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Bhat AM, Bhat IA, Malik MA, Kaiser P, Ramajayan P, Rayees SR, Ahmed Z, Tasduq SA. Inhibition of IKK complex by (2 methyl butyryl) Shikonin, a naturally occurring naphthoquinone, abrogates melanoma growth and progression via modulation of the IKK/NFκB /EMT signaling axis. Int Immunopharmacol 2025; 148:114026. [PMID: 39823792 DOI: 10.1016/j.intimp.2025.114026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 12/26/2024] [Accepted: 01/03/2025] [Indexed: 01/20/2025]
Abstract
Melanoma is an aggressive form of malignancy that originates from melanin-producing cells known as melanocytes underlying the basal layer of the epidermis with a poor prognosis, low survival rates, and limited treatment options. Although several specific and effective systematic strategies for treating melanoma have been established, the underlying molecular mechanism of melanoma progression, mortality and the promising therapeutic options remain elusive. Shikonin (SK), a natural naphthoquinone derived from a medicinal herbaceous plant, has been shown to inhibit the proliferation of several cancer cells. However, its role in the context of melanoma is poorly understood. In the present study, the anti-melanoma activity of (2-methylbutyryl) Shikonin was assessed under in vitro and in vivo models. In vitro findings revealed that (2-methylbutyryl) Shikonin significantly reduced the viability and promoted apoptosis in the B16F10 melanoma cells. Additionally (2-methylbutyryl) Shikonin significantly suppressed migration and invasion of melanoma cells by regulating IKK/NFκB/EMT signalling axis thereby attenuating nuclear translocation and subsequent transcription of NF-κB downstream target genes. Furthermore, (2-methylbutyryl) Shikonin administration significantly reduced tumor size and weight in the xenograft melanoma mice model. Our data presents novel insights that justify additional preclinical and clinical validations of (2-methylbutyryl) Shikonin for melanoma therapy.
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Affiliation(s)
- Aalim Maqsood Bhat
- Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Irshad Ahmad Bhat
- Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Mushtaq Ahmad Malik
- Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Peerzada Kaiser
- Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - P Ramajayan
- Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Sheikh R Rayees
- Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Zabeer Ahmed
- Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Sheikh Abdullah Tasduq
- Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
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Sevim Nalkiran H, Biri I, Nalkiran I, Uzun H, Durur S, Bedir R. CDC20 and CCNB1 Overexpression as Prognostic Markers in Bladder Cancer. Diagnostics (Basel) 2024; 15:59. [PMID: 39795587 PMCID: PMC11719780 DOI: 10.3390/diagnostics15010059] [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: 10/18/2024] [Revised: 12/05/2024] [Accepted: 12/27/2024] [Indexed: 01/13/2025] Open
Abstract
Background: Bladder cancer (BC) is one of the ten most common cancers worldwide, with a high recurrence rate and significant variation in clinical outcomes based on tumor grade and stage. This study aimed to investigate the gene expression profiles at different cancer stages to assess their potential prognostic value. Methods: RNA was extracted from paraffin-embedded BC tissues and the gene expression levels of CDC20 and CCNB1 were analyzed using qRT-PCR. A total of 54 BC patient samples were included in the analysis and categorized into low-grade (LG) (n = 23) and high-grade (HG) (n = 31) tumors, as well as stages pTa, pT1, and pT2. Results: CDC20 gene expression was significantly higher in the HG group (mean fold-change: 16.1) compared to the LG group (mean fold-change: 10.54), indicating a significant association with tumor grade (p = 0.039). However, no significant differences were observed in CDC20 expression across the cancer stages. For CCNB1, while gene expression was significantly elevated in higher-stage tumors (pT2 vs. pTa; p = 0.038), no significant association was found between CCNB1 expression and tumor grade. Survival analysis revealed that increased CCNB1 expression and advanced cancer stage were associated with poorer overall survival, whereas no significant impact of CDC20 expression or tumor grade on survival was observed. Correlation analysis indicated a positive relationship between CDC20 expression and tumor grade (r = 0.284, p = 0.038) and between CCNB1 expression and tumor stage (r = 0.301, p = 0.027). Conclusions: Our findings suggest that CDC20 overexpression is linked to higher tumor grades, while CCNB1 overexpression is associated with more advanced cancer stages in BC. These results underscore the potential utility of CDC20 and CCNB1 as biomarkers for tumor prognosis and as therapeutic targets. Further studies with larger cohorts are needed to validate these findings and better understand the molecular mechanisms driving BC progression.
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Affiliation(s)
- Hatice Sevim Nalkiran
- Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Türkiye; (H.S.N.); (I.B.); (S.D.)
| | - Ilknur Biri
- Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Türkiye; (H.S.N.); (I.B.); (S.D.)
| | - Ihsan Nalkiran
- Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Türkiye; (H.S.N.); (I.B.); (S.D.)
| | - Hakki Uzun
- Department of Urology, Faculty of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Türkiye;
| | - Sumeyye Durur
- Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Türkiye; (H.S.N.); (I.B.); (S.D.)
| | - Recep Bedir
- Department of Medical Pathology, Faculty of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Türkiye;
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Ansari A, Bhattacharyya T, Das P, Chandra Y, Kundu TK, Banerjee R. Lipid-Conjugated Reduced Haloperidol in Association with Glucose-Based Nanospheres: A Strategy for Glioma Treatment. Mol Pharm 2024; 21:5053-5070. [PMID: 39302161 DOI: 10.1021/acs.molpharmaceut.4c00468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2024]
Abstract
Aggressive glioma exhibits a poor survival rate. Increased tumor aggression is linked to both tumor cells and tumor-associated macrophages (TAMs), which induce pro-aggression, invasion, and metastasis. Imperatively, for effective treatment, it is important to target both glioma cells and TAMs. Haloperidol, a neuropsychotic drug, avidly targets the sigma receptor (SR), which is expressed in higher levels in both the cell types. Herein, we present the development of a novel cationic lipid-conjugated reduced haloperidol (±RHPC8), which aims to mediate the SR-targeted antiglioma effect. Hypothetically, ±RHPC8 would act simultaneously as an SR-targeting ligand and anticancer agent. As the blood-brain barrier (BBB) obstructs direct targeting of in situ glioma, we used BBB-crossing glucose-based carbon nanospheres (CSPs) to deliver ±RHPC8 within the glioma tumor-bearing mouse brain. The resultant ±RHPC8-CSP nanoconjugate targeted SR-expressing glioma cells. In both orthotopic and subcutaneous mouse tumor models, ±RHPC8-CSP prolonged survival and regressed tumors compared to other treated groups. Notably, ±RHPC8-CSP was significantly taken up by SR-expressing TAMs thus resulting in macrophage polarization from M2 to M1, as exhibited by markedly reduced expression of immunosuppressive cytokines released by TAMs, including TGF-β, IL-10, and VEGF. In conclusion, the designed ±RHPC8-CSP nanoconjugate presented an effective nanodrug delivery system for brain cancer treatment.
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Affiliation(s)
- Aasia Ansari
- Department of Oils, Lipid, Science & Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad 201002, India
| | - Tithi Bhattacharyya
- Department of Oils, Lipid, Science & Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad 201002, India
| | - Pritam Das
- Department of Oils, Lipid, Science & Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad 201002, India
| | - Yogesh Chandra
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
| | - Tapas K Kundu
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bangalore 560 064, India
| | - Rajkumar Banerjee
- Department of Oils, Lipid, Science & Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad 201002, India
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Bhattacharya R, Kumari J, Banerjee S, Tripathi J, Parihar SS, Mohan N, Sinha P. Hippo effector, Yorkie, is a tumor suppressor in select Drosophila squamous epithelia. Proc Natl Acad Sci U S A 2024; 121:e2319666121. [PMID: 39288176 PMCID: PMC11441523 DOI: 10.1073/pnas.2319666121] [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: 11/17/2023] [Accepted: 08/20/2024] [Indexed: 09/19/2024] Open
Abstract
Mammalian Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) and Drosophila Yorkie (Yki) are transcription cofactors of the highly conserved Hippo signaling pathway. It has been long assumed that the YAP/TAZ/Yki signaling drives cell proliferation during organ growth. However, its instructive role in regulating developmentally programmed organ growth, if any, remains elusive. Out-of-context gain of YAP/TAZ/Yki signaling often turns oncogenic. Paradoxically, mechanically strained, and differentiated squamous epithelia display developmentally programmed constitutive nuclear YAP/TAZ/Yki signaling. The unknown, therefore, is how a growth-promoting YAP/TAZ/Yki signaling restricts proliferation in differentiated squamous epithelia. Here, we show that reminiscent of a tumor suppressor, Yki negatively regulates the cell growth-promoting PI3K/Akt/TOR signaling in the squamous epithelia of Drosophila tubular organs. Thus, downregulation of Yki signaling in the squamous epithelium of the adult male accessory gland (MAG) up-regulates PI3K/Akt/TOR signaling, inducing cell hypertrophy, exit from their cell cycle arrest, and, finally, culminating in squamous cell carcinoma (SCC). Thus, blocking PI3K/Akt/TOR signaling arrests Yki loss-induced MAG-SCC. Further, MAG-SCCs, like other lethal carcinomas, secrete a cachectin, Impl2-the Drosophila homolog of mammalian IGFBP7-inducing cachexia and shortening the lifespan of adult males. Moreover, in the squamous epithelium of other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, downregulation of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy. Our results reveal that Yki signaling plays an instructive, antiproliferative role in the squamous epithelia of tubular organs.
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Affiliation(s)
- Rachita Bhattacharya
- Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
- Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
| | - Jaya Kumari
- Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
| | - Shweta Banerjee
- Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
- Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
| | - Jyoti Tripathi
- Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
- Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
| | - Saurabh Singh Parihar
- Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
- Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
| | - Nitin Mohan
- Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
- Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
| | - Pradip Sinha
- Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
- Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Uttar Pradesh208016, India
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Schmitt L, Hoppe J, Cea-Medina P, Bruch PM, Krings KS, Lechtenberg I, Drießen D, Peter C, Bhatia S, Dietrich S, Stork B, Fritz G, Gohlke H, Müller TJJ, Wesselborg S. Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin-dependent kinases (CDKs). Cell Death Discov 2024; 10:279. [PMID: 38862521 PMCID: PMC11167047 DOI: 10.1038/s41420-024-02056-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/31/2024] [Accepted: 06/03/2024] [Indexed: 06/13/2024] Open
Abstract
A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles' heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.
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Affiliation(s)
- Laura Schmitt
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Julia Hoppe
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Pablo Cea-Medina
- Institute for Pharmaceutical and Medicinal Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Peter-Martin Bruch
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Karina S Krings
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Ilka Lechtenberg
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Daniel Drießen
- Institute of Organic Chemistry and Macromolecular Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Christoph Peter
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Sanil Bhatia
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Sascha Dietrich
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Björn Stork
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Gerhard Fritz
- Institute of Toxicology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Holger Gohlke
- Institute for Pharmaceutical and Medicinal Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Center (JSC) and Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straße, 52425, Jülich, Germany
| | - Thomas J J Müller
- Institute of Organic Chemistry and Macromolecular Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Sebastian Wesselborg
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Düsseldorf, Germany.
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Ebrahimighaei R, Tarassova N, Bond SC, McNeill MC, Hathway T, Vohra H, Newby AC, Bond M. Extracellular matrix stiffness controls cardiac fibroblast proliferation via the nuclear factor-Y (NF-Y) transcription factor. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119640. [PMID: 37996060 DOI: 10.1016/j.bbamcr.2023.119640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/10/2023] [Accepted: 11/10/2023] [Indexed: 11/25/2023]
Abstract
The proliferative expansion of cardiac fibroblasts (CF) contributes towards cardiac fibrosis, which results in myocardial stiffening, cardiac dysfunction, and heart failure. CF sense and respond to increased stiffness of their local extracellular matrix, modulating their phenotype towards increased collagen synthesis and higher proliferation, leading potentially to a vicious circle of positive feedback. Here we describe a novel mechanism that mediates increased CF proliferation in response to a pathologically stiff Exteracellular matrix (ECM). The mechanism we describe is independent of the well-characterised mechano-sensitive transcript factors, YAP-TEAD and MKL1-SRF, which our data indicate are only responsible for part of the genes induced by stiffened ECM. Instead, our data identify Nuclear Factor-Y (NF-Y) as a novel mechanosensitive transcription factor, which mediates enhanced CF proliferation in response to a stiff ECM. We show that levels of NF-YA protein, the major regulatory subunit of NF-Y, and NF-Y transcriptional activity, are increased by a stiff ECM. Indeed, NF-Y activity drives the expression of multiple cell-cycle genes. Furthermore, NF-YA protein levels are dependent on FAK signalling suggesting a mechanistic link to ECM composition. Consistent with its role as a mechano-sensor, inhibition of NF-Y using siRNA or dominant negative mutant blocks CF proliferation on plastic in vitro, which models a stiff ECM, whereas ectopic expression of NF-YA increases the proliferation of cells interacting under conditions that model a physiologically soft ECM. In summary, our data demonstrate that NF-Y is a biomechanically sensitive transcription factor that promotes CF proliferation in a model of pathologically stiffened ECM.
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Affiliation(s)
- Reza Ebrahimighaei
- Department of Translational Health Sciences, Bristol Medical School, Bristol, BS2 8HW, United Kingdom
| | - Nathalie Tarassova
- Department of Translational Health Sciences, Bristol Medical School, Bristol, BS2 8HW, United Kingdom.
| | - Samuel C Bond
- Clifton High School, Clifton, Bristol, BS8 3JD, United Kingdom.
| | - Madeleine C McNeill
- Department of Translational Health Sciences, Bristol Medical School, Bristol, BS2 8HW, United Kingdom.
| | - Tom Hathway
- Department of Translational Health Sciences, Bristol Medical School, Bristol, BS2 8HW, United Kingdom.
| | - Hunaid Vohra
- Department of Translational Health Sciences, Bristol Medical School, Bristol, BS2 8HW, United Kingdom.
| | - Andrew C Newby
- Department of Translational Health Sciences, Bristol Medical School, Bristol, BS2 8HW, United Kingdom.
| | - Mark Bond
- Department of Translational Health Sciences, Bristol Medical School, Bristol, BS2 8HW, United Kingdom.
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ERZURUMLU Y, DOĞAN HK, ÇATAKLI D. Anticancer Effect of Theranekron ® on Androgen-Dependent Prostate Cancer Cells. Turk J Pharm Sci 2024; 20:368-373. [PMID: 38254333 PMCID: PMC10803929 DOI: 10.4274/tjps.galenos.2023.47905] [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: 12/20/2022] [Accepted: 01/21/2023] [Indexed: 02/10/2023]
Abstract
Objectives Prostate cancer (PCa) is a significant health problem in men worldwide. Although there are numerous treatment choices for PCa, acquired resistance limits treatment success. Therefore, there is a need for new approaches as powerful resources for use in alternative or supportive therapeutic strategies for anticancer therapeutics. Theranekron® is a commercially available alcoholic extract of Tarantula cubensis. Recent studies have shown the potent anticancer effect of theranekron in human tumors, including PCa. Herein, we comparatively examined the antiproliferative activity of theranekron and its biochemical action on androgenic signaling and cell cycle-related cyclin proteins in androgen-dependent PCa cells, LNCaP, VCaP, and 22Rv1. Materials and Methods Human androgen-dependent PCa cells, LNCaP (CRL-1740TM), 22Rv1 (CRL-2505TM), and VCaP (CRL-2876TM) were used to evaluate the effect of theranekron in vitro. The impact of theranekron on cell viability was evaluated using a WST-1-based viability test. Its impact on AR, cyclin A2, cyclin B1, and cyclin E1 was examined by immunoblotting. To test the anti-malignant effect of theranekron on 3D tumor formation of PCa cells, soft agar assay was used. Results Our results indicated that theranekron treatment significantly reduced the viability of PCa cells. It remarkably decreased the protein levels of AR, cyclin A2, cyclin B1, and cyclin E1 in a dose-dependent manner. In addition, Theranekron administration strongly limited the 3D tumor formation of LNCaP, 22Rv1, and VCaP cells. Conclusion Our findings strongly suggest that theranekron may offer potent therapeutic efficacy against androgen-dependent PCa cells. Moreover, it may be a potent component for preventing acquired resistance to chemotherapeutics.
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Affiliation(s)
- Yalçın ERZURUMLU
- Süleyman Demirel University, Faculty of Pharmacy, Department of Biochemistry, Isparta, Türkiye
| | - Hatice Kübra DOĞAN
- Süleyman Demirel University, Institute of Science, Department of Bioengineering, Isparta, Türkiye
| | - Deniz ÇATAKLI
- Süleyman Demirel University, Faculty of Medicine, Department of Pharmacology, Isparta, Türkiye
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Zhao D, Meng Y, Dian Y, Zhou Q, Sun Y, Le J, Zeng F, Chen X, He Y, Deng G. Molecular landmarks of tumor disulfidptosis across cancer types to promote disulfidptosis-target therapy. Redox Biol 2023; 68:102966. [PMID: 38035663 PMCID: PMC10698012 DOI: 10.1016/j.redox.2023.102966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/11/2023] [Accepted: 11/14/2023] [Indexed: 12/02/2023] Open
Abstract
The mystery about the mechanistic basis of disulfidptosis has recently been unraveled and shows promise as an effective treatment modality for triggering cancer cell death. However, the limited understanding of the role of disulfidptosis in tumor progression and drug sensitivity has hindered the development of disulfidptosis-targeted therapy and combinations with other therapeutic strategies. Here, we established a disulfidptosis signature model to estimate tumor disulfidptosis status in approximately 10,000 tumor samples across 33 cancer types and revealed its prognostic value. Then, we characterized disulfidptosis-associated molecular features and identified various types of molecular alterations that correlate with both drug-resistant and drug-sensitive responses to anti-tumor drugs. We further showed the vast heterogeneity in disulfidptosis status among 760 cancer cell lines across 25 cancer types. We experimentally validated that disulfidptosis score-high cell lines are more susceptible to glucose starvation-induced disulfidptosis compared to their counterparts with low scores. Finally, we investigated the impact of disulfidptosis status on drug response and revealed that disulfidptosis induction may enhance sensitivity to anti-cancer drugs, but in some cases, it could also lead to drug resistance in cultured cells. Overall, our multi-omics analysis firstly elucidates a comprehensive profile of disulfidptosis-related molecular alterations, prognosis, and potential therapeutic therapies at a pan-cancer level. These findings may uncover opportunities to utilize multiple drug sensitivities induced by disulfidptosis, thereby offering practical implications for clinical cancer therapy.
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Affiliation(s)
- Deze Zhao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan 410008, China; Furong Laboratory, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan 410008, China; Furong Laboratory, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yating Dian
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan 410008, China; Furong Laboratory, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Qian Zhou
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan 410008, China; Furong Laboratory, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yuming Sun
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jiayuan Le
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan 410008, China; Furong Laboratory, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Furong Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan 410008, China; Furong Laboratory, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Yi He
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan 410008, China; Furong Laboratory, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan 410008, China; Furong Laboratory, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
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9
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Wang N, Wang H. Identification of metabolism-related gene signature in lung adenocarcinoma. Medicine (Baltimore) 2023; 102:e36267. [PMID: 38013279 PMCID: PMC10681599 DOI: 10.1097/md.0000000000036267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 11/01/2023] [Indexed: 11/29/2023] Open
Abstract
AIM Lung cancer is one of the most common cancers in China and has a high mortality rate. Most patients who are diagnosed have lost the opportunity to undergo surgery. Aberrant metabolism is closely associated with tumorigenesis. We aimed to identify an effective metabolism-related prediction model for assessing prognosis based on the cancer genome atlas (TCGA) and GSE116959 databases. METHODS TCGA and GSE116959 datasets from Gene Expression Omnibus were used to obtain lung adenocarcinoma (LUAD) data. Additionally, we captured metabolism-related genes (MRGs) from the GeneCards database. First, we extracted differentially expressed genes using R to analyze the LUAD data. We then selected the same differentially expressed genes, including 168 downregulated and 77 upregulated genes. Finally, 218 differentially expressed MRGs (DEMRGs) were included to perform functional enrichment analysis and construct a protein-protein interaction network with the help of Cytoscape and Search Tool for the Retrieval of Interacting Genes database. Cytoscape was used to visualize the intensive intervals in the network. Then univariate and Least Absolute Shrinkage and Selection Operator Cox regression analyses, which assisted in identifying the overall survival (OS)-related DEMRGs and building a 10-DEMRG prognosis model, were performed. The prognostic values, tumor immunity relevance, and molecular mechanism were further investigated. A nomogram incorporating signature, age, gender, and TNM stage was established. RESULTS A 10-DEMRG model was established to forecast the OS of LUAD through Least Absolute Shrinkage and Selection Operator regression analysis. This prognostic signature stratified LUAD patients into low-risk and high-risk groups. The receiver operating characteristic curve and K-M analysis indicated good performance of the DEMRGs signature at predicting OS in the TCGA dataset. Univariate and multivariate Cox regression also revealed that the DEMRGs signature was an independent prognosis factor in LUAD. We noticed that the risk score was substantially related to the clinical parameters of LUAD patients, covering age and stage. Immune analysis results showed that risk score was associated with some immune cells and immune checkpoints. Nomogram also verified the clinical value of the DEMRGs signature. CONCLUSION In this study, we constructed a DEMRGs signature and established a prognostic nomogram that is robust and reliable to predict OS in LUAD. Overall, the findings could help with therapeutic customization and personalized therapies.
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Affiliation(s)
- Ning Wang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Hui Wang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
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10
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Zhou X, Zhao Q, Xiao M. Hsa_circ_0137652 Regulates miR-1205/CCNB1 Axis to Accelerate the Malignancy of Breast Cancer. Mol Biotechnol 2023; 65:1824-1835. [PMID: 36807271 DOI: 10.1007/s12033-023-00684-4] [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: 09/26/2022] [Accepted: 01/29/2023] [Indexed: 02/23/2023]
Abstract
CircRNAs have become a hotspot in tumor research owing to their high stability and specific functions. We investigated the function of hsa_circ_0137652 in the onset and progression of breast cancer (BC). The expression of circ_0137652, miR-1205, and CCNB1 in BC tissues and cell lines were detected using RT-qPCR and/or western blotting. Dual-luciferase reporter and RNA immunoprecipitation chip assays were used to confirm any potential connections between circ_0137652, miR-1205, and CCNB1. CCK-8 and clone formation assays (CFA) were used to measure the proliferation of BC cells. The Transwell assay was used to investigate the migration of BC cells, and the impact of circ_0137652 on BC tumor formation in vivo was validated using animal experiments. RT-qPCR results showed that circ_0137652 and CCNB1 in breast cancer tissues were notably upregulated in normal tissues, whereas miR-1205 was prominently downregulated. After silencing circ_0137652, the growth and migration of BC cells were reduced. Animal experiments showed that circ_0137652 hampers the tumorigenesis of BC cells in vivo. Additionally, we found that circ_0137652 functions as a sponge for miR-1205. Moreover, the miR-1205 inhibitor notably facilitated cell proliferation and migration and attenuated the action of circ_0137652 knockdown. Furthermore, miR-1205 inhibits BC progression by targeting CCNB1. Circ_0137652 controls the miR-1205/CCNB1 axis to induce increased breast cancer malignancy. Our findings suggest that circ_0137652 may be a novel target for BC therapy.
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Affiliation(s)
- Xu Zhou
- Department of Thyroid and Breast Surgery, Wuhan Red Cross Hospital, No. 392, Hong Kong Road, Jianghan District, Wuhan, 430015, Hubei, China
| | - Qiang Zhao
- Department of Rehabilitation Medicine, Wuhan Hankou Hospital, Wuhan, 430012, Hubei, China
| | - Min Xiao
- Department of Thyroid and Breast Surgery, Wuhan Red Cross Hospital, No. 392, Hong Kong Road, Jianghan District, Wuhan, 430015, Hubei, China.
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11
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Kubina R, Krzykawski K, Sokal A, Madej M, Dziedzic A, Kadela-Tomanek M. New Propargyloxy Derivatives of Galangin, Kaempferol and Fisetin-Synthesis, Spectroscopic Analysis and In Vitro Anticancer Activity on Head and Neck Cancer Cells. Cells 2023; 12:2288. [PMID: 37759511 PMCID: PMC10528839 DOI: 10.3390/cells12182288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Head and neck cancer (HNC) therapy is limited; therefore, new solutions are increasingly being sought among flavonoids, which exhibit numerous biological properties, including potential anticancer activity. However, because they are mostly insoluble in water, are unstable and have low bioavailability, they are subjected to chemical modification to obtain new derivatives with better properties. This study aimed to synthesize and analyze new propargyloxy derivatives of galangin, kaempferol and fisetin, and to evaluate their anticancer activity against selected HNC cell lines. The obtained derivatives were assessed by spectroscopic analysis; next, their anticancer activity was evaluated using a flow cytometer and real-time cell analysis. The results showed that only the fisetin derivative was suitable for further analysis, due to the lack of crystal formation of the compound. The fisetin derivative statistically significantly increases the number of cells in the G2/M phase (p < 0.05) and increases cyclin B1 levels. A statistically significant increase in the number of apoptotic cells after being exposed to the tested compound was also observed (p < 0.05). The data indicate that the obtained fisetin derivative exhibits anticancer activity by affecting the cell cycle and increasing apoptosis in selected HNC lines, which suggests its potential use as a new medicinal agent in the future.
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Affiliation(s)
- Robert Kubina
- Department of Pathology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Ostrogórska 30, 41-200 Sosnowiec, Poland
- Silesia LabMed, Centre for Research and Implementation, Medical University of Silesia in Katowice, 18 Medyków Str., 40-752 Katowice, Poland; (K.K.); (M.M.)
| | - Kamil Krzykawski
- Silesia LabMed, Centre for Research and Implementation, Medical University of Silesia in Katowice, 18 Medyków Str., 40-752 Katowice, Poland; (K.K.); (M.M.)
| | - Arkadiusz Sokal
- Students Scientific Group of Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland;
| | - Marcel Madej
- Silesia LabMed, Centre for Research and Implementation, Medical University of Silesia in Katowice, 18 Medyków Str., 40-752 Katowice, Poland; (K.K.); (M.M.)
| | - Arkadiusz Dziedzic
- Department of Conservative Dentistry with Endodontics, Medical University of Silesia, 40-055 Katowice, Poland;
| | - Monika Kadela-Tomanek
- Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland;
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12
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Ahn S, Kwon A, Oh Y, Rhee S, Song WK. Microtubule Acetylation-Specific Inhibitors Induce Cell Death and Mitotic Arrest via JNK/AP-1 Activation in Triple-Negative Breast Cancer Cells. Mol Cells 2023; 46:387-398. [PMID: 36794420 PMCID: PMC10258459 DOI: 10.14348/molcells.2023.2192] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 02/17/2023] Open
Abstract
Microtubule acetylation has been proposed as a marker of highly heterogeneous and aggressive triple-negative breast cancer (TNBC). The novel microtubule acetylation inhibitors GM-90257 and GM-90631 (GM compounds) cause TNBC cancer cell death but the underlying mechanisms are currently unknown. In this study, we demonstrated that GM compounds function as anti-TNBC agents through activation of the JNK/AP-1 pathway. RNA-seq and biochemical analyses of GM compound-treated cells revealed that c-Jun N-terminal kinase (JNK) and members of its downstream signaling pathway are potential targets for GM compounds. Mechanistically, JNK activation by GM compounds induced an increase in c-Jun phosphorylation and c-Fos protein levels, thereby activating the activator protein-1 (AP-1) transcription factor. Notably, direct suppression of JNK with a pharmacological inhibitor alleviated Bcl2 reduction and cell death caused by GM compounds. TNBC cell death and mitotic arrest were induced by GM compounds through AP-1 activation in vitro. These results were reproduced in vivo, validating the significance of microtubule acetylation/JNK/AP-1 axis activation in the anti-cancer activity of GM compounds. Moreover, GM compounds significantly attenuated tumor growth, metastasis, and cancer-related death in mice, demonstrating strong potential as therapeutic agents for TNBC.
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Affiliation(s)
- Suyeon Ahn
- Cell Logistics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
| | - Ahreum Kwon
- Cell Logistics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
| | - Youngsoo Oh
- Cell Logistics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
| | - Sangmyung Rhee
- Department of Life Science, Chung-Ang University, Seoul 06974, Korea
| | - Woo Keun Song
- Cell Logistics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
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13
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Williams KS, Secomb TW, El-Kareh AW. An autonomous mathematical model for the mammalian cell cycle. J Theor Biol 2023; 569:111533. [PMID: 37196820 DOI: 10.1016/j.jtbi.2023.111533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 04/04/2023] [Accepted: 05/10/2023] [Indexed: 05/19/2023]
Abstract
A mathematical model for the mammalian cell cycle is developed as a system of 13 coupled nonlinear ordinary differential equations. The variables and interactions included in the model are based on detailed consideration of available experimental data. A novel feature of the model is inclusion of cycle tasks such as origin licensing and initiation, nuclear envelope breakdown and kinetochore attachment, and their interactions with controllers (molecular complexes involved in cycle control). Other key features are that the model is autonomous, except for a dependence on external growth factors; the variables are continuous in time, without instantaneous resets at phase boundaries; mechanisms to prevent rereplication are included; and cycle progression is independent of cell size. Eight variables represent cell cycle controllers: the Cyclin D1-Cdk4/6 complex, APCCdh1, SCFβTrCP, Cdc25A, MPF, NuMA, the securin-separase complex, and separase. Five variables represent task completion, with four for the status of origins and one for kinetochore attachment. The model predicts distinct behaviors corresponding to the main phases of the cell cycle, showing that the principal features of the mammalian cell cycle, including restriction point behavior, can be accounted for in a quantitative mechanistic way based on known interactions among cycle controllers and their coupling to tasks. The model is robust to parameter changes, in that cycling is maintained over at least a five-fold range of each parameter when varied individually. The model is suitable for exploring how extracellular factors affect cell cycle progression, including responses to metabolic conditions and to anti-cancer therapies.
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Affiliation(s)
| | - Timothy W Secomb
- BIO5 Institute, University of Arizona, Tucson, AZ, USA; Department of Physiology, University of Arizona, Tucson, AZ, USA
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14
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Maharjan S, Lee MG, Kim SY, Lee KS, Nam KS. Morin Sensitizes MDA-MB-231 Triple-Negative Breast Cancer Cells to Doxorubicin Cytotoxicity by Suppressing FOXM1 and Attenuating EGFR/STAT3 Signaling Pathways. Pharmaceuticals (Basel) 2023; 16:ph16050672. [PMID: 37242455 DOI: 10.3390/ph16050672] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Considerable emphasis is being placed on combinatorial chemotherapeutic/natural treatments for breast cancer. This study reveals the synergistic anti-tumor activity of morin and Doxorubicin (Dox) co-treatment on MDA-MB-231 triple-negative breast cancer (TNBC) cell proliferation. Morin/Dox treatment promoted Dox uptake and induced DNA damage and formation of nuclear foci of p-H2A.X. Furthermore, DNA repair proteins, RAD51 and survivin, and cell cycle proteins, cyclin B1 and forkhead Box M1 (FOXM1), were induced by Dox alone but attenuated by morin/Dox co-treatment. In addition, Annexin V/7-AAD analysis revealed that necrotic cell death after co-treatment and apoptotic cell death by Dox alone were associated with the induction of cleaved PARP and caspase-7 without Bcl-2 family involvement. FOXM1 inhibition by thiostrepton showed that co-treatment caused FOXM1-mediated cell death. Furthermore, co-treatment downregulated the phosphorylation of EGFR and STAT3. Flow cytometry showed that the accumulation of cells in the G2/M and S phases might be linked to cellular Dox uptake, p21 upregulation, and cyclin D1 downregulation. Taken together, our study shows that the anti-tumor effect of morin/Dox co-treatment is due to the suppression of FOXM1 and attenuation of EGFR/STAT3 signaling pathways in MDA-MB-231 TNBC cells, which suggests that morin offers a means of improving therapeutic efficacy in TNBC patients.
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Affiliation(s)
- Sushma Maharjan
- Department of Pharmacology, College of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju 38066, Republic of Korea
| | - Min-Gu Lee
- Department of Pharmacology, College of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju 38066, Republic of Korea
| | - So-Young Kim
- Department of Pharmacology, College of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju 38066, Republic of Korea
| | - Kyu-Shik Lee
- Department of Pharmacology, College of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju 38066, Republic of Korea
| | - Kyung-Soo Nam
- Department of Pharmacology, College of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju 38066, Republic of Korea
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15
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Patel JR, Banjara B, Ohemeng A, Davidson AM, Boué SM, Burow ME, Tilghman SL. Novel Therapeutic Combination Targets the Growth of Letrozole-Resistant Breast Cancer through Decreased Cyclin B1. Nutrients 2023; 15:1632. [PMID: 37049472 PMCID: PMC10097176 DOI: 10.3390/nu15071632] [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: 03/03/2023] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
As breast cancer cells transition from letrozole-sensitive to letrozole-resistant, they over-express epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and human epidermal growth factor receptor 2 (HER2) while acquiring enhanced motility and epithelial-to-mesenchymal transition (EMT)-like characteristics that are attenuated and reversed by glyceollin treatment, respectively. Interestingly, glyceollin inhibits the proliferation and tumor progression of triple-negative breast cancer (TNBC) and estrogen-independent breast cancer cells; however, it is unlikely that a single phytochemical would effectively target aromatase-inhibitor (AI)-resistant metastatic breast cancer in the clinical setting. Since our previous report indicated that the combination of lapatinib and glyceollin induced apoptosis in hormone-dependent AI-resistant breast cancer cells, we hypothesized that combination therapy would also be beneficial for hormone independent letrozole-resistant breast cancer cells (LTLT-Ca) compared to AI-sensitive breast cancer cells (AC-1) by decreasing the expression of proteins associated with proliferation and cell cycle progression. While glyceollin + lapatinib treatment caused comparable inhibitory effects on the proliferation and migration in both cell lines, combination treatment selectively induced S and G2/M phase cell cycle arrest of the LTLT-Ca cells, which was mediated by decreased cyclin B1. This phenomenon may represent a unique opportunity to design novel combinatorial therapeutic approaches to target hormone-refractory breast tumors.
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Affiliation(s)
- Jankiben R. Patel
- Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Bipika Banjara
- Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Afia Ohemeng
- Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - A. Michael Davidson
- Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Stephen M. Boué
- Southern Regional Research Center, United States Department of Agriculture, Agricultural Research Service, 1100 Robert E. Lee Blvd., New Orleans, LA 70124, USA
| | - Matthew E. Burow
- Section of Hematology and Medical Oncology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Syreeta L. Tilghman
- Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
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16
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Almeida LYD, Moreira FDS, Santos GASD, Cuadra Zelaya FJM, Ortiz CA, Agostini M, Mariano FS, Bastos DC, Daher URN, Kowalski LP, Coletta RD, Graner E. FASN inhibition sensitizes metastatic OSCC cells to cisplatin and paclitaxel by downregulating cyclin B1. Oral Dis 2023; 29:649-660. [PMID: 34510641 DOI: 10.1111/odi.14017] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 08/03/2021] [Accepted: 08/22/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To investigate the potential effect of fatty acid synthase (FASN) inhibitor orlistat to enhance the effectiveness of chemotherapy drugs widely used to treat oral squamous cell carcinomas (OSCC), such as 5-fluorouracil, cisplatin, and paclitaxel. METHODS The OSCC SCC-9 LN-1 metastatic cell line, which expresses high levels of FASN, was used for drug combination experiments. Cell viability was analyzed by crystal violet staining and automatic cell counting. Apoptosis and cell cycle were analyzed by flow cytometry with Annexin-V/7-AAD and propidium iodide staining, respectively. Cyclin B1, Cdc25C, Cdk1, FASN, and ERBB2 levels were assessed by Western blotting. Finally, cell scratch and transwell assays were performed to assess cell migration and invasion. RESULTS Inhibition of FASN with orlistat sensitized SCC-9 LN-1 cells to the cytotoxic effects of paclitaxel and cisplatin, but not 5-fluorouracil, which was accompanied by a significant reduction in cyclin B1. The suppression of proliferation, migration, and invasion of SCC-9 LN-1 cells induced by orlistat plus cisplatin or paclitaxel was not superior to the effects of chemotherapy drugs alone. CONCLUSION Our results suggest that orlistat enhances the chemosensitivity of SCC-9 LN-1 cells to cisplatin and paclitaxel by downregulating cyclin B1.
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Affiliation(s)
- Luciana Yamamoto de Almeida
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
| | - Fernanda Dos Santos Moreira
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
| | | | | | - César Alexander Ortiz
- Hematology Division, Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, Brazil
| | - Michelle Agostini
- Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Flávia Sammartino Mariano
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
| | - Débora Campanella Bastos
- Department of Biosciences, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
| | - Ulisses Ribaldo Nicolau Daher
- Department of Clinical Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil.,Department of Clinical Oncology, Hospital Amaral Carvalho, São Paulo, Brazil
| | - Luiz Paulo Kowalski
- Department of Otorhinolaryngology and Head and Neck Surgery, A. C. Camargo Cancer Center, São Paulo, Brazil.,Department of Head and Neck Surgery, Medical School, University of São Paulo, São Paulo, Brazil
| | - Ricardo D Coletta
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
| | - Edgard Graner
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
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17
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Zangouei AS, Zangoue M, Taghehchian N, Zangooie A, Rahimi HR, Saburi E, Alavi MS, Moghbeli M. Cell cycle related long non-coding RNAs as the critical regulators of breast cancer progression and metastasis. Biol Res 2023; 56:1. [PMID: 36597150 PMCID: PMC9808980 DOI: 10.1186/s40659-022-00411-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/29/2022] [Indexed: 01/04/2023] Open
Abstract
Cell cycle is one of the main cellular mechanisms involved in tumor progression. Almost all of the active molecular pathways in tumor cells directly or indirectly target the cell cycle progression. Therefore, it is necessary to assess the molecular mechanisms involved in cell cycle regulation in tumor cells. Since, early diagnosis has pivotal role in better cancer management and treatment, it is required to introduce the non-invasive diagnostic markers. Long non-coding RNAs (LncRNAs) have higher stability in body fluids in comparison with mRNAs. Therefore, they can be used as efficient non-invasive markers for the early detection of breast cancer (BCa). In the present review we have summarized all of the reported lncRNAs involved in cell cycle regulation in BCa. It has been reported that lncRNAs mainly affect the cell cycle in G1/S transition through the CCND1/CDK4-6 complex. Present review paves the way of introducing the cell cycle related lncRNAs as efficient markers for the early detection of BCa.
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Affiliation(s)
- Amir Sadra Zangouei
- grid.411583.a0000 0001 2198 6209Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ,grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Zangoue
- grid.411701.20000 0004 0417 4622Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran ,grid.411701.20000 0004 0417 4622Department of Anesthesiology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Negin Taghehchian
- grid.411583.a0000 0001 2198 6209Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Zangooie
- grid.411701.20000 0004 0417 4622Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran ,grid.411701.20000 0004 0417 4622Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Hamid Reza Rahimi
- grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Saburi
- grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahya Sadat Alavi
- grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ,grid.411583.a0000 0001 2198 6209Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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18
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Haynes BM, Cunningham K, Shekhar MPV. RAD6 inhibition enhances paclitaxel sensitivity of triple negative breast cancer cells by aggravating mitotic spindle damage. BMC Cancer 2022; 22:1073. [PMID: 36258187 PMCID: PMC9578210 DOI: 10.1186/s12885-022-10119-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 09/22/2022] [Indexed: 11/28/2022] Open
Abstract
Background Paclitaxel (PTX), a first-line therapy for triple negative breast cancers (TNBC) induces anti-tumor activity by microtubule stabilization and inhibition of cell division. Its dose-limiting toxicity and short half-life, however, pose clinical challenges underscoring the need for strategies that increase its efficiency. RAD6, a E2 ubiquitin conjugating enzyme, is associated with centrosomes at all phases of cell cycle. Constitutive overexpression of the RAD6B homolog in normal breast cells induces centrosome amplification and multipolar spindle formation, indicating its importance in centrosome regulation. Methods TNBC centrosome numbers were scored by pericentrin immunostaining. PTX sensitivities and interactions with SMI#9, a RAD6-selective small molecule inhibitor, on TNBC cell survival were analyzed by MTT and colony forming assays and an isogenic MDA-MB-468 TNBC model of PTX resistance. The molecular mechanisms underlying PTX and SMI#9 induced cytotoxicity were determined by flow cytometry, immunoblot analysis of cyclin B1 and microtubule associated protein TAU, and dual immunofluorescence staining of TAU and α-tubulin. Results Our data show aberrant centrosome numbers and that PTX sensitivities are not correlated with TNBC BRCA1 status. Combining PTX with SMI#9 synergistically enhances PTX sensitivities of BRCA1 wild-type and mutant TNBC cells. Whereas SMI#9/PTX combination treatment increased cyclin B1 levels in MDA-MB-468 cells, it induced cyclin B1 loss in HCC1937 cells with accumulation of reproductively dead giant cells, a characteristic of mitotic catastrophe. Cell cycle analysis revealed drug-induced accumulation of tetraploid cells in S and G2/M phases, and robust increases in cells with 4 N DNA content in HCC1937 cells. TAU overexpression is associated with reduced PTX efficacy. Among the six TAU isoforms, both SMI#9 and PTX downregulated 1N3R TAU in MDA-MB-468 and HCC1937 cells, suggesting a common mechanism of 1N3R regulation. Dual TAU and α-tubulin immunostaining showed that SMI#9 induces monopolar mitotic spindles. Using the isogenic model of PTX resistance, we show that SMI#9 treatment restores PTX sensitivity. Conclusions These data support a common mechanism of microtubule regulation by SMI#9 and PTX and suggest that combining PTX with RAD6 inhibitor may be beneficial for increasing TNBC sensitivities to PTX and alleviating toxicity. This study demonstrates a new role for RAD6 in regulating microtubule dynamics. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10119-z.
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Affiliation(s)
- Brittany M Haynes
- Karmanos Cancer Institute, 4100 John R Street, Detroit, MI, 48201, USA.,Department of Oncology, Wayne State University School of Medicine, 421 E. Canfield Avenue, Detroit, MI, 48201, USA.,Present address: Office of Policy Communications, and Education, National Center for Advancing Translational Sciences, Besthesda, USA
| | - Kristen Cunningham
- Karmanos Cancer Institute, 4100 John R Street, Detroit, MI, 48201, USA.,Department of Oncology, Wayne State University School of Medicine, 421 E. Canfield Avenue, Detroit, MI, 48201, USA
| | - Malathy P V Shekhar
- Karmanos Cancer Institute, 4100 John R Street, Detroit, MI, 48201, USA. .,Department of Oncology, Wayne State University School of Medicine, 421 E. Canfield Avenue, Detroit, MI, 48201, USA. .,Department of Pathology, Wayne State University School of Medicine, 421 E. Canfield Avenue, Detroit, MI, 48201, USA.
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19
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Kim YW, Bak SB, Baek SY, Kim IK, Lee WY, Yun UJ, Park KI. Mylabris phalerata induces the apoptosis and cell cycle delay in HCC, and potentiates the effect of sorafenib based on the molecular and network pharmacology approach. Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00300-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
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20
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Amaldoss MJN, Yang JL, Koshy P, Unnikrishnan A, Sorrell CC. Inorganic nanoparticle-based advanced cancer therapies: promising combination strategies. Drug Discov Today 2022; 27:103386. [PMID: 36182068 DOI: 10.1016/j.drudis.2022.103386] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 08/15/2022] [Accepted: 09/24/2022] [Indexed: 11/17/2022]
Abstract
Inorganic nanoparticles for drug delivery in cancer treatment offer many potential advantages because they can maximize therapeutic effect through targeting ligands while minimizing off-target side-effects through drug adsorption and infiltration. Although inorganic nanoparticles were introduced as drug carriers, they have emerged as having the capacity for combined therapeutic capabilities, including anticancer effects through cytotoxicity, suppression of oncogenes and cancer cell signaling pathway inhibition. The most promising advanced strategies for cancer therapy are as synergistic platforms for RNA interference (siRNA, miRNA, shRNA) and as synergistic drug delivery agents for the inhibition of cancer cell signaling pathways. The present work summarizes relevant current work, the promise of which is suggested by a projected compound annual growth rate of ∼20% for drug delivery alone.
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Affiliation(s)
- Maria John Newton Amaldoss
- Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia; School of Materials Science and Engineering, UNSW Sydney, Sydney, NSW 2052, Australia.
| | - Jia-Lin Yang
- Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Pramod Koshy
- School of Materials Science and Engineering, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Ashwin Unnikrishnan
- Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Charles C Sorrell
- School of Materials Science and Engineering, UNSW Sydney, Sydney, NSW 2052, Australia
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21
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Ingebriktsen LM, Finne K, Akslen LA, Wik E. A novel age-related gene expression signature associates with proliferation and disease progression in breast cancer. Br J Cancer 2022; 127:1865-1875. [PMID: 35995935 DOI: 10.1038/s41416-022-01953-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Breast cancer (BC) diagnosed at ages <40 years presents with more aggressive tumour phenotypes and poorer clinical outcome compared to older BC patients. Here, we explored transcriptional BC alterations to gain a better understanding of age-related tumour biology, also subtype-stratified. METHODS We studied publicly available global BC mRNA expression (n = 3999) and proteomics data (n = 113), exploring differentially expressed genes, enriched gene sets, and gene networks in the young compared to older patients. RESULTS We identified transcriptional patterns reflecting increased proliferation and oncogenic signalling in BC of the young, also in subtype-stratified analyses. Six up-regulated hub genes built a novel age-related score, significantly associated with aggressive clinicopathologic features. A high 6 Gene Proliferation Score (6GPS) demonstrated independent prognostic value when adjusted for traditional clinicopathologic variables and the molecular subtypes. The 6GPS significantly associated also with disease-specific survival within the luminal, lymph node-negative and Oncotype Dx intermediate subset. CONCLUSIONS We here demonstrate evidence of higher tumour cell proliferation in young BC patients, also when adjusting for molecular subtypes, and identified a novel age-based six-gene signature pointing to aggressive tumour features, tumour proliferation, and reduced survival-also in patient subsets with expected good prognosis.
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Affiliation(s)
- L M Ingebriktsen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway
| | - K Finne
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway
| | - L A Akslen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - E Wik
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway. .,Department of Pathology, Haukeland University Hospital, Bergen, Norway.
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22
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Huang Z, Yu C, Yu L, Shu H, Zhu X. The Roles of FHL3 in Cancer. Front Oncol 2022; 12:887828. [PMID: 35686099 PMCID: PMC9171237 DOI: 10.3389/fonc.2022.887828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/18/2022] [Indexed: 12/19/2022] Open
Abstract
The four and a half LIM domain protein 3, also named the LIM-protein FHL3, belongs to the LIM-only family. Based on the special structure of LIM-only proteins, FHL3 can perform significant functions in muscle proliferation and cardiovascular diseases by regulating cell growth and signal transduction. In recent years, there has been increasing evidence of a relation between FHLs and tumor biology, since FHL3 is often overexpressed or downregulated in different cancers. On the one hand, FHL3 can function as a tumor suppressor and influence the expression of downstream genes. On the other hand, FHL3 can also play a role as an oncoprotein in some cancers to promote tumor progression via phosphorylation. Thus, FHL3 is proposed to have a dual effect on cancer progression, reflecting its complex roles in cancer. This review focuses on the roles of FHL3 in cancer progression and discusses the interaction of FHL3 with other proteins and transcription factors. Finally, the clinical significance of FHL3 for the treatment of cancers is discussed.
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Affiliation(s)
- Zhenjun Huang
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Second Clinical Medical College, Nanchang University, Nanchang, China
| | - Chengpeng Yu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liqing Yu
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Second Clinical Medical College, Nanchang University, Nanchang, China
| | - Hongxin Shu
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Second Clinical Medical College, Nanchang University, Nanchang, China
| | - Xianhua Zhu
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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23
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Fan X, Zhao Z, Ma L, Huang X, Zhan Q, Song Y. PTBP1 promotes IRES-mediated translation of cyclin B1 in cancer. Acta Biochim Biophys Sin (Shanghai) 2022; 54:696-707. [PMID: 35643957 PMCID: PMC9828304 DOI: 10.3724/abbs.2022046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 01/11/2022] [Indexed: 11/25/2022] Open
Abstract
Cyclin B1 is an essential cyclin-dependent protein that involves in the G2/M transition. Multiple studies report that cyclin B1 is upregulated in cancers and promotes cancer progression. However, the mechanism of cyclin B1 upregulation remains unclear. Here we report that the 5'UTR of cyclin B1 mRNA contains an internal ribosome entry site (IRES) by using a bicistronic fluorescent reporter. We show that IRES can initiate the translation of cyclin B1, and the IRES-mediated translation is further activated under cell stress. Interacting trans-acting factors (ITAFs) are required by most IRES to initiate the translation. We find that PTBP1 promotes the IRES-mediated translation of cyclin B1 by binding to the 5'UTR of cyclin B1. On top of that, PTBP1 promotes the malignancy of ESCC cells. Our data suggest that the IRES-mediated translation of cyclin B1 plays an essential role in the cyclin B1 upregulation in cancers.
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Affiliation(s)
- Xinyi Fan
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021 China
- Department of Radiation OncologyWeill Cornell Medical CollegeNew YorkNY10065USA
| | - Zitong Zhao
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021 China
| | - Liying Ma
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021 China
| | | | - Qimin Zhan
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021 China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Laboratory of Molecular OncologyPeking University Cancer Hospital & InstituteBeijing100142China
| | - Yongmei Song
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021 China
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24
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Acquisition of paclitaxel resistance modulates the biological traits of gastric cancer AGS cells and facilitates epithelial to mesenchymal transition and angiogenesis. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:515-533. [PMID: 35122114 DOI: 10.1007/s00210-022-02217-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
PURPOSE This study aims to develop a paclitaxel (PTX)-resistant gastric cancer AGS cells (AGS-R) and evaluate the mechanisms of drug resistance. METHODS AGS cells were successively treated with increasing PTX concentrations. Cross-resistance of established AGS-R, the molecular patterns of cell survival, evasion of apoptosis, epithelial-mesenchymal transition (EMT), and the angiogenic potential were evaluated. RESULTS AGS-R was induced within six months of PTX exposure. Extension of the treatment resulted in PTX-resistance beyond clinical levels. The established AGS-R showed resistance to vincristine and doxorubicin but not cisplatin. Upon induction of resistance, the expressions of MDR-1 (P < 0.001) and MRP-1 (P < 0.01) genes and proteins significantly increased. AGS-R cells had elevated levels of BCL-2, pro-CASP3, cleaved-NOTCH1, HES1, HEY1, NF-κB, PI3K, p-AKT, HIF-1α, Cyclin A, and B1 as compared with parental cells (at least P < 0.01). The protein levels of BAX, CASP3, P53, and P21 (at least P < 0.01) as well as intracellular ROS (P < 0.001) were reduced in AGS-R. A relative arrest at the G2/M phase (15.8 ± 0.75 vs. 26.7 ± 1.67) of the cell cycle and enrichment of AGS-R cells for CD44 marker (9 ± 0.6 vs. 1 ± 0.8) (P < 0.001) were detected by flow cytometry. While the E-cadherin expression was reduced (P < 0.001), the protein levels of Vimentin, N-cadherin, SLUG, and SNAIL were increased (at least P < 0.05). The angiogenic activity and release of VEGF and MMP2/9 were increased in AGS-R cells relative to the AGS line (P < 0.001). CONCLUSION AGS-R cells could bypass chemotherapy stress by expressing the genes coding for efflux pumps and altering some key signaling in favor of survival, EMT, and angiogenesis.
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25
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Fang L, Liu Q, Cui H, Zheng Y, Wu C. Bioinformatics Analysis Highlight Differentially Expressed CCNB1 and PLK1 Genes as Potential Anti-Breast Cancer Drug Targets and Prognostic Markers. Genes (Basel) 2022; 13:654. [PMID: 35456460 PMCID: PMC9027215 DOI: 10.3390/genes13040654] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/03/2022] [Accepted: 04/06/2022] [Indexed: 02/01/2023] Open
Abstract
Breast cancer is one of the most common malignant tumors in women worldwide. Early diagnosis, treatment, and prognosis of breast cancer are global challenges. Identification of valid predictive diagnosis and prognosis biomarkers and drug targets are crucial for breast cancer prevention. This study characterizes differentially expressed genes (DEGs) based on the TCGA database by using DESeq2, edgeR, and limma. A total of 2032 DEGs, including 1026 up-regulated genes and 1006 down-regulated genes were screened. Followed with WGCNA, PPI analysis, GEPIA 2, and HPA database verification, thirteen hub genes including CDK1, BUB1, BUB1B, CDC20, CCNB2, CCNB1, KIF2C, NDC80, CDCA8, CENPF, BIRC5, AURKB, PLK1, MAD2L1, and CENPE were obtained, and they may serve as potential therapeutic targets of breast cancer. Especially, overexpression of CCNB1 and PLK1 are strongly associated with the low survival rate of breast cancer patients, demonstrating their potentiality as prognostic markers. Moreover, CCNB1 and PLK1 are highly expressed in all breast cancer stages, suggesting that they could be further studied as potential drug targets. Taken together, our study highlights CCNB1 and PLK1 as potential anti-breast cancer drug targets and prognostic markers.
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Affiliation(s)
- Leiming Fang
- School of Biomedical Engineering, Dalian University of Technology, Dalian 116024, China; (L.F.); (Q.L.); (H.C.)
| | - Qi Liu
- School of Biomedical Engineering, Dalian University of Technology, Dalian 116024, China; (L.F.); (Q.L.); (H.C.)
| | - Hongtu Cui
- School of Biomedical Engineering, Dalian University of Technology, Dalian 116024, China; (L.F.); (Q.L.); (H.C.)
| | - Yunji Zheng
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China;
| | - Chengjun Wu
- School of Biomedical Engineering, Dalian University of Technology, Dalian 116024, China; (L.F.); (Q.L.); (H.C.)
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Anthocyanidins Inhibit Growth and Chemosensitize Triple-Negative Breast Cancer via the NF-κB Signaling Pathway. Cancers (Basel) 2021; 13:cancers13246248. [PMID: 34944868 PMCID: PMC8699375 DOI: 10.3390/cancers13246248] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/06/2021] [Accepted: 12/08/2021] [Indexed: 11/30/2022] Open
Abstract
Simple Summary Breast cancer is the most common female cancer diagnosed in the U.S. and the second most common cause of cancer death in women. Chemotherapeutics used to treat breast cancer often have side effects, which are sometimes life-threatening. Moreover, the tumors can develop resistance over time, making breast cancer treatment challenging. In this paper, we show that the oral administration of colored pigments isolated from bilberry/blueberry, called anthocyanidins (Anthos), significantly decrease MDA-MB-231 orthoxenograft tumor volume, inhibit the growth and metastasis of breast cancer, sensitize drug-resistant tumor cells, and exhibit a lower rate of lymph node and lung metastasis, compared to control. Our results also suggest regulation of cell-cycle progression and inhibition of NF-κB activation as mechanisms underpinning the anti-proliferative activity of Anthos in breast cancer. These mechanistic insights are expected to be valuable for clinical translation of berry Anthos, either alone or as adjuvant to chemotherapy, for the treatment of breast cancer patients. Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Due to the lack of drug-targetable receptors, chemotherapy is the only systemic treatment option. Although chemotherapeutic drugs respond initially in TNBC, many patients relapse and have a poor prognosis. Poor survival after metastatic relapse is largely attributed to the development of resistance to chemotherapeutic drugs. In this study, we show that bilberry-derived anthocyanidins (Anthos) can inhibit the growth and metastasis of TNBC and chemosensitize paclitaxel (PAC)-resistant TNBC cells by modulating the NF-κB signaling pathway, as well as metastatic and angiogenic mediators. Anthos administered orally significantly decreased MDA-MB-231 orthoxenograft tumor volume and led to lower rates of lymph node and lung metastasis, compared to control. Treatment of PAC-resistant MDA-MB-231Tx cells with Anthos and PAC in combination lowered the IC50 of PAC by nearly 20-fold. The combination treatment also significantly (p < 0.01) decreased the tumor volume in MDA-MB-231Tx orthoxenografts, compared to control. In contrast, Anthos and PAC alone were ineffective against MDA-MB-231Tx tumors. Our approach of using Anthos to inhibit the growth and metastasis of breast cancers, as well as to chemosensitize PAC-resistant TNBC, provides a highly promising and effective strategy for the management of TNBC.
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27
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Tsai TH, Lieu AS, Huang TY, Kwan AL, Lin CL, Hsu YC. Induction of Mitosis Delay and Apoptosis by CDDO-TFEA in Glioblastoma Multiforme. Front Pharmacol 2021; 12:756228. [PMID: 34858180 PMCID: PMC8630575 DOI: 10.3389/fphar.2021.756228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/25/2021] [Indexed: 12/02/2022] Open
Abstract
Background: Glioblastoma multiforme (GBM) is the vicious malignant brain tumor in adults. Despite advances multi-disciplinary treatment, GBM constinues to have a poor overall survival. CDDO-trifluoroethyl-amide (CDDO-TEFA), a trifluoroethylamidederivative of CDDO, is an Nrf2/ARE pathway activator. CDDO-TEFEA is used to inhibit proliferation and induce apoptosis in glioma cells. However, it not clear what effect it may have on tumorigenesis in GBM. Methods: This in vitro study evaluated the effects of CDDO-TFEA on GBM cells. To do this, we treated GBM8401 cell lines with CDDO-TFEA and assessed apoptosis, cell cycle. DNA content and induction of apoptosis were analyzed by flow cytometry and protein expression by Western blot analysis. Results: CDDO-TFEA significantly inhibited the cell viability and induced cell apoptosis on GBM 8401 cell line. The annexin-FITC/PI assay revealed significant changes in the percentage of apoptotic cells. Treatment with CDDO-TFEA led to a significant reduction in the GBM8401 cells' mitochondrial membrane potential. A significant rise in the percentage of caspase-3 activity was detected in the treated cells. In addition, treatment with CDDO-TFEA led to an accumulation of G2/M-phase cells. In addition, these results suggest that regarding increased protein synthesis during mitosis in the MPM-2 staining, indicative of a delay in the G2 checkpoint. An analysis of Cyclin B1, CDK1, Cyclin B1/CDK1 complex and CHK1 and CHK2 expression suggested that cell cycle progression seems also to be regulated by CDDO-TFEA. Therefore, CDDO-TFEA may not only induce cell cycle G2/M arrest, it may also exert apoptosis in established GBM cells. Conclusion: CDDO-TFEA can inhibit proliferation, cell cycle progression and induce apoptosis in GBM cells in vitro, possibly though its inhibition of Cyclin B1, CDK1 expression, and Cyclin B1/CDK1 association and the promotion of CHK1 and CHK2 expression.
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Affiliation(s)
- Tai-Hsin Tsai
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institutes of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ann-Shung Lieu
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institutes of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tzuu-Yuan Huang
- Department of Neurosurgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Aij-Lie Kwan
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institutes of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Lung Lin
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institutes of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Chiang Hsu
- School of Medicine, I‐Shou University, Kaohsiung, Taiwan
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Motamedi M, Xiao MZX, Iyer A, Gniadecki R. Patterns of Gene Expression in Cutaneous T-Cell Lymphoma: Systematic Review of Transcriptomic Studies in Mycosis Fungoides. Cells 2021; 10:cells10061409. [PMID: 34204115 PMCID: PMC8229125 DOI: 10.3390/cells10061409] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/01/2021] [Accepted: 06/04/2021] [Indexed: 02/07/2023] Open
Abstract
Mycosis fungoides (MF) is the most prevalent type of skin lymphoma. In its early stages, it has a favorable prognosis. However, in its late stages, it is associated with an increased risk of mortality. This systematic review aimed to identify the transcriptomic changes involved in MF pathogenesis and progression. A literature search was conducted using the database PubMed, followed by the extraction of 2245 genes which were further filtered to 150 recurrent genes that appeared in two or more publications. Categorization of these genes identified activated pathways involved in pathways such as cell cycle and proliferation, chromosomal instability, and DNA repair. We identified 15 genes implicated in MF progression, which were involved in cell proliferation, immune checkpoints, resistance to apoptosis, and immune response. In highlighting the discrepancies in the way MF transcriptomic data is obtained, further research can focus on not only unifying their approach but also focus on the 150 pertinent genes identified in this review.
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Affiliation(s)
- Melika Motamedi
- Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada; (M.M.); (M.Z.X.X.); (A.I.)
| | - Maggie Z. X. Xiao
- Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada; (M.M.); (M.Z.X.X.); (A.I.)
| | - Aishwarya Iyer
- Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada; (M.M.); (M.Z.X.X.); (A.I.)
| | - Robert Gniadecki
- Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada; (M.M.); (M.Z.X.X.); (A.I.)
- 8-112 Clinical Sciences Building, University of Alberta, Edmonton, AB T6G 2G3, Canada
- Correspondence: ; Tel.: +1-(780)-407-1555
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Silencing of Nek2 suppresses the proliferation, migration and invasion and induces apoptosis of breast cancer cells by regulating ERK/MAPK signaling. J Mol Histol 2021; 52:809-821. [PMID: 34009515 DOI: 10.1007/s10735-021-09979-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/08/2021] [Indexed: 02/08/2023]
Abstract
Breast cancer is a frequent cancer among women. The current study investigated the biological functions of Nek2 in breast cancer and its possible mechanism. The mRNA expression of Nek2 in breast epithelial cells and eight breast cancer cell lines was detected by qRT-PCR. Silencing Nek2 was transfected into MDA-MB-231 and MCF7 cells to examine its roles in the viability, migration, invasion, cell colony, apoptosis and cell cycle of the breast cancer cells by performing CCK-8, wound scratch, Transwell, clone formation and flow cytometry assays, respectively. The expressions of related genes were detected using qRT-PCR and Western blot. MAPK pathway agonist IGF (insulin-like growth factor-1) was added into MDA-MB-231 and MCF7 cells and then cell viability was examined. Nek2 expression was frequently up-regulated in breast cancer cell lines, and silencing Nek2 significantly inhibited the viability, cell migration, invasion and clone formation, promoted cell apoptosis of MDA-MB-231 and MCF7 cells, and arrested cell cycle in G0/G1 phase. Furthermore, knocking down Nek2 decreased the mRNA and protein expressions of Bcl-2, CyclinB1 and CyclinD1, and increased Bax and p27 expressions. Moreover, knocking down Nek2 inhibited the phosphorylation of ERK and p38, and almost completely reversed the expression of p-ERK increased by IGF, but Nek2 knockdown had no obvious effect on p-p38. The inhibitory effect of Nek2 silencing on the cell viability was mainly realized by the inhibition of ERK/MAPK signaling. Nek2 plays an important role in the regulation of the progression of breast cancer in vitro probably through regulating the ERK/MAPK signaling.
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Kashyap D, Garg VK, Sandberg EN, Goel N, Bishayee A. Oncogenic and Tumor Suppressive Components of the Cell Cycle in Breast Cancer Progression and Prognosis. Pharmaceutics 2021; 13:pharmaceutics13040569. [PMID: 33920506 PMCID: PMC8072616 DOI: 10.3390/pharmaceutics13040569] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/03/2021] [Accepted: 04/13/2021] [Indexed: 02/08/2023] Open
Abstract
Cancer, a disease of inappropriate cell proliferation, is strongly interconnected with the cell cycle. All cancers consist of an abnormal accumulation of neoplastic cells, which are propagated toward uncontrolled cell division and proliferation in response to mitogenic signals. Mitogenic stimuli include genetic and epigenetic changes in cell cycle regulatory genes and other genes which regulate the cell cycle. This suggests that multiple, distinct pathways of genetic alterations lead to cancer development. Products of both oncogenes (including cyclin-dependent kinase (CDKs) and cyclins) and tumor suppressor genes (including cyclin-dependent kinase inhibitors) regulate cell cycle machinery and promote or suppress cell cycle progression, respectively. The identification of cyclins and CDKs help to explain and understand the molecular mechanisms of cell cycle machinery. During breast cancer tumorigenesis, cyclins A, B, C, D1, and E; cyclin-dependent kinase (CDKs); and CDK-inhibitor proteins p16, p21, p27, and p53 are known to play significant roles in cell cycle control and are tightly regulated in normal breast epithelial cells. Following mitogenic stimuli, these components are deregulated, which promotes neoplastic transformation of breast epithelial cells. Multiple studies implicate the roles of both types of components-oncogenic CDKs and cyclins, along with tumor-suppressing cyclin-dependent inhibitors-in breast cancer initiation and progression. Numerous clinical studies have confirmed that there is a prognostic significance for screening for these described components, regarding patient outcomes and their responses to therapy. The aim of this review article is to summarize the roles of oncogenic and tumor-suppressive components of the cell cycle in breast cancer progression and prognosis.
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Affiliation(s)
- Dharambir Kashyap
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, Punjab, India;
| | | | - Elise N. Sandberg
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA;
| | - Neelam Goel
- University Institute of Engineering and Technology, Panjab University, Chandigarh 160 014, Punjab, India
- Correspondence: (N.G.); or (A.B.)
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA;
- Correspondence: (N.G.); or (A.B.)
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Rajagopal P, Jayandharan GR, Krishnan UM. Evaluation of the Anticancer Activity of pH-Sensitive Polyketal Nanoparticles for Acute Myeloid Leukemia. Mol Pharm 2021; 18:2015-2031. [PMID: 33780253 DOI: 10.1021/acs.molpharmaceut.0c01243] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Polyketals are a class of acid-responsive polymers that have been relatively less explored for drug delivery applications compared to polyesters. The degradation of these polymers is accelerated in an acidic medium and does not result in acidic byproducts. Their biocompatibility depends on the diol used for the synthesis. The present work aims to synthesize, characterize, and fabricate nanospheres of an aliphatic polyketal for delivery of the nucleotide analogue cytarabine toward the treatment of acute myeloid leukemia (AML). The internalization mechanism of the nanospheres was probed, and its implication on the nuclear localization and escape from the endo-lysosomal compartments were studied. The drug-loaded polyketal nanoparticles reduced the cell viability to a greater extent compared with the free drug. The effect of the drug-loaded polyketal nanoparticles on the differential gene expression of leukemic cells was investigated for the first time to understand their therapeutic implications. It was found that treatment with drug-loaded polyketal nanoparticles downregulated AML-specific genes involved in cell proliferation and recurrence compared to the free drug. The protein expression studies were performed for selected genes obtained from gene expression analysis. Biodistribution studies showed that the poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK) nanoparticles exhibit prolonged circulation time. Overall, our results suggest that polyketal-based delivery of cytarabine represents a more effective alternative strategy for AML therapy.
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Affiliation(s)
- Pratheppa Rajagopal
- Centre for Nanotechnology & Advanced Biomaterials, SASTRA Deemed University Thanjavur 613401, India.,School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, India
| | - Giridhara R Jayandharan
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, Uttar Pradesh, India.,The Mehta Family Centre for Engineering In Medicine, Indian Institute of Technology, Kanpur 208016, Uttar Pradesh, India
| | - Uma Maheswari Krishnan
- Centre for Nanotechnology & Advanced Biomaterials, SASTRA Deemed University Thanjavur 613401, India.,School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, India.,School of Arts, Science & Humanities, SASTRA Deemed University, Thanjavur 613401, India
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Li Y, Guo F, Chen T, Zhang L, Qin Y. Anthraquinone derivative C10 inhibits proliferation and cell cycle progression in colon cancer cells via the Jak2/Stat3 signaling pathway. Toxicol Appl Pharmacol 2021; 418:115481. [PMID: 33722666 DOI: 10.1016/j.taap.2021.115481] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 02/27/2021] [Accepted: 03/03/2021] [Indexed: 12/19/2022]
Abstract
Since its discovery, anthraquinone has become very valuable as a lead compound in the development of anti-cancer drugs. Previously, we designed and synthesized a new type of amide anthraquinone derivative (1-nitro-2-acylanthraquinone glycine, C10) with good activity against colon cancer. However, its effect and the underlying mechanism are unclear. In this study, C10 significantly inhibited the proliferation of HCT116 and HT29 colon cancer cells by blocking the cell cycle at the G2/M phase. C10 also plays a role in cell cycle arrest by reducing the protein and gene expression levels of cyclin B1 and its downstream signaling molecule cyclin-dependent kinase (CDK1). In addition, molecular docking studies showed that C10 has high affinity for Jak2, the first target in the cell cycle-related Jak2/Stat3 signaling pathway. Furthermore, C10 downregulated the expression of Jak2/Stat3 signaling pathway-related signaling molecules proteins and genes, and up-regulated the expression of PIAS-3, the upstream signaling molecule of Stat3, thereby down-regulating Stat3 phosphorylation. C10 reversed the expression of Jak2/Stat3 signaling pathway-related molecules activated by IL-6. Overall, our results indicate for the first time that C10 induces cell cycle arrest and inhibits cell proliferation by inhibiting the Jak2/Stat3 signaling pathway. This study provides new insights into the potential role of Jak2/Stat3 in the regulating cell cycle-related signaling pathways that mediate the inhibitory effects of C10 on colon cancer cell proliferation.
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Affiliation(s)
- Yuying Li
- Key Laboratory of Chemical Biology and Molecular Engineering of the Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China.
| | - Fang Guo
- Key Laboratory of Chemical Biology and Molecular Engineering of the Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China
| | - Tinggui Chen
- Key Laboratory of Chemical Biology and Molecular Engineering of the Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China
| | - Liwei Zhang
- Key Laboratory of Chemical Biology and Molecular Engineering of the Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China
| | - Yu Qin
- Key Laboratory of Chemical Biology and Molecular Engineering of the Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China
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Sarkar D, Diermeier SD. Circular RNAs: Potential Applications as Therapeutic Targets and Biomarkers in Breast Cancer. Noncoding RNA 2021; 7:2. [PMID: 33466455 PMCID: PMC7838774 DOI: 10.3390/ncrna7010002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/26/2020] [Accepted: 12/31/2020] [Indexed: 12/24/2022] Open
Abstract
Circular RNAs (circRNAs) are a class of non-coding RNAs that form a covalently closed loop. A number of functions and mechanisms of action for circRNAs have been reported, including as miRNA sponge, exerting transcriptional and translational regulation, interacting with proteins, and coding for peptides. CircRNA dysregulation has also been implicated in many cancers, such as breast cancer. Their relatively high stability and presence in bodily fluids makes cancer-associated circRNAs promising candidates as a new biomarker. In this review, we summarize the research undertaken on circRNAs associated with breast cancer, discuss circRNAs as biomarkers, and present circRNA-based therapeutic approaches.
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Affiliation(s)
| | - Sarah D. Diermeier
- Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand;
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Chong ZX, Yeap SK, Ho WY. Roles of circulating microRNA(s) in human breast cancer. Arch Biochem Biophys 2020; 695:108583. [DOI: 10.1016/j.abb.2020.108583] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 09/05/2020] [Accepted: 09/08/2020] [Indexed: 12/14/2022]
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Venetis K, Invernizzi M, Sajjadi E, Curigliano G, Fusco N. Cellular immunotherapy in breast cancer: The quest for consistent biomarkers. Cancer Treat Rev 2020; 90:102089. [PMID: 32889360 DOI: 10.1016/j.ctrv.2020.102089] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most common malignancy in women worldwide, with a relatively high proportion of patients experiencing resistance to standard treatments. Cellular immunotherapy (CI), which is based on the extraction, modification, and re-infusion of the patient's immune cells, is showing promising results in these patients. Among CI possible approaches, adoptive cell therapy (ACT) and dendritic cell (DC) vaccination are the most comprehensively explored in both primary/translational research studies and clinical trials. ACT may include the use of tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR)-, or chimeric antigen receptor (CAR)-engineered T-cells. There are indications suggesting that a biomarker-based approach might be beneficial in effectively selecting breast cancer patients for CI. Here, we sought to provide the current knowledge of CI in breast cancer, focusing on candidate biomarkers, ongoing clinical trials, limitations, and immediate future perspectives.
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Affiliation(s)
- Konstantinos Venetis
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; Ph.D. Program in Translational Medicine, University of Milan, 20133 Milan, Italy; Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy
| | - Marco Invernizzi
- Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy
| | - Elham Sajjadi
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy
| | - Giuseppe Curigliano
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy.
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy.
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Saggam A, Tillu G, Dixit S, Chavan-Gautam P, Borse S, Joshi K, Patwardhan B. Withania somnifera (L.) Dunal: A potential therapeutic adjuvant in cancer. JOURNAL OF ETHNOPHARMACOLOGY 2020; 255:112759. [PMID: 32173425 DOI: 10.1016/j.jep.2020.112759] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/05/2020] [Accepted: 03/08/2020] [Indexed: 05/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Withania somnifera (L.) Dunal (WS) is one of the moststudied Rasayana botanicals used in Ayurveda practice for its immunomodulatory, anti-aging, adaptogenic, and rejuvenating effects. The botanical is being used for various clinical indications, including cancer. Several studies exploring molecular mechanisms of WS suggest its possible role in improving clinical outcomes in cancer management. Therefore, research on WS may offer new insights in rational development of therapeutic adjuvants for cancer. AIM OF THIS REVIEW The review aims at providing a detailed analysis of in silico, in vitro, in vivo, and clinical studies related to WS and cancer. It suggests possible role of WS in regulating molecular mechanisms associated with carcinogenesis. The review discusses potential of WS in cancer management in terms of cancer prevention, anti-cancer activity, and enhancing efficacy of cancer therapeutics. MATERIAL AND METHODS The present narrative review offers a critical analysis of published literature on WS studies in cancer. The reported studies were analysed in the context of pathophysiology of cancer, commonly referred as 'cancer hallmarks'. The review attempts to bridge Ayurveda knowledge with biological insights into molecular mechanisms of cancer. RESULTS Critical analysisof the published literature suggests an anti-cancer potential of WS with a key role in cancer prevention. The possible mechanisms for these effects are associated with the modulation of apoptotic, proliferative, and metastatic markers in cancer. WS can attenuate inflammatory responses and enzymes involved in invasion and metastatic progression of cancer.The properties of WS are likely to be mediated through withanolides, which may activate tumor suppressor proteins to restrict proliferation of cancer cells. Withanolides also regulate the genomic instability, and energy metabolism of cancer cells. The reported studies indicate the need for deeper understanding of molecular mechanisms of WS in inhibiting angiogenesis and promoting immunosurveillance. Additionally, WS can augment efficacy and safety of cancer therapeutics. CONCLUSION The experimentally-supported evidence of immunomodulatory, anti-cancer, adaptogenic, and regenerative attributes of WS suggest its therapeutic adjuvant potential in cancer management. The adjuvant properties of withanolides can modulate multidrug resistance and reverse chemotherapy-induced myelosuppression. These mechanisms need to be further explored in systematically designed translational and clinical studies that will pave the way for integration of WS as a therapeutic adjuvant in cancer management.
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Affiliation(s)
- Akash Saggam
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India
| | - Girish Tillu
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India
| | | | - Preeti Chavan-Gautam
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India
| | - Swapnil Borse
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India
| | - Kalpana Joshi
- Department of Biotechnology, Sinhgad College of Engineering, Pune, India
| | - Bhushan Patwardhan
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India.
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Karaosmanoğlu O. P38-β/SAPK-inhibiting and apoptosis-inducing activities of (E)-4-chloro-2-((3-ethoxy-2-hydroxybenzylidene) amino)phenol. Hum Exp Toxicol 2020; 39:1374-1389. [PMID: 32394730 DOI: 10.1177/0960327120924112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The present study has three purposes; first evaluating cytotoxicity of (E)-4-chloro-2-((3-ethoxy-2-hydroxybenzylidene)amino)phenol (ACES), second deciphering ACES-mediated cellular death mechanism, and third estimating ACES-mediated alterations in the expressions of mitogen-activated protein kinase (MAPK) pathway-related genes. Neutral red uptake assay, cell cycle analysis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) measurements, caspase 3/7 and 9 activations, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were implemented. IC50 values of ACES-treated five cells were around 4-6 µg/mL. However, Caco-2 and Huh-7 cells were found to be twofold resistant and fivefold sensitive with IC50 values of 11 µg/mL and 0.93 µg/mL, respectively. In this study, it was initially reported that ACES exhibits selective cytotoxicity to Huh-7 cells. In addition, ACES induced apoptosis by nuclear fragmentation, MMP disruption, and intracellular ROS elevation in MCF-7 cells. qRT-PCR experiment indicated the expressions of 30 genes including ATF2, CREB1, MYC, NFATC4 (NFAT3), CCNA1, CCNB1, CCND2, CDK2, CDKN1A (p21CIP1), CDKN1C (p57KIP2), CDKN2A (p16INK4a), CDKN2B (p15INK4b), DLK1, NRAS, CDC42, PAK1, MAP4K1 (HPK1), MAP3K3 (MEKK3), MAP2K3 (MEK3), MAP2K6 (MEK6), MOS, MAPK1 (ERK2), MAPK8 (JNK1), MAPK10 (JNK3), MAPK11 (p38-β), LAMTOR3 (MP1), MAPK8IP2 (JIP-1), PRDX6 (AOP2), COL1A1, and HSPA5 (Grp78) were downregulated at least 1.5-fold. Moreover, ACES effectively inhibited expressions of genes that code for elements of p38-β/stress-activated protein kinase (SAPK) pathway. ACES has the potential to be used for the reversal of trastuzumab resistance in breast cancer patients by inhibiting p38/SAPK pathway in MCF-7 cells. Therefore, with the selective cytotoxic, apoptosis-inducing, and p38-β/SAPK-inhibiting activities, ACES can be utilized for developing a novel anticancer drug.
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Affiliation(s)
- O Karaosmanoğlu
- Department of Biology, Kamil Özdağ Faculty of Science, Karamanoğlu Mehmetbey University, Karaman, Turkey
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Al‐Zeheimi N, Adham SA. Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP-1 and HER2 expression and converted MCF7 breast cancer subtype. Br J Pharmacol 2020; 177:2024-2041. [PMID: 31883395 PMCID: PMC7161552 DOI: 10.1111/bph.14966] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 11/05/2019] [Accepted: 11/19/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE Patients with locally advanced breast cancer usually receive third-generation neoadjuvant chemotherapy (NAC). Although NAC treatment improved the overall survival, patients' response varies, some acquire resistance and others exhibit a conversion in their breast cancer molecular subtype. We aimed to identify the molecular changes involved in NAC resistance attempting to find new therapeutic targets in different breast cancer subtypes. EXPERIMENTAL APPROACH We modelled NAC treatments used in clinical practice and generated resistant cell lines in vitro. The resistant cells were generated by consecutive treatment with four cycles of doxorubicin (adriamycin)/cyclophosphamide (4xAC) followed by an additional four cycles of paclitaxel (4xAC + 4xPAC). KEY RESULTS Our data revealed distinct mechanisms of resistance depending on breast cancer subtype and drugs used. MDA-MB-231 cells resistant to 4xAC + 4xPAC activated neuropilin-1/TNC/integrin β3/FAK/NF-κBp65 axis and displayed a decrease in breast cancer resistance protein (BCRP/ABCB2). However, MCF7 cells resistant to 4xAC treatments induced HER2 expression, which converted MCF7 subtype from luminal A to luminal B HER2 type, up-regulated neuropilin-1, oestrogen receptor-α, and EGFR, and activated PI3K/Akt/NF-κBp65 axis. However, MCF7 cells resistant to 4xAC + 4xPAC exhibited down-regulation of the survival axis and up-regulated BCRP/ABCG2. Co-immunoprecipitation demonstrated a novel interaction between HER2 and neuropilin-1 driving the resistance features. CONCLUSIONS AND IMPLICATIONS The concurrent increase in neuropilin-1 and HER2 upon resistance and the inverse relationship between neuropilin-1 and BCRP/ABCG2 suggest that, in addition to HER2, neuropilin-1 status should be assessed in patients undergoing NAC, and as a potential drug target for refractory breast cancer.
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Affiliation(s)
- Noura Al‐Zeheimi
- Department of Biology, College of ScienceSultan Qaboos UniversityMuscatOman
| | - Sirin A. Adham
- Department of Biology, College of ScienceSultan Qaboos UniversityMuscatOman
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Moon SJ, Kim JH, Kong SH, Shin CS. Protein Expression of Cyclin B1, Transferrin Receptor, and Fibronectin Is Correlated with the Prognosis of Adrenal Cortical Carcinoma. Endocrinol Metab (Seoul) 2020; 35:132-141. [PMID: 32207273 PMCID: PMC7090291 DOI: 10.3803/enm.2020.35.1.132] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/25/2019] [Accepted: 01/13/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Adrenal cortical carcinoma (ACC) is a rare cancer with a variable prognosis. Several prognostic factors of ACC have been previously reported, but a proteomic analysis has not yet been performed. This study aimed to investigate prognostic biomarkers for ACC using a proteomic approach. METHODS We used reverse-phase protein array data from The Cancer Proteome Atlas, and identified differentially expressed proteins in metastatic ACCs. Multivariate Cox regression analysis adjusted by age and staging was used for survival analysis, and the C-index and category-free net reclassification improvement (cfNRI) were utilized to evaluate additive prognostic value. RESULTS In 46 patients with ACC, cyclin B1, transferrin receptor (TfR1), and fibronectin were significantly overexpressed in patients with distant metastasis. In multivariate models, high expression of cyclin B1 and TfR1 was significantly associated with mortality (hazard ratio [HR], 6.13; 95% confidence interval [CI], 1.02 to 36.7; and HR, 6.59; 95% CI, 1.14 to 38.2; respectively), whereas high fibronectin expression was not (HR, 3.92; 95% CI, 0.75 to 20.4). Combinations of high cyclin B1/high TfR1, high cyclin B1/high fibronectin, and high TfR1/high fibronectin were strongly associated with mortality ([HR, 13.72; 95% CI, 1.89 to 99.66], [HR, 9.22; 95% CI, 1.34 to 63.55], and [HR, 18.59; 95% CI, 2.54 to 135.88], respectively). In reclassification analyses, cyclin B1, TfR1, fibronectin, and combinations thereof improved the prognostic performance (C-index, 0.78 to 0.82-0.86; cfNRI, all P values <0.05). CONCLUSION In ACC patients, the overexpression of cyclin B1, TfR1, and fibronectin and combinations thereof were associated with poor prognosis.
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Affiliation(s)
- Sun Joon Moon
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Hee Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University College of Medicine, Seoul, Korea.
| | - Sung Hye Kong
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Chan Soo Shin
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
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Paganin-Gioanni A, Rols MP, Teissié J, Golzio M. Cyclin B1 knockdown mediated by clinically approved pulsed electric fields siRNA delivery induces tumor regression in murine melanoma. Int J Pharm 2020; 573:118732. [DOI: 10.1016/j.ijpharm.2019.118732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 09/18/2019] [Accepted: 09/23/2019] [Indexed: 02/06/2023]
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Wang C, Wang X, Liu J, Huang Z, Li C, Liu Y, Sang X, Yang L, Wang S, Su Y, Liu C, Liu Y, Wang Z. Embryonic stem cell microenvironment suppresses the malignancy of cutaneous melanoma cells by down-regulating PI3K/AKT pathway. Cancer Med 2019; 8:4265-4277. [PMID: 31173492 PMCID: PMC6675703 DOI: 10.1002/cam4.2207] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 03/31/2019] [Accepted: 04/12/2019] [Indexed: 12/18/2022] Open
Abstract
Malignant cancer cells engage in a dynamic reciprocity with the tumor microenvironment (TME) that promotes tumor growth, development, and resistance to therapy. Early embryonic blastocyst microenvironments can reverse the tumorigenic phenotype of malignant cancer cells via ameliorating of TME. It is potential to apply embryonic stem cell (ESC) microenvironment to suppress the malignant behaviors of cancer cells. This study aimed to investigate a better method and the mechanism of ESC microenvironment supplied by ESCs on suppressing the malignancy of cutaneous melanoma cells. Cutaneous melanoma cell line A2058 were cultured and divided into four groups: (a) A2058-only (Control); (b) A2058 and ESCs continuously co-cultured (Group One); (c) A2058 co-cultured with daily refreshed ESCs (Group two); (d) Group one with VO-Ohpic, inhibitor of PTEN (VO-Ohpic Group). The results showed that, compared to control group, A2058 cells in group one exhibited decreased cellular proliferation, migration, invasiveness and vasculogenic mimicry concomitant with an increase in cell apoptosis, accompanied by down-regulation of PI3K/AKT pathway. Besides, the above mentioned anti-tumor effects on A2058 cells were significantly enhanced in group two but statistically weakened after administration of VO-Ohpic compared to group one. We demonstrate that ESC microenvironment reduces the malignancy of A2058 by down-regulating PI3K/AKT pathway. Notably, such anti-tumor effects can be enhanced by appropriately increasing the quality and quantity of ESCs in co-culture system. Our results suggest that ESC microenvironment could be an effective and safe approach to treating cancer.
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Affiliation(s)
- Chenjie Wang
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Xiaoran Wang
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Jiahui Liu
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Zheqian Huang
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Chaoyang Li
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Ying Liu
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Xuan Sang
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Liu Yang
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Shoubi Wang
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Yaru Su
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Chengxiu Liu
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Yizhi Liu
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
| | - Zhichong Wang
- State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat‐sen UniversityGuangzhou 510060China
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Li J, Dang N, Martinez-Lopez N, Jowsey PA, Huang D, Lightowlers RN, Gao F, Huang JY. M2I-1 disrupts the in vivo interaction between CDC20 and MAD2 and increases the sensitivities of cancer cell lines to anti-mitotic drugs via MCL-1s. Cell Div 2019; 14:5. [PMID: 31249607 PMCID: PMC6570884 DOI: 10.1186/s13008-019-0049-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 06/05/2019] [Indexed: 01/04/2023] Open
Abstract
Background Drugs such as taxanes, epothilones, and vinca alkaloids are widely used in the treatment of breast, ovarian, and lung cancers but come with major side effects such as neuropathy and loss of neutrophils and as single agents have a lack of efficacy. M2I-1 (MAD2 inhibitor-1) has been shown to disrupt the CDC20-MAD2 interaction, and consequently, the assembly of the mitotic checkpoint complex (MCC). Results We report here that M2I-1 can significantly increase the sensitivity of several cancer cell lines to anti-mitotic drugs, with cell death occurring after a prolonged mitotic arrest. In the presence of nocodazole or taxol combined with M2I-1 cell death is triggered by the premature degradation of Cyclin B1, the perturbation of the microtubule network, and an increase in the level of the pro-apoptotic protein MCL-1s combined with a marginal increase in the level of NOXA. The elevated level of MCL-1s and the marginally increased NOXA antagonized the increased level of MCL-1, a pro-survival protein of the Bcl-2 family. Conclusion Our results provide some important molecular mechanisms for understanding the relationship between the mitotic checkpoint and programmed cell death and demonstrate that M2I-1 exhibits antitumor activity in the presence of current anti-mitotic drugs such as taxol and nocodazole and has the potential to be developed as an anticancer agent.
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Affiliation(s)
- Jianquan Li
- 1Institute for Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK.,3Present Address: Intensive Care Unit, Guizhou Provincial People's Hospital, Guiyang, People's Republic of China
| | - Nanmao Dang
- 1Institute for Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
| | - Nuria Martinez-Lopez
- 1Institute for Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
| | - Paul A Jowsey
- 2Medical Toxicology Centre, Institute of Cellular Medicine, NIHR Health Protection Research Unit, Newcastle University, Claremont Place, Newcastle upon Tyne, NE1 4AA UK
| | - Dong Huang
- 1Institute for Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK.,4Present Address: Department of Pediatric Critical Care Medicine, Guizhou Provincial People's Hospital, Guiyang, People's Republic of China
| | - Robert N Lightowlers
- 1Institute for Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
| | - Fei Gao
- 1Institute for Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
| | - Jun-Yong Huang
- 1Institute for Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
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Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells. Cancers (Basel) 2019; 11:cancers11050711. [PMID: 31126091 PMCID: PMC6563099 DOI: 10.3390/cancers11050711] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 05/15/2019] [Accepted: 05/16/2019] [Indexed: 12/31/2022] Open
Abstract
Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC50 < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use.
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Long J, Bai Y, Yang X, Lin J, Yang X, Wang D, He L, Zheng Y, Zhao H. Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for hepatocellular carcinoma. Cancer Cell Int 2019; 19:90. [PMID: 31007608 PMCID: PMC6458652 DOI: 10.1186/s12935-019-0817-y] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 04/05/2019] [Indexed: 12/15/2022] Open
Abstract
Background Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression; therefore, lncRNAs are considered a major part of the competitive endogenous RNA (ceRNA) network and have attracted growing attention. The present study explored the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in hepatocellular carcinoma (HCC) and their potential impact on HCC patient prognosis. Methods In this study, we systematically studied the expression profiles and prognostic value of lncRNA, miRNA, and mRNA from a total of 838 HCC patients from five HCC cohorts (TCGA, GSE54236, GSE76427, GSE64041 and GSE14520). The TCGA, GSE54236 and GSE76427 HCC cohorts were utilized to establish a prognosis-related network of dysregulated ceRNAs by bioinformatics methods. The GSE64041 and GSE14520 HCC cohorts were utilized to verify the expression of candidate genes. Results In total, 721 lncRNAs, 73 miRNAs, and 1563 mRNAs were aberrantly expressed in HCC samples. A ceRNA network including 26 lncRNAs, four miRNAs, and six mRNAs specific to HCC was established. The survival analysis showed that four lncRNAs (MYCNOS, DLX6-AS1, LINC00221, and CRNDE) and two mRNAs (CCNB1 and SHCBP1) were prognostic biomarkers for patients with HCC in both the TCGA and GEO databases. Conclusion The proposed ceRNA network may help elucidate the regulatory mechanism by which lncRNAs function as ceRNAs and contribute to the pathogenesis of HCC. Importantly, the candidate lncRNAs, miRNAs, and mRNAs involved in the ceRNA network can be further evaluated as potential therapeutic targets and prognostic biomarkers for HCC. Electronic supplementary material The online version of this article (10.1186/s12935-019-0817-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Junyu Long
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yi Bai
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaobo Yang
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jianzhen Lin
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xu Yang
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dongxu Wang
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Li He
- 2Department of Medicine, University of Alabama at Birmingham, Birmingham, AL USA
| | - Yongchang Zheng
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Farshadi E, Yan J, Leclere P, Goldbeter A, Chaves I, van der Horst GTJ. The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1. Cell Cycle 2019; 18:16-33. [PMID: 30558467 PMCID: PMC6343743 DOI: 10.1080/15384101.2018.1558638] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 11/23/2018] [Accepted: 11/26/2018] [Indexed: 01/09/2023] Open
Abstract
We previously identified a tight bidirectional phase coupling between the circadian clock and the cell cycle. To understand the role of the CLOCK/BMAL1 complex, representing the main positive regulator of the circadian oscillator, we knocked down Bmal1 or Clock in NIH3T33C mouse fibroblasts (carrying fluorescent reporters for clock and cell cycle phase) and analyzed timing of cell division in individual cells and cell populations. Inactivation of Bmal1 resulted in a loss of circadian rhythmicity and a lengthening of the cell cycle, originating from delayed G2/M transition. Subsequent molecular analysis revealed reduced levels of Cyclin B1, an important G2/M regulator, upon suppression of Bmal1 gene expression. In complete agreement with these experimental observations, simulation of Bmal1 knockdown in a computational model for coupled mammalian circadian clock and cell cycle oscillators (now incorporating Cyclin B1 induction by BMAL1) revealed a lengthening of the cell cycle. Similar data were obtained upon knockdown of Clock gene expression. In conclusion, the CLOCK/BMAL1 complex controls cell cycle progression at the level of G2/M transition through regulation of Cyclin B1 expression.
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Affiliation(s)
- Elham Farshadi
- Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jie Yan
- Unit of Theoretical Chronobiology, Faculty of Sciences, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Pierre Leclere
- Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Albert Goldbeter
- Unit of Theoretical Chronobiology, Faculty of Sciences, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Inês Chaves
- Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
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Liu W, Ouyang S, Zhou Z, Wang M, Wang T, Qi Y, Zhao C, Chen K, Dai L. Identification of genes associated with cancer progression and prognosis in lung adenocarcinoma: Analyses based on microarray from Oncomine and The Cancer Genome Atlas databases. Mol Genet Genomic Med 2018; 7:e00528. [PMID: 30556321 PMCID: PMC6393652 DOI: 10.1002/mgg3.528] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 10/28/2018] [Accepted: 11/07/2018] [Indexed: 12/27/2022] Open
Abstract
Background Lung adenocarcinoma (LUAD) accounts for approximately 40% of all lung cancer patients. There is an urgent need to understand the mechanisms of cancer progression in LUAD and to identify useful biomarkers to predict prognosis. Methods In this study, Oncomine database was used to identify potential genes contributed to cancer progression. Bioinformatics analysis including pathway enrichment and text mining was used to explain the potential roles of identified genes in LUAD. The Cancer Genome Atlas database was used to analyze the association of gene expression with survival result. Results Our results indicated that 80 genes were significantly dysregulated in LUAD according to four microarrays covering 356 cases of LUAD and 164 cases of normal lung tissues. Twenty genes were consistently and stably dysregulated by more than twofold. Ten of 20 genes had a relationship with overall survival or disease‐free survival in a cohort of 516 LUAD patients, and 19 genes were associated with tumor stage, gender, age, lymph node, or smoking. Low expression of AGER and high expression of CCNB1 were specifically associated with poor survival. Conclusion Our findings implicate AGER and CCNB1 might be potential biomarkers for diagnosis and prognosis targets for LUAD.
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Affiliation(s)
- Wei Liu
- Department of Gastroenterology in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Songyun Ouyang
- Department of Respiratory and Sleep Medicine in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Zhigang Zhou
- Department of Radiology in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Meng Wang
- Department of Radiology in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Tingting Wang
- Department of Medical Examination in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Yu Qi
- Department of Thoracic Surgery in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Chunling Zhao
- Department of Respiratory and Sleep Medicine in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Kuisheng Chen
- Department of Pathology in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Liping Dai
- Department of Respiratory and Sleep Medicine in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
- Department of Tumor Research in the Institute of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
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Rios-Fuller TJ, Ortiz-Soto G, Lacourt-Ventura M, Maldonado-Martinez G, Cubano LA, Schneider RJ, Martinez-Montemayor MM. Ganoderma lucidum extract (GLE) impairs breast cancer stem cells by targeting the STAT3 pathway. Oncotarget 2018; 9:35907-35921. [PMID: 30542507 PMCID: PMC6267592 DOI: 10.18632/oncotarget.26294] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 10/24/2018] [Indexed: 12/11/2022] Open
Abstract
The aggressive nature of triple negative breast cancer (TNBC) may be explained in part by the presence of breast cancer stem cells (BCSCs), a subpopulation of cells, which are involved in tumor initiation, progression, metastasis, recurrence, and therapy resistance. The signal transducer and activator of transcription 3 (STAT3) pathway participates in the development and progression of BCSCs, but its role in TNBC remains unclear. Here, we report that Ganoderma lucidum extract (GLE), a medicinal mushroom with anticancer activity, acts on BCSCs in vitro and in TNBC pre-clinical animal tumor models by downregulating the STAT3 pathway. We show that GLE significantly reduces TNBC cell viability, and down-regulates total and phosphorylated STAT3 expression. This is consistent with the reduction of OCT4, NANOG and SOX2 expression, reduction in the BCSC population by loss of the ALDH1 and CD44+/CD24– population, the deformation of mammospheres, and the strong reduction in animal tumor volume and tumor weight. Analysis of the BCSC compartment in tumors revealed that GLE decreases the STAT3 pathway and the expression of OCT4, NANOG, and SOX2 in BCSCs. These findings demonstrate that the anti-cancer activity of GLE targets BCSCs of TNBC through the downregulation of the STAT3 pathway.
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Affiliation(s)
- Tiffany J Rios-Fuller
- Universidad Central del Caribe-School of Medicine, Bayamon, Puerto Rico, United States of America
| | - Gabriela Ortiz-Soto
- Universidad Central del Caribe-School of Medicine, Bayamon, Puerto Rico, United States of America
| | - Mercedes Lacourt-Ventura
- Universidad Central del Caribe-School of Medicine, Bayamon, Puerto Rico, United States of America
| | | | - Luis A Cubano
- Universidad Central del Caribe-School of Medicine, Bayamon, Puerto Rico, United States of America
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An BC, Choi YD, Oh IJ, Kim JH, Park JI, Lee SW. GPx3-mediated redox signaling arrests the cell cycle and acts as a tumor suppressor in lung cancer cell lines. PLoS One 2018; 13:e0204170. [PMID: 30260967 PMCID: PMC6160013 DOI: 10.1371/journal.pone.0204170] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 09/03/2018] [Indexed: 12/15/2022] Open
Abstract
Glutathione peroxidase 3 (GPx3), a major scavenger of reactive oxygen species (ROS) in plasma, acts as a redox signal modulator. However, the mechanism underlying GPx3-mediated suppression of cancer cell growth is unclear. The aim of this study was to identify these mechanisms with respect to lung cancer. To enhance the redox modulating properties of GPx3, lung cancer cells were subjected to serum starvation for 12 h, resulting in ROS generation in the absence of oxidant treatment. We then investigated whether suppression of tumorigenesis under conditions of oxidative stress was dependent on GPx3. The results showed that GPx3 effectively suppressed proliferation, migration, and invasion of lung cancer cells under oxidative stress. In addition, GPx3 expression led to a significant reduction in ROS production by cancer cells and induced G2/M phase arrest. We also found that inactivation of cyclin B1 significantly suppressed by nuclear factor-κB(NF-κB) inactivation in lung cancer cells was dependent on GPx3 expression. To further elucidate the mechanism(s) underlying GPx3-medited suppression of tumor proliferation, we next examined the effect of GPx3-mediated redox signaling on the ROS-MKP3-extracellular signal-regulated kinase (Erk)-NF-κB-cyclin B1 pathway and found that GPx3 strongly suppressed activation of the Erk-NF-κB-cyclin B1 signaling cascade by protecting MKP3 (an Erk-specific phosphatase) from the effects of ROS. Thus, this study demonstrates for the first time that the GPx3 suppresses proliferation of lung cancer cells by modulating redox-mediated signals.
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Affiliation(s)
- Byung Chull An
- Department of Anatomy, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea
| | - Yoo-Duk Choi
- Department of Pathology, Chonnam National University Hospital, Dong-gu, Gwangju, Korea
| | - In-Jae Oh
- Department of Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea
| | - Ju Han Kim
- Department of Internal Medicine, Chonnam National University Hospital, Dong-gu, Gwangju, Korea
| | - Jae-Il Park
- Animal Facility of Aging Science, Korea Basic Science Institute, Buk-gu, Gwangju, Korea
| | - Seung-won Lee
- Department of Anatomy, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea
- * E-mail:
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Amawi H, Hussein NA, Ashby CR, Alnafisah R, Sanglard LM, Manivannan E, Karthikeyan C, Trivedi P, Eisenmann KM, Robey RW, Tiwari AK. Bax/Tubulin/Epithelial-Mesenchymal Pathways Determine the Efficacy of Silybin Analog HM015k in Colorectal Cancer Cell Growth and Metastasis. Front Pharmacol 2018; 9:520. [PMID: 29875662 PMCID: PMC5974752 DOI: 10.3389/fphar.2018.00520] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 04/30/2018] [Indexed: 12/31/2022] Open
Abstract
The inhibition of apoptosis, disruption of cellular microtubule dynamics, and over-activation of the epithelial mesenchymal transition (EMT), are involved in the progression, metastasis, and resistance of colorectal cancer (CRC) to chemotherapy. Therefore, the design of a molecule that can target these pathways could be an effective strategy to reverse CRC progression and metastasis. In this study, twelve novel silybin derivatives, HM015a-HM015k (15a−15k) and compound 17, were screened for cytotoxicity in CRC cell lines. Compounds HM015j and HM015k (15k and 15j) significantly decreased cell proliferation, inhibited colony formation, and produced cell cycle arrest in CRC cells. Furthermore, 15k significantly induced the formation of reactive oxygen species and apoptosis. It induced the cleavage of the intrinsic apoptotic protein (Bax p21) to its more efficacious fragment, p18. Compound 15k also inhibited tubulin expression and disrupted its structure. Compound 15k significantly decreased metastatic LOVO cell migration and invasion. Furthermore, 15k reversed mesenchymal morphology in HCT116 and LOVO cells. Additionally, 15k significantly inhibited the expression of the mesenchymal marker N-cadherin and upregulated the expression of the epithelial marker, E-cadherin. Compound 15k inhibited the expression of key proteins known to induce EMT (i.e., DVL3, β-catenin, c-Myc) and upregulated the anti-metastatic protein, cyclin B1. Overall, in vitro, 15k significantly inhibited CRC progression and metastasis by inhibiting apoptosis, tubulin activity and the EMT pathways. Overall, these data suggest that compound 15k should be tested in vivo in a CRC animal model for further development.
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Affiliation(s)
- Haneen Amawi
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
| | - Noor A Hussein
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
| | - Charles R Ashby
- Pharmaceutical Sciences, College of Pharmacy, St. John's University, Queens, NY, United States
| | - Rawan Alnafisah
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
| | - Leticia M Sanglard
- Biomedical Sciences, College of Veterinary Medicine, Tuskegee University, Tuskegee, AL, United States
| | | | | | - Piyush Trivedi
- School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India
| | - Kathryn M Eisenmann
- Department of Cancer Biology, University of Toledo, Toledo, OH, United States
| | - Robert W Robey
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Amit K Tiwari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
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Patwardhan D, Mani S, Passemard S, Gressens P, El Ghouzzi V. STIL balancing primary microcephaly and cancer. Cell Death Dis 2018; 9:65. [PMID: 29352115 PMCID: PMC5833631 DOI: 10.1038/s41419-017-0101-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/04/2017] [Accepted: 10/23/2017] [Indexed: 11/25/2022]
Abstract
Cell division and differentiation are two fundamental physiological processes that need to be tightly balanced to achieve harmonious development of an organ or a tissue without jeopardizing its homeostasis. The role played by the centriolar protein STIL is highly illustrative of this balance at different stages of life as deregulation of the human STIL gene expression has been associated with either insufficient brain development (primary microcephaly) or cancer, two conditions resulting from perturbations in cell cycle and chromosomal segregation. This review describes the recent advances on STIL functions in the control of centriole duplication and mitotic spindle integrity, and discusses how pathological perturbations of its finely tuned expression result in chromosomal instability in both embryonic and postnatal situations, highlighting the concept that common key factors are involved in developmental steps and tissue homeostasis.
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Affiliation(s)
- Dhruti Patwardhan
- PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Centre for Neuroscience, IISC Bangalore, India
| | - Shyamala Mani
- PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Curadev Pharma, B 87, Sector 83, Noida, UP, 201305,, India
| | - Sandrine Passemard
- PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- AP HP, Hôpital Robert Debré, Service de Génétique Clinique, Paris, France
| | - Pierre Gressens
- PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, UK
| | - Vincent El Ghouzzi
- PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
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