancing patient care and survival.
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Affiliation(s)
- Seyed Esmaeil Ahmadi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Elahe Rahimian
- Department of Medical Translational Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany
| | - Samira Rahimi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Bahman Zarandi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehran Bahraini
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maral Soleymani
- Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Mehrab Safdari
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ashkan Shabannezhad
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Niloofar Jaafari
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Majid Safa
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
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5
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Qayoom H, Haq BU, Sofi S, Jan N, Jan A, Mir MA. Targeting mutant p53: a key player in breast cancer pathogenesis and beyond. Cell Commun Signal 2024; 22:484. [PMID: 39390510 PMCID: PMC11466041 DOI: 10.1186/s12964-024-01863-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 09/30/2024] [Indexed: 10/12/2024] Open
Abstract
The p53 mutation is the most common genetic mutation associated with human neoplasia. TP53 missense mutations, which frequently arise early in breast cancer, are present in over thirty percent of breast tumors. In breast cancer, p53 mutations are linked to a more aggressive course of the disease and worse overall survival rates. TP53 mutations are mostly seen in triple-negative breast cancer, a very diverse kind of the disease. The majority of TP53 mutations originate in the replacement of individual amino acids within the p53 protein's core domain, giving rise to a variety of variations referred to as "mutant p53s." In addition to gaining carcinogenic qualities through gain-of-function pathways, these mutants lose the typical tumor-suppressive features of p53 to variable degrees. The gain-of-function impact of stabilized mutant p53 causes tumor-specific dependency and resistance to therapy. P53 is a prospective target for cancer therapy because of its tumor-suppressive qualities and the numerous alterations that it experiences in tumors. Phenotypic abnormalities in breast cancer, notably poorly differentiated basal-like tumors are frequently linked to high-grade tumors. By comparing data from cell and animal models with clinical outcomes in breast cancer, this study investigates the molecular mechanisms that convert gene alterations into the pathogenic consequences of mutant p53's tumorigenic activity. The study delves into current and novel treatment approaches aimed at targeting p53 mutations, taking into account the similarities and differences in p53 regulatory mechanisms between mutant and wild-type forms, as well.
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Affiliation(s)
- Hina Qayoom
- Cancer Biology Lab, Department of Bioresources, School of Biological Sciences, University of Kashmir Srinagar, Kashmir Srinagar, J&K, 190006, India
| | - Burhan Ul Haq
- Cancer Biology Lab, Department of Bioresources, School of Biological Sciences, University of Kashmir Srinagar, Kashmir Srinagar, J&K, 190006, India
| | - Shazia Sofi
- Cancer Biology Lab, Department of Bioresources, School of Biological Sciences, University of Kashmir Srinagar, Kashmir Srinagar, J&K, 190006, India
| | - Nusrat Jan
- Cancer Biology Lab, Department of Bioresources, School of Biological Sciences, University of Kashmir Srinagar, Kashmir Srinagar, J&K, 190006, India
| | - Asma Jan
- Cancer Biology Lab, Department of Bioresources, School of Biological Sciences, University of Kashmir Srinagar, Kashmir Srinagar, J&K, 190006, India
| | - Manzoor A Mir
- Cancer Biology Lab, Department of Bioresources, School of Biological Sciences, University of Kashmir Srinagar, Kashmir Srinagar, J&K, 190006, India.
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6
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Song B, Yang P, Zhang S. Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy. Cancer Commun (Lond) 2024; 44:297-360. [PMID: 38311377 PMCID: PMC10958678 DOI: 10.1002/cac2.12520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 01/03/2024] [Accepted: 01/11/2024] [Indexed: 02/10/2024] Open
Abstract
Cancer is a leading cause of death worldwide. Targeted therapies aimed at key oncogenic driver mutations in combination with chemotherapy and radiotherapy as well as immunotherapy have benefited cancer patients considerably. Tumor protein p53 (TP53), a crucial tumor suppressor gene encoding p53, regulates numerous downstream genes and cellular phenotypes in response to various stressors. The affected genes are involved in diverse processes, including cell cycle arrest, DNA repair, cellular senescence, metabolic homeostasis, apoptosis, and autophagy. However, accumulating recent studies have continued to reveal novel and unexpected functions of p53 in governing the fate of tumors, for example, functions in ferroptosis, immunity, the tumor microenvironment and microbiome metabolism. Among the possibilities, the evolutionary plasticity of p53 is the most controversial, partially due to the dizzying array of biological functions that have been attributed to different regulatory mechanisms of p53 signaling. Nearly 40 years after its discovery, this key tumor suppressor remains somewhat enigmatic. The intricate and diverse functions of p53 in regulating cell fate during cancer treatment are only the tip of the iceberg with respect to its equally complicated structural biology, which has been painstakingly revealed. Additionally, TP53 mutation is one of the most significant genetic alterations in cancer, contributing to rapid cancer cell growth and tumor progression. Here, we summarized recent advances that implicate altered p53 in modulating the response to various cancer therapies, including chemotherapy, radiotherapy, and immunotherapy. Furthermore, we also discussed potential strategies for targeting p53 as a therapeutic option for cancer.
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Affiliation(s)
- Bin Song
- Laboratory of Radiation MedicineWest China Second University HospitalSichuan UniversityChengduSichuanP. R. China
| | - Ping Yang
- Laboratory of Radiation MedicineWest China Second University HospitalSichuan UniversityChengduSichuanP. R. China
| | - Shuyu Zhang
- Laboratory of Radiation MedicineWest China Second University HospitalSichuan UniversityChengduSichuanP. R. China
- The Second Affiliated Hospital of Chengdu Medical CollegeChina National Nuclear Corporation 416 HospitalChengduSichuanP. R. China
- Laboratory of Radiation MedicineNHC Key Laboratory of Nuclear Technology Medical TransformationWest China School of Basic Medical Sciences & Forensic MedicineSichuan UniversityChengduSichuanP. R. China
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7
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Bharathiraja P, Yadav P, Sajid A, Ambudkar SV, Prasad NR. Natural medicinal compounds target signal transduction pathways to overcome ABC drug efflux transporter-mediated multidrug resistance in cancer. Drug Resist Updat 2023; 71:101004. [PMID: 37660590 PMCID: PMC10840887 DOI: 10.1016/j.drup.2023.101004] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/11/2023] [Accepted: 08/19/2023] [Indexed: 09/05/2023]
Abstract
ATP-binding cassette (ABC) transporters such as ABCB1, ABCG2, and ABCC1 are the major players in drug efflux-mediated multidrug resistance (MDR), which severely affects the efficacy of chemotherapy. Several synthetic compounds block the drug transport by ABC transporters; however, they exhibit a narrow therapeutic window, and produce side effects in non-target normal tissues. Conversely, the downregulation of the expression of ABC drug transporters seems to be a promising strategy to reverse MDR in cancer cells. Several signaling pathways, such as NF-κB, STAT3, Gli, NICD, YAP/TAZ, and Nrf2 upregulate the expression of ABC drug transporters in drug-resistant cancers. Recently, natural medicinal compounds have gained importance to overcome the ABC drug-efflux pump-mediated MDR in cancer. These compounds target transcription factors and the associated signal transduction pathways, thereby downregulating the expression of ABC transporters in drug-resistant cancer cells. Several potent natural compounds have been identified as lead candidates to synergistically enhance chemotherapeutic efficacy, and a few of them are already in clinical trials. Therefore, modulation of signal transduction pathways using natural medicinal compounds for the reversal of ABC drug transporter-mediated MDR in cancer is a novel approach for improving the efficiency of the existing chemotherapeutics. In this review, we discuss the modulatory role of natural medicinal compounds on cellular signaling pathways that regulate the expression of ABC transporters in drug-resistant cancer cells.
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Affiliation(s)
- Pradhapsingh Bharathiraja
- Department of Biochemistry & Biotechnology, Annamalai University, Annamalai Nagar 608 002, Tamil Nadu, India
| | - Priya Yadav
- Department of Biochemistry & Biotechnology, Annamalai University, Annamalai Nagar 608 002, Tamil Nadu, India
| | - Andaleeb Sajid
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892-4256, USA
| | - Suresh V Ambudkar
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892-4256, USA.
| | - N Rajendra Prasad
- Department of Biochemistry & Biotechnology, Annamalai University, Annamalai Nagar 608 002, Tamil Nadu, India.
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8
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Schulz JA, Hartz AMS, Bauer B. ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier: Potential New Targets to Improve Brain Drug Delivery. Pharmacol Rev 2023; 75:815-853. [PMID: 36973040 PMCID: PMC10441638 DOI: 10.1124/pharmrev.120.000025] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 03/29/2023] Open
Abstract
The drug efflux transporters ABCB1 and ABCG2 at the blood-brain barrier limit the delivery of drugs into the brain. Strategies to overcome ABCB1/ABCG2 have been largely unsuccessful, which poses a tremendous clinical problem to successfully treat central nervous system (CNS) diseases. Understanding basic transporter biology, including intracellular regulation mechanisms that control these transporters, is critical to solving this clinical problem.In this comprehensive review, we summarize current knowledge on signaling pathways that regulate ABCB1/ABCG2 at the blood-brain barrier. In Section I, we give a historical overview on blood-brain barrier research and introduce the role that ABCB1 and ABCG2 play in this context. In Section II, we summarize the most important strategies that have been tested to overcome the ABCB1/ABCG2 efflux system at the blood-brain barrier. In Section III, the main component of this review, we provide detailed information on the signaling pathways that have been identified to control ABCB1/ABCG2 at the blood-brain barrier and their potential clinical relevance. This is followed by Section IV, where we explain the clinical implications of ABCB1/ABCG2 regulation in the context of CNS disease. Lastly, in Section V, we conclude by highlighting examples of how transporter regulation could be targeted for therapeutic purposes in the clinic. SIGNIFICANCE STATEMENT: The ABCB1/ABCG2 drug efflux system at the blood-brain barrier poses a significant problem to successful drug delivery to the brain. The article reviews signaling pathways that regulate blood-brain barrier ABCB1/ABCG2 and could potentially be targeted for therapeutic purposes.
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Affiliation(s)
- Julia A Schulz
- Department of Pharmaceutical Sciences, College of Pharmacy (J.A.S., B.B.), Sanders-Brown Center on Aging and Department of Pharmacology and Nutritional Sciences, College of Medicine (A.M.S.H.), University of Kentucky, Lexington, Kentucky
| | - Anika M S Hartz
- Department of Pharmaceutical Sciences, College of Pharmacy (J.A.S., B.B.), Sanders-Brown Center on Aging and Department of Pharmacology and Nutritional Sciences, College of Medicine (A.M.S.H.), University of Kentucky, Lexington, Kentucky
| | - Björn Bauer
- Department of Pharmaceutical Sciences, College of Pharmacy (J.A.S., B.B.), Sanders-Brown Center on Aging and Department of Pharmacology and Nutritional Sciences, College of Medicine (A.M.S.H.), University of Kentucky, Lexington, Kentucky
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9
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Skinner KT, Palkar AM, Hong AL. Genetics of ABCB1 in Cancer. Cancers (Basel) 2023; 15:4236. [PMID: 37686513 PMCID: PMC10487083 DOI: 10.3390/cancers15174236] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/10/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
ABCB1, also known as MDR1, is a gene that encodes P-glycoprotein (P-gp), a membrane-associated ATP-dependent transporter. P-gp is widely expressed in many healthy tissues-in the gastrointestinal tract, liver, kidney, and at the blood-brain barrier. P-gp works to pump xenobiotics such as toxins and drugs out of cells. P-gp is also commonly upregulated across multiple cancer types such as ovarian, breast, and lung. Overexpression of ABCB1 has been linked to the development of chemotherapy resistance across these cancers. In vitro work across a wide range of drug-sensitive and -resistant cancer cell lines has shown that upon treatment with chemotherapeutic agents such as doxorubicin, cisplatin, and paclitaxel, ABCB1 is upregulated. This upregulation is caused in part by a variety of genetic and epigenetic mechanisms. This includes single-nucleotide variants that lead to enhanced P-gp ATPase activity without increasing ABCB1 RNA and protein levels. In this review, we summarize current knowledge of genetic and epigenetic mechanisms leading to ABCB1 upregulation and P-gp-enhanced ATPase activity in the setting of chemotherapy resistance across a variety of cancers.
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Affiliation(s)
- Katie T. Skinner
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; (K.T.S.); (A.M.P.)
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA
| | - Antara M. Palkar
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; (K.T.S.); (A.M.P.)
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA
| | - Andrew L. Hong
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; (K.T.S.); (A.M.P.)
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
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10
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Chen R, Chen H, Peng H, Zheng Y, Lin Z, Lin X. Multi-Walled Carbon Nanotube Array Modified Electrode with 3D Sensing Interface as Electrochemical DNA Biosensor for Multidrug-Resistant Gene Detection. BIOSENSORS 2023; 13:764. [PMID: 37622850 PMCID: PMC10452495 DOI: 10.3390/bios13080764] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/26/2023]
Abstract
Drug resistance in cancer is associated with overexpression of the multidrug resistance (MDR1) gene, leading to the failure of cancer chemotherapy treatment. Therefore, the establishment of an effective method for the detection of the MDR1 gene is extremely crucial in cancer clinical therapy. Here, we report a novel DNA biosensor based on an aligned multi-walled carbon nanotube (MWCNT) array modified electrode with 3D nanostructure for the determination of the MDR1 gene. The microstructure of the modified electrode was observed by an atomic force microscope (AFM), which demonstrated that the electrode interface was arranged in orderly needle-shaped protrusion arrays. The electrochemical properties of the biosensor were characterized by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS). Chronocoulometry (CC) was used for the quantitative detection of the MDR1 gene. Taking advantage of the good conductivity and large electrode area of the MWCNT arrays, this electrochemical DNA sensor achieved a dynamic range from 1.0 × 10-12 M to 1.0 × 10-8 M with a minimal detection limit of 6.4 × 10-13 M. In addition, this proposed DNA biosensor exhibited high sensitivity, selectivity, and stability, which may be useful for the trace analysis of the MDR1 gene in complex samples.
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Affiliation(s)
| | | | - Huaping Peng
- Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Department of Pharma-Ceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China; (R.C.); (H.C.); (Y.Z.); (Z.L.)
| | | | | | - Xinhua Lin
- Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Department of Pharma-Ceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China; (R.C.); (H.C.); (Y.Z.); (Z.L.)
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11
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Calheiros J, Corbo V, Saraiva L. Overcoming therapeutic resistance in pancreatic cancer: Emerging opportunities by targeting BRCAs and p53. Biochim Biophys Acta Rev Cancer 2023; 1878:188914. [PMID: 37201730 DOI: 10.1016/j.bbcan.2023.188914] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/11/2023] [Accepted: 05/11/2023] [Indexed: 05/20/2023]
Abstract
Pancreatic cancer (PC) is characterized by (epi)genetic and microenvironmental alterations that negatively impact the treatment outcomes. New targeted therapies have been pursued to counteract the therapeutic resistance in PC. Aiming to seek for new therapeutic options for PC, several attempts have been undertaken to exploit BRCA1/2 and TP53 deficiencies as promising actionable targets. The elucidation of the pathogenesis of PC highlighted the high prevalence of p53 mutations and their connection with the aggressiveness and therapeutic resistance of PC. Additionally, PC is associated with dysfunctions in several DNA repair-related genes, including BRCA1/2, which sensitize tumours to DNA-damaging agents. In this context, poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) were approved for mutant BRCA1/2 PC patients. However, acquired drug resistance has become a major drawback of PARPi. This review emphasizes the importance of targeting defective BRCAs and p53 pathways for advancing personalized PC therapy, with particular focus on how this approach may provide an opportunity to tackle PC resistance.
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Affiliation(s)
- Juliana Calheiros
- LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal
| | - Vincenzo Corbo
- Department of Engineering for Innovation Medicine (DIMI), University and Hospital Trust of Verona, Verona, Italy; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
| | - Lucília Saraiva
- LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.
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12
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Dual roles of TRIM3 in colorectal cancer by retaining p53 in the cytoplasm to decrease its nuclear expression. Cell Death Discov 2023; 9:85. [PMID: 36894560 PMCID: PMC9998637 DOI: 10.1038/s41420-023-01386-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 02/22/2023] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
Colorectal cancer is a very heterogeneous disease caused by the interaction of genetic and environmental factors. P53, as a frequent mutation gene, plays a critical role in the adenoma-carcinoma transition during the tumorous pathological process. Our team discovered TRIM3 as a tumor-associated gene in CRC by high-content screening techniques. TRIM3 demonstrated both tumor-suppressive and tumorigenic features in cell experiments dependent on the cell status of wild or mutant p53. TRIM3 could directly interact with the C terminus of p53 (residues 320 to 393), a common segment of wtp53 and mutp53. Moreover, TRIM3 could exert different neoplastic features by retaining p53 in the cytoplasm to decrease its nuclear expression in a wtp53 or mutp53-dependent pathway. Chemotherapy resistance develops in nearly all patients with advanced CRC and seriously limits the therapeutic efficacies of anticancer drugs. TRIM3 could reverse the chemotherapy resistance of oxaliplatin in mutp53 CRC cells by degradation of mutp53 in the nuclei to downregulate the multidrug resistance gene. Therefore, TRIM3 could be a potential therapeutic strategy to improve the survival of CRC patients with mutp53.
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13
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S S P, M R R. Synergistic effect of p53 gene/DOX intracellular delivery and P-gp inhibition by pullulan thiomers on cancer cells: in vitro and in vivo evaluations. J Mater Chem B 2023; 11:1365-1377. [PMID: 36655691 DOI: 10.1039/d2tb01770a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Numerous reports emphasize the inverse relationship between the mutant p53 protein and P-glycoprotein overexpression, which adversely affects the chemosensitivity of cancer cells. In this study, the cationised pullulan polysaccharide was conjugated with dithiobutyric acid (PPDBA) for the intracellular delivery of doxorubicin and the p53 gene. The transfection efficiency of PPDBA using the apoptotic gene p53 and its ability to modulate efflux pumps in the presence and absence of glutathione and the subsequent drug retention were studied in different cell lines. The percentage cell death mediated by the PPDBA/p53 nanoplex (4 : 1 ratio) was 59%, and by DOX alone a 50% cell death was attained at 3.13 μM in C6 cells, but the percentage cell death mediated by PPDBA/p53 (4 : 1) in combination with 1 μM DOX was as high as 98%. The effect of PPDBA II/p53/DOX nanoplexes on the mouse tumor model was evaluated in BALB/c mice which demonstrated good efficacy when compared with the drug or gene alone.
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Affiliation(s)
- Priya S S
- Division of Biosurface Technology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Poojappura, Thiruvananthapuram, Kerala, India.
| | - Rekha M R
- Division of Biosurface Technology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Poojappura, Thiruvananthapuram, Kerala, India.
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14
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Patil MR, Bihari A. A comprehensive study of p53 protein. J Cell Biochem 2022; 123:1891-1937. [PMID: 36183376 DOI: 10.1002/jcb.30331] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/02/2022] [Accepted: 09/13/2022] [Indexed: 01/10/2023]
Abstract
The protein p53 has been extensively investigated since it was found 43 years ago and has become a "guardian of the genome" that regulates the division of cells by preventing the growth of cells and dividing them, that is, inhibits the development of tumors. Initial proof of protein existence by researchers in the mid-1970s was found by altering and regulating the SV40 big T antigen termed the A protein. Researchers demonstrated how viruses play a role in cancer by employing viruses' ability to create T-antigens complex with viral tumors, which was discovered in 1979 following a viral analysis and cancer analog research. Researchers later in the year 1989 explained that in Murine Friend, a virus-caused erythroleukemia, commonly found that p53 was inactivated to suggest that p53 could be a "tumor suppressor gene." The TP53 gene, encoding p53, is one of human cancer's most frequently altered genes. The protein-regulated biological functions of all p53s include cell cycles, apoptosis, senescence, metabolism of the DNA, angiogenesis, cell differentiation, and immunological response. We tried to unfold the history of the p53 protein, which was discovered long back in 1979, that is, 43 years of research on p53, and how p53's function has been developed through time in this article.
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Affiliation(s)
- Manisha R Patil
- Department of Computer-Applications, School of Information Technology and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Anand Bihari
- Department of Computational Intelligence, School of Computer Science and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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15
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GOF Mutant p53 in Cancers: A Therapeutic Challenge. Cancers (Basel) 2022; 14:cancers14205091. [PMID: 36291874 PMCID: PMC9600758 DOI: 10.3390/cancers14205091] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/30/2022] Open
Abstract
Simple Summary In normal cells, p53 is a protein which regulates the cell cycle progression to ensure normal cell division, growth, and development. However, in cancer, changes in the p53 DNA sequence, called genetic mutation, results in the protein either losing its normal function or exhibiting advanced pro-tumorigenic functions that lead to cancer. Importantly, cancers with mutations in the p53 protein often represent ones which are more aggressive and more resistant to chemotherapy. As a result, many studies have and continue to investigate multiple ways to target mutant p53-bearing cancer using targeted therapy, gene therapy, immunotherapy, and combination therapies. Knowledge of these strategies is important in improving the overall therapeutic response of cancers with mutant p53. This review highlights new strategies and discusses the progression of such therapies. Abstract TP53 is mutated in the majority of human cancers. Mutations can lead to loss of p53 expression or expression of mutant versions of the p53 protein. These mutant p53 proteins have oncogenic potential. They can inhibit any remaining WTp53 in a dominant negative manner, or they can acquire new functions that promote tumour growth, invasion, metastasis and chemoresistance. In this review we explore some of the mechanisms that make mutant p53 cells resistant to chemotherapy. As mutant p53 tumours are resistant to many traditional chemotherapies, many have sought to explore new ways of targeting mutant p53 tumours and reinstate chemosensitivity. These approaches include targeting of mutant p53 stability, mutant p53 binding partners and downstream pathways, p53 vaccines, restoration of WTp53 function, and WTp53 gene delivery. The current advances and challenges of these strategies are discussed.
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16
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Li J, Guo M, Chen L, Chen Z, Fu Y, Chen Y. p53 amyloid aggregation in cancer: function, mechanism, and therapy. Exp Hematol Oncol 2022; 11:66. [PMID: 36171607 PMCID: PMC9520902 DOI: 10.1186/s40164-022-00317-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 09/13/2022] [Indexed: 11/28/2022] Open
Abstract
Similar to neurodegenerative diseases, the concept that tumors are prion like diseases has been proposed in recent years. p53, the most well-known tumor suppressor, has been extensively studied for its expression, mutation, and function in various tumors. Currently, an interesting phenomenon of p53 prion-like aggregation has been found in several tumors, and studies have found that its pathological aggregation may lead to functional alterations and ultimately affect tumor progression. It has been demonstrated that the mechanism of p53 aggregation involves its mutation, domains, isoform, etc. In addition to p53 itself, some other factors, including Zn2+ concentration, pH, temperature and chaperone abnormalities, can also contribute to p53 aggregation. Although there are some studies about the mechanism and role of p53 aggregation and amyloidosis in tumors, there still exist some controversies. In this paper, we review the mechanism of p53 amyloid fibril structure and discuss the characteristics and effects of p53 amyloid aggregation, as well as the pathogenic mechanism leading to the occurrence of aggregation in tumors. Finally, we summarize the various inhibitors targeting p53 aggregation and prion-like behavior. In conclusion, a comprehensive understanding of p53 aggregation can expand our understanding of the causes leading its loss of physiological function and that targeting p53 aggregation might be a promising therapeutic strategy for tumor therapy.
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Affiliation(s)
- Jingzhi Li
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.,Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Ming Guo
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Lin Chen
- Molecular and Computational Biology Program, Department of Biological Sciences and Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA
| | - Zhuchu Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Ying Fu
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. .,Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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17
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Anticancer Therapeutic Strategies Targeting p53 Aggregation. Int J Mol Sci 2022; 23:ijms231911023. [PMID: 36232329 PMCID: PMC9569952 DOI: 10.3390/ijms231911023] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/10/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
p53 is a tumor suppressor protein that is mutated in more than 50% of cancer cases. When mutated, it frequently results in p53 oncogenic gain of function (GOF), resulting in a greater tendency to aggregate in the phase separation and phase transition pathway. GOFs related to p53 aggregation include chemoresistance, which makes therapy even more difficult. The therapies available for the treatment of cancer are still quite limited, so the study of new molecules and therapeutic targets focusing on p53 aggregates is a promising strategy against cancer. In this review, we classify anticancer molecules with antiaggregation properties into four categories: thiol alkylating agents, designed peptides, agents with chaperone-based mechanisms that inhibit p53 aggregation, and miscellaneous compounds with anti-protein aggregation properties that have been studied in neurodegenerative diseases. Furthermore, we highlight autophagy as a possible degradation pathway for aggregated p53. Here, considering cancer as a protein aggregation disease, we review strategies that have been used to disrupt p53 aggregates, leading to cancer regression.
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18
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Gao X, Zheng X, Zhang Y, Dong L, Sun L, Zhao N, Ding C, Ma Z, Wang Y. Deficient or R273H and R248W Mutations of p53 Promote Chemoresistance to 5-FU via TCF21/CD44 Axis-Mediated Enhanced Stemness in Colorectal Carcinoma. Front Cell Dev Biol 2022; 9:788331. [PMID: 35071232 PMCID: PMC8766496 DOI: 10.3389/fcell.2021.788331] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 12/06/2021] [Indexed: 12/16/2022] Open
Abstract
Background: p53 mutations are highly frequent in various human cancers and are reported to contribute to tumor malignance and chemoresistance. In this study, we explored the mechanism by which mutant p53 promotes carcinogenesis and chemoresistance and provided novel insights into cancer therapy. Materials and methods: A total of 409 patients with colorectal carcinoma from TCGA database were subdivided into two groups according to the p53 status, namely, mutant p53 and wild-type p53, following with GSEA analysis. The differences of the clinicopathologic index were also analyzed. Two HCT116 cell lines containing hot spots at codons R273H and R248W of p53 were constructed based on HCT116 with knockout p53, respectively. Cell viability, mobility, clonogenesis, and stemness were detected by CCK8, transwell migration and invasion, colonogenic, and sphere formation assays. Resistance to 5-FU was examined by live-dead staining and flow cytometry. qPCR, Western blot, and luciferase reporter assay were performed to identify that deficient or mutant p53 promoted chemoresistance of the colorectal carcinoma cell line HCT116 through the TCF21/CD44 signaling pathway, with the following rescue assays by overexpression of TCF21 and knockdown of CD44. Results: Patients with recurrence harbor a higher frequency of mutant p53 than those without recurrence (p < 0.05). The mutant p53 group developed a larger tumor than the wild-type one. GSEA analysis showed that oncogenic signatures were enriched in the mutant p53 group. Extracellular assays showed that cancer cells with deficient or mutant p53 (R273H and R248W, respectively) promoted colon cancer cell growth, migration, invasion, and stemness. The mutant cancer cells were also observed to be significantly resistant to 5-FU. Xenografts also confirmed that HCT116 cells harboring deficient or mutant p53 promoted cancer growth and 5-FU tolerance. Luciferase reporter assay showed that deficient or mutant p53 R237H and R248W endowed cancer cells with chemoresistance by activating CD44 via repressing the nuclear transcription factor TCF21 expression. Overexpression of TCF21 or knockdown of CD44 could rescue the sensitivity to 5-FU in deficient and mutant p53 HCT116 cell lines. Conclusion: Our results, for the first time, reveal a novel deficient or mutant p53/TCF21/CD44 signaling pathway which promotes chemoresistance in colorectal carcinoma. The axis could be an effective therapeutic strategy against deficient- or mutant p53-driven chemoresistance.
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Affiliation(s)
- Xiaolei Gao
- Central Laboratory, Beijing, China.,Department of Oral and Maxillofacial Surgery, Beijing, China.,National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Xuan Zheng
- Central Laboratory, Beijing, China.,Department of Oral and Maxillofacial Surgery, Beijing, China
| | - Yixin Zhang
- Central Laboratory, Beijing, China.,Department of Oral and Maxillofacial Surgery, Beijing, China
| | - Liying Dong
- Central Laboratory, Beijing, China.,Department of Oral and Maxillofacial Surgery, Beijing, China
| | - Liangjie Sun
- Central Laboratory, Beijing, China.,Department of Oral and Maxillofacial Surgery, Beijing, China
| | - Na Zhao
- Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, United States.,Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | | | - Zeyun Ma
- Department of VIP Service, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yixiang Wang
- Central Laboratory, Beijing, China.,Department of Oral and Maxillofacial Surgery, Beijing, China
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19
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New Advances in the Research of Resistance to Neoadjuvant Chemotherapy in Breast Cancer. Int J Mol Sci 2021; 22:ijms22179644. [PMID: 34502549 PMCID: PMC8431789 DOI: 10.3390/ijms22179644] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 12/24/2022] Open
Abstract
Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of medicine today, the clinical application of neoadjuvant chemotherapy has brought new hope to the treatment of breast cancer. Although the efficacy of neoadjuvant chemotherapy has been confirmed, drug resistance is one of the main reasons for its treatment failure, contributing to the difficulty in the treatment of breast cancer. This article focuses on multiple mechanisms of action and expounds a series of recent research advances that mediate drug resistance in breast cancer cells. Drug metabolizing enzymes can mediate a catalytic reaction to inactivate chemotherapeutic drugs and develop drug resistance. The drug efflux system can reduce the drug concentration in breast cancer cells. The combination of glutathione detoxification system and platinum drugs can cause breast cancer cells to be insensitive to drugs. Changes in drug targets have led to poorer efficacy of HER2 receptor inhibitors. Moreover, autophagy, epithelial–mesenchymal transition, and tumor microenvironment can all contribute to the development of resistance in breast cancer cells. Based on the relevant research on the existing drug resistance mechanism, the current treatment plan for reversing the resistance of breast cancer to neoadjuvant chemotherapy is explored, and the potential drug targets are analyzed, aiming to provide a new idea and strategy to reverse the resistance of neoadjuvant chemotherapy drugs in breast cancer.
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20
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Liu Y, Zheng C, Huang Y, He M, Xu WW, Li B. Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm (Beijing) 2021; 2:315-340. [PMID: 34766149 PMCID: PMC8554658 DOI: 10.1002/mco2.55] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 12/25/2020] [Accepted: 12/28/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer is a leading cause of death worldwide. Surgery is the primary treatment approach for cancer, but the survival rate is very low due to the rapid progression of the disease and presence of local and distant metastasis at diagnosis. Adjuvant chemotherapy and radiotherapy are important components of the multidisciplinary approaches for cancer treatment. However, resistance to radiotherapy and chemotherapy may result in treatment failure or even cancer recurrence. Radioresistance in cancer is often caused by the repair response to radiation-induced DNA damage, cell cycle dysregulation, cancer stem cells (CSCs) resilience, and epithelial-mesenchymal transition (EMT). Understanding the molecular alterations that lead to radioresistance may provide new diagnostic markers and therapeutic targets to improve radiotherapy efficacy. Patients who develop resistance to chemotherapy drugs cannot benefit from the cytotoxicity induced by the prescribed drug and will likely have a poor outcome with these treatments. Chemotherapy often shows a low response rate due to various drug resistance mechanisms. This review focuses on the molecular mechanisms of radioresistance and chemoresistance in cancer and discusses recent developments in therapeutic strategies targeting chemoradiotherapy resistance to improve treatment outcomes.
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Affiliation(s)
- Ya‐Ping Liu
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhouP. R. China
| | - Can‐Can Zheng
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhouP. R. China
| | - Yun‐Na Huang
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering MedicineNational Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouP. R. China
| | - Ming‐Liang He
- Department of Biomedical SciencesCity University of Hong KongHong KongChina
| | - Wen Wen Xu
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering MedicineNational Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouP. R. China
| | - Bin Li
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhouP. R. China
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21
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Zhang C, Liu J, Xu D, Zhang T, Hu W, Feng Z. Gain-of-function mutant p53 in cancer progression and therapy. J Mol Cell Biol 2021; 12:674-687. [PMID: 32722796 PMCID: PMC7749743 DOI: 10.1093/jmcb/mjaa040] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/28/2020] [Accepted: 07/08/2020] [Indexed: 12/21/2022] Open
Abstract
p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in >50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor-suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.
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Affiliation(s)
- Cen Zhang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ 08903, USA
| | - Juan Liu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ 08903, USA
| | - Dandan Xu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ 08903, USA
| | - Tianliang Zhang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ 08903, USA
| | - Wenwei Hu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ 08903, USA
| | - Zhaohui Feng
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ 08903, USA
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22
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Hernández Borrero LJ, El-Deiry WS. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer 2021; 1876:188556. [PMID: 33932560 PMCID: PMC8730328 DOI: 10.1016/j.bbcan.2021.188556] [Citation(s) in RCA: 267] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022]
Abstract
TP53 is the most commonly mutated gene in human cancer with over 100,000 literature citations in PubMed. This is a heavily studied pathway in cancer biology and oncology with a history that dates back to 1979 when p53 was discovered. The p53 pathway is a complex cellular stress response network with multiple diverse inputs and downstream outputs relevant to its role as a tumor suppressor pathway. While inroads have been made in understanding the biology and signaling in the p53 pathway, the p53 family, transcriptional readouts, and effects of an array of mutants, the pathway remains challenging in the realm of clinical translation. While the role of mutant p53 as a prognostic factor is recognized, the therapeutic modulation of its wild-type or mutant activities remain a work-in-progress. This review covers current knowledge about the biology, signaling mechanisms in the p53 pathway and summarizes advances in therapeutic development.
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Affiliation(s)
- Liz J Hernández Borrero
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, United States of America; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America
| | - Wafik S El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, United States of America; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America.
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23
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Beyaz H, Uludag H, Kavaz D, Rizaner N. Mechanisms of Drug Resistance and Use of Nanoparticle Delivery to Overcome Resistance in Breast Cancers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1347:163-181. [PMID: 34287795 DOI: 10.1007/5584_2021_648] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Breast cancer is the leading cancer type diagnosed among women in the world. Unfortunately, drug resistance to current breast cancer chemotherapeutics remains the main challenge for a higher survival rate. The recent progress in the nanoparticle platforms and distinct features of nanoparticles that enhance the efficacy of therapeutic agents, such as improved delivery efficacy, increased intracellular cytotoxicity, and reduced side effects, hold great promise to overcome the observed drug resistance. Currently, multifaceted investigations are probing the resistance mechanisms associated with clinical drugs, and identifying new breast cancer-associated molecular targets that may lead to improved therapeutic approaches with the nanoparticle platforms. Nanoparticle platforms including siRNA, antibody-specific targeting and the role of nanoparticles in cellular processes and their effect on breast cancer were discussed in this article.
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Affiliation(s)
- Huseyin Beyaz
- Bioengineering Department, Faculty of Engineering, Cyprus International University, Nicosia, Turkey.
| | - Hasan Uludag
- Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, Canada
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
- Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Doga Kavaz
- Bioengineering Department, Faculty of Engineering, Cyprus International University, Nicosia, Turkey
- Biotechnology Research Center, Cyprus International University, Nicosia, Turkey
| | - Nahit Rizaner
- Bioengineering Department, Faculty of Engineering, Cyprus International University, Nicosia, Turkey
- Biotechnology Research Center, Cyprus International University, Nicosia, Turkey
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24
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Ghatak D, Das Ghosh D, Roychoudhury S. Cancer Stemness: p53 at the Wheel. Front Oncol 2021; 10:604124. [PMID: 33505918 PMCID: PMC7830093 DOI: 10.3389/fonc.2020.604124] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022] Open
Abstract
The tumor suppressor p53 maintains an equilibrium between self-renewal and differentiation to sustain a limited repertoire of stem cells for proper development and maintenance of tissue homeostasis. Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming. A few reports in recent years have indicated that prevalent TP53 oncogenic gain-of-function (GOF) mutations further boosts the stemness properties of cancer cells. In this review, we discuss the role of wild type p53 in regulating pluripotency of normal stem cells and various mechanisms that control the balance between self-renewal and differentiation in embryonic and adult stem cells. We also highlight how inactivating and GOF mutations in p53 stimulate stemness in cancer cells. Further, we have explored the various mechanisms of mutant p53-driven cancer stemness, particularly emphasizing on the non-coding RNA mediated epigenetic regulation. We have also analyzed the association of cancer stemness with other crucial gain-of-function properties of mutant p53 such as epithelial to mesenchymal transition phenotypes and chemoresistance to understand how activation of one affects the other. Given the critical role of cancer stem-like cells in tumor maintenance, cancer progression, and therapy resistance of mutant p53 tumors, targeting them might improve therapeutic efficacy in human cancers with TP53 mutations.
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Affiliation(s)
- Dishari Ghatak
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Damayanti Das Ghosh
- Division of Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India
| | - Susanta Roychoudhury
- Division of Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India
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Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance. Int J Mol Sci 2020; 21:ijms21238991. [PMID: 33256191 PMCID: PMC7730978 DOI: 10.3390/ijms21238991] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/23/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022] Open
Abstract
Chemotherapy and radiation often induce a number of cellular responses, such as apoptosis, autophagy, and senescence. One of the major regulators of these processes is p53, an essential tumor suppressor that is often mutated or lost in many cancer types and implicated in early tumorigenesis. Gain of function (GOF) p53 mutations have been implicated in increased susceptibility to drug resistance, by compromising wildtype anti-tumor functions of p53 or modulating key p53 processes that confer chemotherapy resistance, such as autophagy. Autophagy, a cellular survival mechanism, is initially induced in response to chemotherapy and radiotherapy, and its cytoprotective nature became the spearhead of a number of clinical trials aimed to sensitize patients to chemotherapy. However, increased pre-clinical studies have exemplified the multifunctional role of autophagy. Additionally, compartmental localization of p53 can modulate induction or inhibition of autophagy and may play a role in autophagic function. The duality in p53 function and its effects on autophagic function are generally not considered in clinical trial design or clinical therapeutics; however, ample pre-clinical studies suggest they play a role in tumor responses to therapy and drug resistance. Further inquiry into the interconnection between autophagy and p53, and its effects on chemotherapeutic responses may provide beneficial insights on multidrug resistance and novel treatment regimens for chemosensitization.
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Zhu G, Pan C, Bei JX, Li B, Liang C, Xu Y, Fu X. Mutant p53 in Cancer Progression and Targeted Therapies. Front Oncol 2020; 10:595187. [PMID: 33240819 PMCID: PMC7677253 DOI: 10.3389/fonc.2020.595187] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 10/12/2020] [Indexed: 12/17/2022] Open
Abstract
TP53 is the most frequently mutated tumor suppressor gene in human cancer. The majority of mutations of p53 are missense mutations, leading to the expression of the full length p53 mutant proteins. Mutant p53 (Mutp53) proteins not only lose wild-type p53-dependent tumor suppressive functions, but also frequently acquire oncogenic gain-of-functions (GOF) that promote tumorigenesis. In this review, we summarize the recent advances in our understanding of the oncogenic GOF of mutp53 and the potential therapies targeting mutp53 in human cancers. In particular, we discuss the promising drugs that are currently under clinical trials as well as the emerging therapeutic strategies, including CRISPR/Cas9 based genome edition of mutant TP53 allele, small peptide mediated restoration of wild-type p53 function, and immunotherapies that directly eliminate mutp53 expressing tumor cells.
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Affiliation(s)
- Gaoyang Zhu
- Postdoctoral Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Chaoyun Pan
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jin-Xin Bei
- Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Bo Li
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Chen Liang
- Shenzhen International Institute for Biomedical Research, Shenzhen, China
| | - Yang Xu
- Department of Pediatrics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.,Division of Biological Sciences, University of California, San Diego, La Jolla, CA, United States
| | - Xuemei Fu
- Department of Pediatrics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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Seelig A. P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers. Front Oncol 2020; 10:576559. [PMID: 33194688 PMCID: PMC7649427 DOI: 10.3389/fonc.2020.576559] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 08/31/2020] [Indexed: 12/31/2022] Open
Abstract
P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP) binding cassette transporter (ABCB1) intensely investigated because it is an obstacle to successful pharmacotherapy of cancers. P-glycoprotein prevents cellular uptake of a large number of structurally and functionally diverse compounds, including most cancer therapeutics and in this way causes multidrug resistance (MDR). To overcome MDR, and thus improve cancer treatment, an understanding of P-glycoprotein inhibition at the molecular level is required. With this goal in mind, we propose rules that predict whether a compound is a modulator, substrate, inhibitor, or inducer of P-glycoprotein. This new set of rules is derived from a quantitative analysis of the drug binding and transport properties of P-glycoprotein. We further discuss the role of P-glycoprotein in immune surveillance and cell metabolism. Finally, the predictive power of the proposed rules is demonstrated with a set of FDA approved drugs which have been repurposed for cancer therapy.
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Affiliation(s)
- Anna Seelig
- Biozentrum, University of Basel, Basel, Switzerland
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Moxley AH, Reisman D. Context is key: Understanding the regulation, functional control, and activities of the p53 tumour suppressor. Cell Biochem Funct 2020; 39:235-247. [PMID: 32996618 DOI: 10.1002/cbf.3590] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/27/2020] [Accepted: 09/01/2020] [Indexed: 12/12/2022]
Abstract
The p53 tumour suppressor is considered one of the most critical genes in cancer biology. By upregulating apoptosis, cell cycle arrest, and DNA damage repair in normal cells, p53 prevents the propagation of cells with tumorigenic potential; therefore, mutations in p53 are associated with carcinogenic transformation and can be accompanied by the accumulation of a novel gain-of-function oncogenic protein, mutant p53. Although p53 is most often understood to utilize context-dependent post-translational modifications to achieve regulation of its many target genes, recent research has also sought to define other mechanisms of regulating p53 gene expression prior to translation and to understand how this alternative regulation of p53 may influence target gene expression and cellular outcome. This review attempts to summarize what is known about p53 regulation at the transcriptional, post-transcriptional, and post-translational levels while paying special attention to the ways in which context may influence p53 regulation and subsequent regulation of its target genes.
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Affiliation(s)
- Anne H Moxley
- Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, USA
| | - David Reisman
- Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, USA
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You D, Richardson JR, Aleksunes LM. Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition. Drug Metab Dispos 2020; 48:459-480. [PMID: 32193359 PMCID: PMC7250367 DOI: 10.1124/dmd.119.089953] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 02/13/2020] [Indexed: 02/06/2023] Open
Abstract
Multidrug resistance protein 1 (MDR1, ABCB1, P-glycoprotein) and breast cancer resistance protein (BCRP, ABCG2) are key efflux transporters that mediate the extrusion of drugs and toxicants in cancer cells and healthy tissues, including the liver, kidneys, and the brain. Altering the expression and activity of MDR1 and BCRP influences the disposition, pharmacodynamics, and toxicity of chemicals, including a number of commonly prescribed medications. Histone acetylation is an epigenetic modification that can regulate gene expression by changing the accessibility of the genome to transcriptional regulators and transcriptional machinery. Recently, studies have suggested that pharmacological inhibition of histone deacetylases (HDACs) modulates the expression and function of MDR1 and BCRP transporters as a result of enhanced histone acetylation. This review addresses the ability of HDAC inhibitors to modulate the expression and the function of MDR1 and BCRP transporters and explores the molecular mechanisms by which HDAC inhibition regulates these transporters. While the majority of studies have focused on histone regulation of MDR1 and BCRP in drug-resistant and drug-sensitive cancer cells, emerging data point to similar responses in nonmalignant cells and tissues. Elucidating epigenetic mechanisms regulating MDR1 and BCRP is important to expand our understanding of the basic biology of these two key transporters and subsequent consequences on chemoresistance as well as tissue exposure and responses to drugs and toxicants. SIGNIFICANCE STATEMENT: Histone deacetylase inhibitors alter the expression of key efflux transporters multidrug resistance protein 1 and breast cancer resistance protein in healthy and malignant cells.
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Affiliation(s)
- Dahea You
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey (D.Y.); Department of Environmental Health Sciences, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, Florida (J.R.R.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (J.R.R., L.M.A.); and Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, New Jersey (L.M.A.)
| | - Jason R Richardson
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey (D.Y.); Department of Environmental Health Sciences, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, Florida (J.R.R.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (J.R.R., L.M.A.); and Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, New Jersey (L.M.A.)
| | - Lauren M Aleksunes
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey (D.Y.); Department of Environmental Health Sciences, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, Florida (J.R.R.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (J.R.R., L.M.A.); and Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, New Jersey (L.M.A.)
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30
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Jun S, Kim SW, Kim B, Chang IY, Park SJ. Oncogenic Ras downregulates mdr1b expression through generation of reactive oxygen species. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2020; 24:267-276. [PMID: 32392918 PMCID: PMC7193907 DOI: 10.4196/kjpp.2020.24.3.267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 01/31/2020] [Accepted: 02/06/2020] [Indexed: 11/15/2022]
Abstract
In the present study, we investigated the effect of oncogenic H-Ras on rat mdr1b expression in NIH3T3 cells. The constitutive expression of H-RasV12 was found to downregulate the mdr1b promoter activity and mdr1b mRNA expression. The doxorubicin-induced mdr1b promoter activity of the H-RasV12 expressing NIH3T3 cells was markedly lower than that of control NIH3T3 cells. Additionally, there is a positive correlation between the level of H-RasV12 expression and a sensitivity to doxorubicin toxicity. To examine the detailed mechanism of H-RasV12-mediated down-regulation of mdr1b expression, antioxidant N-acetylcysteine (NAC) and NADPH oxidase inhibitor diphenylene iodonium (DPI) were used. Pretreating cells with either NAC or DPI significantly enhanced the oncogenic H-Ras-mediated down-regulation of mdr1b expression and markedly prevented doxorubicin-induced cell death. Moreover, NAC and DPI treatment led to a decrease in ERK activity, and the ERK inhibitors PD98059 or U0126 enhanced the mdr1b-Luc activity of H-RasV12-NIH3T3 and reduced doxorubicin-induced apoptosis. These data suggest that RasV12 expression could downregulate mdr1b expression through intracellular reactive oxygen species (ROS) production, and ERK activation induced by ROS, is at least in part, contributed to the downregulation of mdr1b expression.
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Affiliation(s)
- Semo Jun
- Departments of Premedical Sciences, College of Medicine, Chosun University, Gwangju 61452, Korea
| | - Seok Won Kim
- Departments of Neurosurgery, College of Medicine, Chosun University, Gwangju 61452, Korea
| | - Byeol Kim
- Departments of Premedical Sciences, College of Medicine, Chosun University, Gwangju 61452, Korea
| | - In-Youb Chang
- Departments of Anatomy, College of Medicine, Chosun University, Gwangju 61452, Korea
| | - Seon-Joo Park
- Departments of Premedical Sciences, College of Medicine, Chosun University, Gwangju 61452, Korea
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Wang Z, Zhan Y, Xu J, Wang Y, Sun M, Chen J, Liang T, Wu L, Xu K. β-Sitosterol Reverses Multidrug Resistance via BCRP Suppression by Inhibiting the p53-MDM2 Interaction in Colorectal Cancer. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:3850-3858. [PMID: 32167760 DOI: 10.1021/acs.jafc.0c00107] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Phytosterols are widely present in vegetable oils, nuts, cereal products, fruits, and berries. Phytosterol-induced treatment sensitivity has recently shed light on alleviating multidrug resistance in cancer therapy. Here, we demonstrated that β-sitosterol, the most common dietary phytosterol, recovers oxaliplatin (OXA) sensitivity in drug-resistant colorectal cancer (CRC) cells by inhibiting breast cancer resistance protein (BCRP) expression. We further showed evidence that β-sitosterol could activate p53 by disrupting the p53-MDM2 interaction, leading to an increase in p53 translocation to the nucleus and silencing the nuclear factor-κB (NF-κB) pathway, which is necessary for BCRP expression. Finally, we suggested that the combination of OXA and β-sitosterol has a synergistic tumor suppression effect in vivo using a xenograft mouse model. These results revealed that β-sitosterol is able to mediate the p53/NF-κB/BCRP signaling axis to regulate the response of CRC to chemotherapy. The combined application of β-sitosterol and OXA can be a potential way to improve CRC treatment.
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Affiliation(s)
- Ziyuan Wang
- Department of Pathology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
- Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Yueping Zhan
- Interventional Cancer Institute of Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai 200062, China
| | - Jian Xu
- Interventional Cancer Institute of Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai 200062, China
| | - Yang Wang
- Department of Pathology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Mingyu Sun
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
- Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Jia Chen
- Department of Pathology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Tingyu Liang
- Department of Pathology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Lili Wu
- Department of Pathology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Ke Xu
- Interventional Cancer Institute of Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai 200062, China
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Fultang N, Illendula A, Lin J, Pandey MK, Klase Z, Peethambaran B. ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1. Sci Rep 2020; 10:1821. [PMID: 32020017 PMCID: PMC7000766 DOI: 10.1038/s41598-020-58864-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/19/2020] [Indexed: 12/20/2022] Open
Abstract
Chemoresistance is one of the leading causes of mortality in breast cancer (BC). Understanding the molecules regulating chemoresistance is critical in order to combat chemoresistant BC. Drug efflux pump ABCB1 is overexpressed in chemoresistant neoplasms where it effluxes various chemotherapeutic agents from cells. Because it is expressed in normal and cancerous cells alike, attempts at targeting ABCB1 directly have failed due to low specificity and disruption of normal tissue. A proposed method to inhibit ABCB1 is to target its cancer-specific, upstream regulators, mitigating damage to normal tissue. Few such cancer-specific upstream regulators have been described. Here we characterize ROR1 as an upstream regulator of ABCB1. ROR1 is highly expressed during development but not expressed in normal adult tissue. It is however highly expressed in several cancers. ROR1 is overexpressed in chemoresistant BC where it correlates with poor therapy response and tumor recurrence. Our data suggests, ROR1 inhibition sensitizes BC cells to chemo drugs. We also show ROR1 regulates ABCB1 stability and transcription via MAPK/ERK and p53. Validating our overall findings, inhibition of ROR1 directly correlated with decreased efflux of chemo-drugs from cells. Overall, our results highlight ROR1’s potential as a therapeutic target for multidrug resistant malignancies.
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Affiliation(s)
- Norman Fultang
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania, 19104, United States of America
| | - Abhinav Illendula
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania, 19104, United States of America
| | - Jianhuang Lin
- The Wistar Institute, Philadelphia, Pennsylvania, 19104, United States of America
| | - Manoj K Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, New Jersey, 08103, USA
| | - Zachary Klase
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania, 19104, United States of America
| | - Bela Peethambaran
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania, 19104, United States of America.
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Zhou J, Guo Z, Kang S, Qin J, Gong L, Sun D, Guo L, Zhu L, Bai Y, Zhang Z, Zhou X, Zhang Y. Reduced expression of the P-glycoprotein gene PxABCB1 is linked to resistance to Bacillus thuringiensis Cry1Ac toxin in Plutella xylostella (L.). PEST MANAGEMENT SCIENCE 2020; 76:712-720. [PMID: 31359575 DOI: 10.1002/ps.5569] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 07/12/2019] [Accepted: 07/23/2019] [Indexed: 05/15/2023]
Abstract
BACKGROUND Rapid evolution of pest resistance has seriously threatened the sustainable use of Bacillus thuringiensis (Bt). The diamondback moth, Plutella xylostella (L.), is the first pest to develop resistance to Bt biopesticides in the open field, which renders it an excellent model to explore the molecular basis of Bt resistance in insects. Our previous midgut transcriptome and RNA-Seq profiles showed that the P-glycoprotein gene PxABCB1 was down-regulated in two Cry1Ac-resistant P. xylostella strains, suggesting its potential involvement in Cry1Ac resistance in P. xylostella. RESULTS In this study, the bona fide full-length cDNA sequence of the PxABCB1 gene was cloned and analyzed, and the expression of the PxABCB1 gene was detected in all tissues and developmental stages, with the highest expression in midgut tissue and the female adult stage. Although no consistent non-synonymous mutations were identified between the susceptible and resistant strains, PxABCB1 gene expression was remarkably decreased in all resistant strains, and the association was further validated by Cry1Ac selection in the moderately resistant SZ-R strain. Moreover, knockdown of the PxABCB1 gene expression resulted in significantly reduced larval susceptibility to Cry1Ac toxin in the DBM1Ac-S strain, and decreased expression of the PxABCB1 gene was tightly linked to Cry1Ac resistance in P. xylostella. CONCLUSION Our results demonstrated that down-regulation of the PxABCB1 gene is associated with both laboratory-selected and field-evolved Cry1Ac resistance in P. xylostella. This knowledge will be conducive to further elucidating the complicated molecular basis of Bt resistance and developing new insect resistance management tactics. © 2019 Society of Chemical Industry.
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Affiliation(s)
- Junlei Zhou
- Longping Branch, Graduate School of Hunan University, Changsha, China
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Zhaojiang Guo
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Shi Kang
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Jianying Qin
- Longping Branch, Graduate School of Hunan University, Changsha, China
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Lijun Gong
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Dan Sun
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Le Guo
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Liuhong Zhu
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yang Bai
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Zhuzhu Zhang
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Xiaomao Zhou
- Longping Branch, Graduate School of Hunan University, Changsha, China
| | - Youjun Zhang
- Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
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Mrozikiewicz-Rakowska B, Malinowski M, Nehring P, Bartkowiak-Wieczorek J, Bogacz A, Żurawińska-Grzelka E, Krasnodębski P, Muszyński J, Grzela T, Przybyłkowski A, Czupryniak L. The MDR1/ABCB1 gene rs 1045642 polymorphism in colorectal cancer. Arch Med Sci 2020; 16:112-117. [PMID: 32051713 PMCID: PMC6963158 DOI: 10.5114/aoms.2017.70329] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 06/29/2017] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Colorectal cancer (CRC) is one of the most frequently diagnosed tumors in Western countries. CRC is a heterogeneous group of tumors with regards to its molecular pathogenesis and genetic factors. Both genetic variations and anthropometric factors may affect morbidity in CRC patients. The aim of this study was to assess the impact of multidrug resistance 1/ATP-binding cassette sub-family B member 1 gene (MDR1/ABCB1) polymorphism rs1045642 and general anthropometric factors on the CRC risk. MATERIAL AND METHODS The study included 250 patients who underwent colonoscopy and polypectomy between 2006 and 2013 in a single endoscopy unit in Warsaw, Poland. RESULTS The CRC was diagnosed in 50 individuals, and 200 patients were included in the control group. Cases and controls were matched for mean age and sex (p > 0.05). Factors that were found to significantly increase the risk of CRC were ulcerative colitis (8/35 in the CRC group vs. 8/181 in the control group; p = 0.001), family history of CRC (11/33 vs. 26/172; p = 0.05), and diabetes mellitus (12/34 vs. 28/170; p = 0.04). Allele T of the rs 1045642 polymorphism was more frequently present in CRC cases (in both a co-dominant and recessive model) and in males (in a co-dominant model), although these associations were not statistically significant (p > 0.05). CONCLUSIONS The MDR1/ABCB1 gene polymorphism rs 1045642 may be involved in the pathogenesis of CRC and this relationship may be sex-specific for males. However, further population studies are necessary to assess this relationship.
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Affiliation(s)
| | - Marian Malinowski
- 1 Department of Obstetrics and Gynecology, Medical Centre of Postgraduate Education, Warsaw, Poland
| | - Piotr Nehring
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Joanna Bartkowiak-Wieczorek
- Laboratory of Experimental Pharmacogenetics, Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poznan, Poland
| | - Anna Bogacz
- Department of Stem Cells and Regenerative Medicine, Institute of Natural Fibers and Medicinal Plants, Poznan, Poland
| | - Ewa Żurawińska-Grzelka
- Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Przemysław Krasnodębski
- Cell Molecular Biology Laboratory, Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland
| | - Jacek Muszyński
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Grzela
- Cell Molecular Biology Laboratory, Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Leszek Czupryniak
- Department of Diabetology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
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Pitolli C, Wang Y, Mancini M, Shi Y, Melino G, Amelio I. Do Mutations Turn p53 into an Oncogene? Int J Mol Sci 2019; 20:E6241. [PMID: 31835684 PMCID: PMC6940991 DOI: 10.3390/ijms20246241] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/26/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023] Open
Abstract
The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.
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Affiliation(s)
- Consuelo Pitolli
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- MRC Toxicology Unit, University of Cambridge, Pathology Building, Tennis Court Road, Cambridge CB2 1PQ, UK
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 100012, China; (Y.W.); (Y.S.)
| | - Mara Mancini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- IDI-IRCCS, Biochemistry Laboratory, 00167 Rome, Italy
| | - Yufang Shi
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 100012, China; (Y.W.); (Y.S.)
- Institutes for Translational Medicine, Soochow University, Suzhou 215006, China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- MRC Toxicology Unit, University of Cambridge, Pathology Building, Tennis Court Road, Cambridge CB2 1PQ, UK
| | - Ivano Amelio
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- MRC Toxicology Unit, University of Cambridge, Pathology Building, Tennis Court Road, Cambridge CB2 1PQ, UK
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Gain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis. Int J Mol Sci 2019; 20:ijms20246197. [PMID: 31817996 PMCID: PMC6940767 DOI: 10.3390/ijms20246197] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/25/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023] Open
Abstract
The p53 protein is mutated in about 50% of human cancers. Aside from losing the tumor-suppressive functions of the wild-type form, mutant p53 proteins often acquire inherent, novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function (GOF). A growing body of evidence suggests that these pro-oncogenic functions of mutant p53 proteins are mediated by affecting the transcription of various genes, as well as by protein-protein interactions with transcription factors and other effectors. In the current review, we discuss the various GOF effects of mutant p53, and how it may serve as a central node in a network of genes and proteins, which, altogether, promote the tumorigenic process. Finally, we discuss mechanisms by which "Mother Nature" tries to abrogate the pro-oncogenic functions of mutant p53. Thus, we suggest that targeting mutant p53, via its reactivation to the wild-type form, may serve as a promising therapeutic strategy for many cancers that harbor mutant p53. Not only will this strategy abrogate mutant p53 GOF, but it will also restore WT p53 tumor-suppressive functions.
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Ceballos MP, Rigalli JP, Ceré LI, Semeniuk M, Catania VA, Ruiz ML. ABC Transporters: Regulation and Association with Multidrug Resistance in Hepatocellular Carcinoma and Colorectal Carcinoma. Curr Med Chem 2019; 26:1224-1250. [PMID: 29303075 DOI: 10.2174/0929867325666180105103637] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/19/2017] [Accepted: 11/21/2017] [Indexed: 02/07/2023]
Abstract
For most cancers, the treatment of choice is still chemotherapy despite its severe adverse effects, systemic toxicity and limited efficacy due to the development of multidrug resistance (MDR). MDR leads to chemotherapy failure generally associated with a decrease in drug concentration inside cancer cells, frequently due to the overexpression of ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2), which limits the efficacy of chemotherapeutic drugs. The aim of this review is to compile information about transcriptional and post-transcriptional regulation of ABC transporters and discuss their role in mediating MDR in cancer cells. This review also focuses on drug resistance by ABC efflux transporters in cancer cells, particularly hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells. Some aspects of the chemotherapy failure and future directions to overcome this problem are also discussed.
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Affiliation(s)
- María Paula Ceballos
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - Juan Pablo Rigalli
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.,Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Lucila Inés Ceré
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - Mariana Semeniuk
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - Viviana Alicia Catania
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - María Laura Ruiz
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
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Cheng XZ, Zhou HL, Tang SX, Jiang T, Chen Q, Gao R, Ding YL. Intercellular transfer of P-glycoprotein mediates the formation of stable multi-drug resistance in human bladder cancer BIU-87 cells. Biol Open 2019; 8:bio041889. [PMID: 30967374 PMCID: PMC6550073 DOI: 10.1242/bio.041889] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/29/2019] [Indexed: 11/21/2022] Open
Abstract
We investigated the biological characteristics of acquired drug-resistant cells (AqMDRs) formed by intercellular P-glycoprotein (P-gp) transfer and whether AqMDRs can form stable drug-resistant strains. Drug-sensitive BIU-87 cells were co-cultured with doxorubicin (DOX)-resistant derivative BIU-87/DOX cells in transwell chambers for up to 96 h. The presence of P-gp in recipient cell membranes (AqMDRs) was detected by confocal microscopy, CCK-8, western blot, and RT-PCR were used to detect resistance index (RI), P-gp expression and MDR1 mRNA expression in AqMDRs after 0, 4, 8, 16, and 20 passages and frozen/resuscitated twentieth generation AqMDRs. There was an increase in P-gp transfer with longer co-culture times of drug-resistant and sensitive strains. Without DOX, although the AqMDR numbers increased with each passage, the RI and P-gp expression decreased gradually, and the expression level of MDR1 mRNA did not change significantly. With DOX, the RI and P-gp expression increased slightly, and the MDR1 mRNA expression level gradually increased to the BIU-87/DOX level. AqMDRs can grow stably at drug concentrations slightly higher than the IC50 of sensitive strains, which sensitive strains cannot survive. P-gp transfer between cells gradually increases with longer co-culturing of drug-resistant and sensitive strains. The drug resistance of AqMDRs decreases without drug intervention, but with drug intervention, cells can maintain resistance and gradually develop into stable drug-resistant cells. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Xiao-Zhi Cheng
- Department of Urology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People's Republic of China
- Department of Urology, Huanggang Central Hospital, Huanggang 438000, People's Republic of China
| | - Hui-Liang Zhou
- Department of Urology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People's Republic of China
| | - Song-Xi Tang
- Department of Urology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People's Republic of China
| | - Tao Jiang
- Department of Urology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People's Republic of China
| | - Qin Chen
- Department of Urology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People's Republic of China
| | - Rui Gao
- Department of Urology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People's Republic of China
| | - Yi-Lang Ding
- Department of Urology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People's Republic of China
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Zhou X, Hao Q, Lu H. Mutant p53 in cancer therapy-the barrier or the path. J Mol Cell Biol 2019; 11:293-305. [PMID: 30508182 PMCID: PMC6487791 DOI: 10.1093/jmcb/mjy072] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/14/2018] [Accepted: 11/14/2018] [Indexed: 12/11/2022] Open
Abstract
Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers. Approximately 80% of p53 mutations are single point mutations with several hotspot mutations. Besides loss of function and dominant-negative effect on the wild-type p53 activity, the hotspot p53 mutants also acquire new oncogenic functions, so-called 'gain-of-functions' (GOF). Because the GOF of mutant p53 is highly associated with late-stage malignance and drug resistance, these p53 mutants have become hot targets for developing novel cancer therapies. In this essay, we review some recent progresses in better understanding of the role of mutant p53 GOF in chemoresistance and the underlying mechanisms, and discuss the pros and cons of targeting mutant p53 for the development of anti-cancer therapies.
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Affiliation(s)
- Xiang Zhou
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, and Key Laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, China
| | - Qian Hao
- Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Hua Lu
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
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Pellerano M, Naud-Martin D, Mahuteau-Betzer F, Morille M, Morris MC. Fluorescent Biosensor for Detection of the R248Q Aggregation-Prone Mutant of p53. Chembiochem 2019; 20:605-613. [PMID: 30548750 DOI: 10.1002/cbic.201800531] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 12/10/2018] [Indexed: 01/28/2023]
Abstract
The p53 tumour suppressor and guardian of the genome undergoes missense mutations that lead to functional inactivation in 50 % of human cancers. These mutations occur mostly in the DNA-binding domain of the protein, and several of these result in conformational changes that lead to amyloid-like protein aggregation. Herein, we describe a fluorescent biosensor that reports on the R248Q mutant of p53 in vitro and in living cells, engineered through conjugation of an environmentally sensitive probe onto a peptide derived from the primary aggregation segment of p53. This biosensor was characterised both in vitro and by means of fluorescence microscopy following facilitated delivery into cultured cells. It is shown that this biosensor preferentially reports on the p53 R248Q mutant in the PC9 lung cancer cell line compared with other lung cancer cell lines harbouring either wild-type or no p53.
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Affiliation(s)
- Morgan Pellerano
- Institut des Biomolécules Max Mousseron-IBMM-UMR 5247, Université de Montpellier, Faculté de Pharmacie, 15, Av. Charles Flahault, 34093, Montpellier, France
| | - Delphine Naud-Martin
- Institut Curie, PSL Research University, CNRS, INSERM, UMR9187-U1196, 91405, Orsay, France
| | | | - Marie Morille
- Institut Charles Gerhardt-UMR 5253 CNRS-UM-ENSCM, Université de Montpellier, Faculté de Pharmacie, 15, Av. Charles Flahault, 34093, Montpellier, France
| | - May C Morris
- Institut des Biomolécules Max Mousseron-IBMM-UMR 5247, Université de Montpellier, Faculté de Pharmacie, 15, Av. Charles Flahault, 34093, Montpellier, France
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Nie X, Liu C, Guo Q, Zheng MJ, Gao LL, Li X, Liu DW, Zhu LC, Liu JJ, Lin B. TMEFF1 overexpression and its mechanism for tumor promotion in ovarian cancer. Cancer Manag Res 2019; 11:839-855. [PMID: 30697076 PMCID: PMC6340504 DOI: 10.2147/cmar.s186080] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background Transmembrane protein with epidermal growth factor-like and two follistatin-like domains 1 (TMEFF1) has an anticarcinogenic effect in brain tumors. However, little is known about the role of TMEFF1 in epithelial ovarian cancer (EOC). Materials and methods TMEFF1 expression in EOC was detected by immunohistochemistry; its relationship with clinical pathological parameters and its influence on prognosis were analyzed. The MTT, scratch, Transwell assays, and flow cytometry were used to assess the malignant behavior of ovarian cancer cell. Changes in node proteins in MAPK and PI3K/AKT signaling pathways and the expression of epithelial–mesenchymal transformation markers were measured by Western blot. The regulatory effect of p53 on TMEFF1 was verified by chromatin immunoprecipitation (ChIP) assay and Western blot. Results TMEFF1 expression was higher in the EOC group than in the borderline and benign tumor groups and normal ovary group; its high expression was significantly related to International Federation of Gynecology and Obstetrics stage (P=0.024) and independently predicted shorter overall survival (P<0.01). TMEFF1 overexpression in ovarian cancer cells induced increased cellular proliferation, migration, and invasion but reduced apoptosis. In addition, the percentage of phosphorylated node proteins in MAPK and PI3K/AKT signaling pathways increased significantly. The expression of E-cadherin decreased but that of vimentin and N-cadherin increased. After the addition of MAPK (PD98059) and PI3K (GDC-0941) pathway inhibitors, ovarian cancer cells overexpressing TMEFF1 showed suppressed malignant behavior. TMEFF1 protein expression in an ovarian cancer cell lines (CAOV3 and ES-2) was downregulated after the inhibition of TP53. The transcription factor, p53, bound the promoter region of the TMEFF1 gene according to ChIP. Conclusion TMEFF1 is a carcinogenic gene in ovarian cancer and can be regulated by p53 transcription. Through MAPK and PI3K/AKT signaling pathways, TMEFF1 promotes the malignant behavior in EOC. Therefore, TMEFF1 may be considered as a potential therapeutic target for ovarian cancer.
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Affiliation(s)
- Xin Nie
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China, .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China,
| | - Cong Liu
- Department of Obstetrics and Gynaecology, Wuxi Materal and Child Health Hospital, Jiangsu, China
| | - Qian Guo
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China, .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China,
| | - Ming-Jun Zheng
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China, .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China,
| | - Ling-Ling Gao
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China, .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China,
| | - Xiao Li
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China, .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China,
| | - Da-Wo Liu
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China, .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China,
| | - Lian-Cheng Zhu
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China, .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China,
| | - Juan-Juan Liu
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China, .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China,
| | - Bei Lin
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China, .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China,
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Abstract
Clonal hematopoiesis is a common, age-related process in which a somatically mutated hematopoietic precursor gives rise to a genetically distinct subpopulation in the blood. This phenomenon has been observed in populations across the globe and, while virtually non-existent in children is estimated to affect >10% of the 70-and-older age group. The mutations are thought to occur in stem cells, which makes them pre-cancerous, and precursors to cancer stem cells. Many of the genes most commonly mutated in clonal hematopoiesis are also recurrently mutated in leukemia, genes such as DNMT3A, TET2, ASXL1, JAK2, and TP53. However, between 40% and 60% of cases arise from the accumulation of what appear to be random mutations outside of known driver genes. Clonal hematopoiesis is frequently present in otherwise healthy individuals and may persist for many years. Though largely asymptomatic, carrying these somatic mutations confers a small but significantly increased risk of leukemic transformation, affecting 0.5-1% carriers per year; although most genes confer an increased risk of transformation, mutations in TP53 and U2AF1 appear to carry a particularly high risk for transformation. Additionally, a patient's history of prior treatment with cytotoxic chemotherapy and/or radiation are correlated with the development of clonal hematopoiesis; in the setting of chemotherapy treatment of solid tumors, hematopoietic mutations in TP53 and PPM1D appear to contribute to outgrowth of clones that may lead to subsequent malignancy. The presence of a clone also imparts a significantly increased risk of cardiovascular disease, which in some cases appears to be due to increased inflammation and atherosclerosis. Clonal hematopoiesis is correlated with several other diseases as well, including diabetes, chronic pulmonary disease, and aplastic anemia, with other associations probably yet to be uncovered.
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Affiliation(s)
- Alexander J Silver
- Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Siddhartha Jaiswal
- Department of Pathology, Stanford University, Stanford, CA, United States.
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Liu T, Wei R, Zhang Y, Chen W, Liu H. Association between NF-κB expression and drug resistance of liver cancer. Oncol Lett 2018; 17:1030-1034. [PMID: 30655862 PMCID: PMC6312998 DOI: 10.3892/ol.2018.9640] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 09/11/2018] [Indexed: 12/22/2022] Open
Abstract
Association between the expression of nuclear factor κB (NF-κB) and the drug resistance of hepatoma cells was investigated. HepG-2 cells and HepG2/ADM cells were cultured, respectively. The morphology and status of the two groups of cells were observed by cell white light. The immunofluorescence by NF-κB and MDR1 staining on HepG-2 cells and HepG2/ADM cells, respectively, was applied and the fluorescence expression in the two groups of cells was observed. RT-qPCR was used to detect the expression of NF-κB and MDR1 mRNA, the NF-κB and MDR1 protein expression was detected by western blot analysis. The results of cell white illumination showed that the structure of HepG-2 and HepG2/ADM cells was complete and the cell morphology was normal, and there was no significant difference, and could be used for comparative study. Immunofluorescence staining showed that the expression of NF-κB and MDR1 in HepG-2 cells was very low, while the expression of NF-κB and MDR1 in HepG2/ADM cells was increased significantly. The RT-qPCR results showed that NF-κB and MDR1 mRNA expression in HepG-2 cells was very low, while NF-κB and MDR1 mRNA expression in HepG-2/ADM cells was significantly increased, and western blot results showed that NF-κB and MDR1 protein expression in HepG-2 cells was very low, while NF-κB and MDR1 protein expression in HepG-2/ADM cells was increased significantly. The results of variance analysis showed that there was significant difference in the expression of the control group and paeonol group (P<0.01). In conclusion, the expression of NF-κB in the drug-resistant cells of liver cancer is closely related to the resistance-related gene MDR1. This result may provide a new solution for the drug resistance of liver cancer.
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Affiliation(s)
- Tao Liu
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Qingdao, Shandong 266033, P.R. China
| | - Rendong Wei
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Qingdao, Shandong 266033, P.R. China
| | - Yiting Zhang
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Qingdao, Shandong 266033, P.R. China
| | - Wen Chen
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Haidong Liu
- Department of Digestive Diseases, The Sixth People's Hospital of Qingdao, Qingdao, Shandong 266033, P.R. China
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Norouzi S, Gorgi Valokala M, Mosaffa F, Zirak MR, Zamani P, Behravan J. Crosstalk in cancer resistance and metastasis. Crit Rev Oncol Hematol 2018; 132:145-153. [PMID: 30447920 DOI: 10.1016/j.critrevonc.2018.09.017] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 07/17/2018] [Accepted: 09/29/2018] [Indexed: 01/26/2023] Open
Abstract
The main obstacles that lead to clinical failure in cancer treatment are the development of resistant to chemotherapy and a rise in invasive characteristics in cancer tumor cells due to prolonged chemotherapeutic processes. Recent studies have revealed some evidence about the existence of a direct relationship between development of drug resistance and triggering of invasive capability in tumor cells. Therefore, devising and application of chemotherapeutic procedures that are not prone to the development of chemotherapy resistance are necessary. Here, we focus on CD147, CD44, ANAX2, P-gp, MMPs, and UCH-L1 proteins involved in the crosstalk between metastasis and cancer treatment. We think that further structural and functional analysis of these proteins may direct scientists towards designing highly effective chemotherapy procedures.
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Affiliation(s)
- Saeed Norouzi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Gorgi Valokala
- Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Mosaffa
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Zirak
- Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvin Zamani
- Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Behravan
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Mediphage Bioceuticals, Inc., 661 University Avenue, Suite 1300, MaRS Centre, West Tower, Toronto, Canada; School of Pharmacy, University of Waterloo, 200 University Ave W., Waterloo, Canada.
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de Souza Salgado YC, Boia Ferreira M, Zablocki da Luz J, Filipak Neto F, Oliveira Ribeiro CAD. Tribromophenol affects the metabolism, proliferation, migration and multidrug resistance transporters activity of murine melanoma cells B16F1. Toxicol In Vitro 2018; 50:40-46. [DOI: 10.1016/j.tiv.2018.02.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 01/18/2018] [Accepted: 02/06/2018] [Indexed: 12/19/2022]
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Alimbetov D, Askarova S, Umbayev B, Davis T, Kipling D. Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells. Int J Mol Sci 2018; 19:ijms19061690. [PMID: 29882812 PMCID: PMC6032165 DOI: 10.3390/ijms19061690] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/31/2018] [Accepted: 06/01/2018] [Indexed: 12/11/2022] Open
Abstract
Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed dramatically over the years owing to rapid advances in oncology research. Developments in cancer therapies, namely surgery, radiotherapy, cytotoxic chemotherapy and selective treatment methods due to better understanding of tumor characteristics, have significantly increased cancer survival. However, many chemotherapeutic regimes still fail, with 90% of the drug failures in metastatic cancer treatment due to chemoresistance, as cancer cells eventually develop resistance to chemotherapeutic drugs. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion, and targeting those mechanisms could improve outcomes of cancer therapy. Recent developments in cancer treatment are focused on combination therapy, whereby cells are sensitized to chemotherapeutic agents using inhibitors of target pathways inducing chemoresistance thus, hopefully, overcoming the problems of drug resistance. In this review, we discuss the role of cell cycle, apoptosis and cell adhesion in cancer chemoresistance mechanisms, possible drugs to target these pathways and, thus, novel therapeutic approaches for cancer treatment.
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Affiliation(s)
- Dauren Alimbetov
- Laboratory of bioengineering and regenerative medicine, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, 53 Kabanbay Batyr Ave, Z05H0P9 Astana, Kazakhstan.
| | - Sholpan Askarova
- Laboratory of bioengineering and regenerative medicine, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, 53 Kabanbay Batyr Ave, Z05H0P9 Astana, Kazakhstan.
| | - Bauyrzhan Umbayev
- Laboratory of bioengineering and regenerative medicine, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, 53 Kabanbay Batyr Ave, Z05H0P9 Astana, Kazakhstan.
| | - Terence Davis
- Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
| | - David Kipling
- Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
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Stiewe T, Haran TE. How mutations shape p53 interactions with the genome to promote tumorigenesis and drug resistance. Drug Resist Updat 2018; 38:27-43. [PMID: 29857816 DOI: 10.1016/j.drup.2018.05.001] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 04/27/2018] [Accepted: 05/03/2018] [Indexed: 12/31/2022]
Abstract
The tumor suppressive transcription factor p53 regulates a wide array of cellular processes that confer upon cells an essential protection against cancer development. Wild-type p53 regulates gene expression by directly binding to DNA in a sequence-specific manner. p53 missense mutations are the most common mutations in malignant cells and can be regarded as synonymous with anticancer drug resistance and poor prognosis. The current review provides an overview of how the extraordinary variety of more than 2000 different mutant p53 proteins, known as the p53 mutome, affect the interaction of p53 with DNA. We discuss how the classification of p53 mutations to loss of function (LOF), gain of function (GOF), and dominant-negative (DN) inhibition of a remaining wild-type allele, hides a complex p53 mutation spectrum that depends on the distinctive nature of each mutant protein, requiring different therapeutic strategies for each mutant p53 protein. We propose to regard the different mutant p53 categories as continuous variables, that may not be independent of each other. In particular, we suggest here to consider GOF mutations as a special subset of LOF mutations, especially when mutant p53 binds to DNA through cooperation with other transcription factors, and we present a model for GOF mechanism that consolidates many observations on the GOF phenomenon. We review how novel mutant p53 targeting approaches aim to restore a wild-type-like DNA interaction and to overcome resistance to cancer therapy.
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Affiliation(s)
- Thorsten Stiewe
- Institute of Molecular Oncology, Philipps-University, 35037 Marburg, Germany.
| | - Tali E Haran
- Department of Biology, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel.
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Begicevic RR, Falasca M. ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance. Int J Mol Sci 2017; 18:E2362. [PMID: 29117122 PMCID: PMC5713331 DOI: 10.3390/ijms18112362] [Citation(s) in RCA: 257] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 11/02/2017] [Accepted: 11/02/2017] [Indexed: 12/19/2022] Open
Abstract
The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC) transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs), endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype. To summarize, we suggest that the increased expression of ABC transporters in CSCs may have precise functional roles and provide the opportunity to target, particularly these cells, by using specific ABC transporter inhibitors.
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Affiliation(s)
- Romana-Rea Begicevic
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA 6102, Australia.
| | - Marco Falasca
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA 6102, Australia.
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Redox sensitive cationic pullulan for efficient gene transfection and drug retention in C6 glioma cells. Int J Pharm 2017; 530:401-414. [DOI: 10.1016/j.ijpharm.2017.08.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 07/28/2017] [Accepted: 08/01/2017] [Indexed: 11/22/2022]
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50
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Aparicio-Cuevas MA, Rivero-Cruz I, Sánchez-Castellanos M, Menéndez D, Raja HA, Joseph-Nathan P, González MDC, Figueroa M. Dioxomorpholines and Derivatives from a Marine-Facultative Aspergillus Species. JOURNAL OF NATURAL PRODUCTS 2017; 80:2311-2318. [PMID: 28796494 DOI: 10.1021/acs.jnatprod.7b00331] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Two new dioxomorpholines, 1 and 2, three new derivatives, 3-5, and the known compound PF1233 B (6) were isolated from a marine-facultative Aspergillus sp. MEXU 27854. Their structures were established by 1D and 2D NMR and HRESIMS data analysis. The absolute configuration of 1 and 2 was elucidated by comparison of experimental and DFT-calculated vibrational circular dichroism spectra. Compounds 3, 5, and 6 were noncytotoxic to a panel of human cancer cell lines with different functional status for the tumor-suppressor protein p53, but were inhibitors of P-glycoprotein-reversing multidrug resistance in a doxorubicin-resistant cell line.
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Affiliation(s)
| | | | | | - Daniel Menéndez
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH , Research Triangle Park, North Carolina 27709, United States
| | - Huzefa A Raja
- Department of Chemistry and Biochemistry, University of North Carolina at Greensboro , Greensboro, North Carolina 27402, United States
| | - Pedro Joseph-Nathan
- Departamento de Química, Centro de Investigación y de Estudios, Avanzados del Instituto Politécnico Nacional , Apartado 14-740, Ciudad de México 07000, México
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