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Liu T, Yan M, Liu F, Ma Y, Fang Y. The role of
p53‐MDM2
signaling in missed abortion and possible pathogenesis. J Obstet Gynaecol Res 2022; 48:2686-2696. [DOI: 10.1111/jog.15385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/03/2022] [Accepted: 07/21/2022] [Indexed: 11/27/2022]
Affiliation(s)
- Ting Liu
- Department of Gynecology and Obstetrics Qilu Hospital of Shandong University Jinan Shandong PR China
| | - Min Yan
- Yidu Central Hospital of Weifang Shandong PR China
| | - Fen Liu
- Department of Gynecology and Obstetrics Qilu Hospital of Shandong University Jinan Shandong PR China
| | - Yuyan Ma
- Department of Gynecology and Obstetrics Qilu Hospital of Shandong University Jinan Shandong PR China
| | - Yan Fang
- Department of Gynecology and Obstetrics Qilu Hospital of Shandong University Jinan Shandong PR China
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2
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Yu Z, Cao W, Han C, Wang Z, Qiu Y, Wang J, Wei M, Wang J, Zhang S, Liu S, Mo S, Chen J. Biomimetic Metal-Organic Framework Nanoparticles for Synergistic Combining of SDT-Chemotherapy Induce Pyroptosis in Gastric Cancer. Front Bioeng Biotechnol 2022; 10:796820. [PMID: 35265591 PMCID: PMC8899015 DOI: 10.3389/fbioe.2022.796820] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 01/07/2022] [Indexed: 01/08/2023] Open
Abstract
In recent years, sonodynamic therapy (SDT) has been widely developed for cancer research as a promising non-invasive therapeutic strategy. Here, we synthesized zeolitic imidazole frameworks-8 (ZIF-8) and utilized its properties to encapsulate hydrophobic Chlorin e6 (Ce6) and hydrophilic tirapazamine (TPZ) for a synergistic sonodynamic chemotherapy, which was also accompanied by the modification of cytomembrane of gastric cancer (GC) cells. Thus, we enabled the biomimetic property to achieve targeted delivery. Ce6-mediated SDT, in combination with ultrasound irradiation, could target the release of reactive oxygen species (ROS) to aggravate further hypoxia and activate TPZ. Combining these effects could induce the pyroptosis of GC cells and play the anti-tumor function, which could provide a potential therapeutic method for cancer therapy.
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Affiliation(s)
- Zhu Yu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
| | - Wenlong Cao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhen Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
| | - Yue Qiu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
| | - Jiancheng Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
| | - Mengda Wei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
| | - Junfu Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
| | - Siwen Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
| | - Senfeng Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shutian Mo
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
| | - Junqiang Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, China
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Klaeske K, Dix M, Adams V, Jawad K, Eifert S, Etz C, Saeed D, Borger MA, Dieterlen MT. Differential Regulation of Myocardial E3 Ligases and Deubiquitinases in Ischemic Heart Failure. Life (Basel) 2021; 11:life11121430. [PMID: 34947961 PMCID: PMC8708923 DOI: 10.3390/life11121430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 11/16/2022] Open
Abstract
The pathological changes of ubiquitination and deubiquitination following myocardial infarction (MI) and chronic heart failure (CHF) have been sparsely examined. We investigated the expression of muscle-specific E3 ubiquitin ligases and deubiquitinases in MI and CHF. Therefore, mice were assigned to coronary artery ligation for 3 days or 10 weeks as well as for sham operation (each n = 10). Expression of E3 ligases (MAFBX, MURF1, CHIP, ITCH, MDM2) and deubiquitinases (A20, CYLD, UCH-L1, USP14, USP19) was determined. After MI and in CHF, the mRNA expression of MURF1, CHIP and MDM2 (all p < 0.05) was decreased. Protein expression analyses revealed that ITCH expression decreased in CHF (p = 0.01), whereas MDM2 expression increased in MI (p = 0.02) and decreased in CHF (p = 0.02). Except for USP19 mRNA expression that decreased at 3 days and 10 weeks (both p < 0.01), the expression of other deubiquitinases remained unaffected after MI and CHF. The expression of myocardial E3 ligases is differentially regulated following MI, raising the question of whether an upstream regulation exists that is activated by MI for tissue protection or whether the downregulation of E3 ligases enables myocardial hypertrophy following MI.
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Affiliation(s)
- Kristin Klaeske
- Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany; (M.D.); (K.J.); (S.E.); (C.E.); (D.S.); (M.A.B.); (M.-T.D.)
- Correspondence: ; Tel.: +49-341865251079; Fax: +49-3418651452
| | - Maria Dix
- Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany; (M.D.); (K.J.); (S.E.); (C.E.); (D.S.); (M.A.B.); (M.-T.D.)
| | - Volker Adams
- Laboratory of Molecular and Experimental Cardiology, Heart Center Dresden, TU Dresden, Fetscherstraße 76, 01307 Dresden, Germany;
- Dresden Cardiovascular Research Institute and Core Laboratories GmbH, Bautzner Straße 122c, 01099 Dresden, Germany
| | - Khalil Jawad
- Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany; (M.D.); (K.J.); (S.E.); (C.E.); (D.S.); (M.A.B.); (M.-T.D.)
| | - Sandra Eifert
- Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany; (M.D.); (K.J.); (S.E.); (C.E.); (D.S.); (M.A.B.); (M.-T.D.)
| | - Christian Etz
- Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany; (M.D.); (K.J.); (S.E.); (C.E.); (D.S.); (M.A.B.); (M.-T.D.)
| | - Diyar Saeed
- Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany; (M.D.); (K.J.); (S.E.); (C.E.); (D.S.); (M.A.B.); (M.-T.D.)
| | - Michael A. Borger
- Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany; (M.D.); (K.J.); (S.E.); (C.E.); (D.S.); (M.A.B.); (M.-T.D.)
| | - Maja-Theresa Dieterlen
- Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany; (M.D.); (K.J.); (S.E.); (C.E.); (D.S.); (M.A.B.); (M.-T.D.)
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Samec M, Liskova A, Koklesova L, Mersakova S, Strnadel J, Kajo K, Pec M, Zhai K, Smejkal K, Mirzaei S, Hushmandi K, Ashrafizadeh M, Saso L, Brockmueller A, Shakibaei M, Büsselberg D, Kubatka P. Flavonoids Targeting HIF-1: Implications on Cancer Metabolism. Cancers (Basel) 2021; 13:E130. [PMID: 33401572 PMCID: PMC7794792 DOI: 10.3390/cancers13010130] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/24/2020] [Accepted: 12/29/2020] [Indexed: 12/24/2022] Open
Abstract
Tumor hypoxia is described as an oxygen deprivation in malignant tissue. The hypoxic condition is a consequence of an imbalance between rapidly proliferating cells and a vascularization that leads to lower oxygen levels in tumors. Hypoxia-inducible factor 1 (HIF-1) is an essential transcription factor contributing to the regulation of hypoxia-associated genes. Some of these genes modulate molecular cascades associated with the Warburg effect and its accompanying pathways and, therefore, represent promising targets for cancer treatment. Current progress in the development of therapeutic approaches brings several promising inhibitors of HIF-1. Flavonoids, widely occurring in various plants, exert a broad spectrum of beneficial effects on human health, and are potentially powerful therapeutic tools against cancer. Recent evidences identified numerous natural flavonoids and their derivatives as inhibitors of HIF-1, associated with the regulation of critical glycolytic components in cancer cells, including pyruvate kinase M2(PKM2), lactate dehydrogenase (LDHA), glucose transporters (GLUTs), hexokinase II (HKII), phosphofructokinase-1 (PFK-1), and pyruvate dehydrogenase kinase (PDK). Here, we discuss the results of most recent studies evaluating the impact of flavonoids on HIF-1 accompanied by the regulation of critical enzymes contributing to the Warburg phenotype. Besides, flavonoid effects on glucose metabolism via regulation of HIF-1 activity represent a promising avenue in cancer-related research. At the same time, only more-in depth investigations can further elucidate the mechanistic and clinical connections between HIF-1 and cancer metabolism.
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Affiliation(s)
- Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.)
| | - Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.)
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.)
| | - Sandra Mersakova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4D, 03601 Martin, Slovakia; (S.M.); (J.S.)
| | - Jan Strnadel
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4D, 03601 Martin, Slovakia; (S.M.); (J.S.)
| | - Karol Kajo
- Department of Pathology, St. Elizabeth Cancer Institute Hospital, 81250 Bratislava, Slovakia;
| | - Martin Pec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Kevin Zhai
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Palackého třída 1946/1, 61200 Brno, Czech Republic;
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, 1477893855 Tehran, Iran;
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, 1419963114 Tehran, Iran;
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey;
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956 Istanbul, Turkey
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Faculty of Pharmacy and Medicine, Sapienza University, 00185 Rome, Italy;
| | - Aranka Brockmueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, D-80336 Munich, Germany; (A.B.); (M.S.)
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, D-80336 Munich, Germany; (A.B.); (M.S.)
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
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Moldogazieva NT, Mokhosoev IM, Terentiev AA. Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK. Cancers (Basel) 2020; 12:E862. [PMID: 32252351 PMCID: PMC7226606 DOI: 10.3390/cancers12040862] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/30/2020] [Accepted: 03/31/2020] [Indexed: 02/06/2023] Open
Abstract
It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatydyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs.
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Affiliation(s)
- Nurbubu T. Moldogazieva
- Laboratory of Bioinformatics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
| | - Innokenty M. Mokhosoev
- Department of Biochemistry and Molecular Biology, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (I.M.M.); (A.A.T.)
| | - Alexander A. Terentiev
- Department of Biochemistry and Molecular Biology, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (I.M.M.); (A.A.T.)
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Lam B, Roudier E. Considering the Role of Murine Double Minute 2 in the Cardiovascular System? Front Cell Dev Biol 2020; 7:320. [PMID: 31921839 PMCID: PMC6916148 DOI: 10.3389/fcell.2019.00320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/21/2019] [Indexed: 01/26/2023] Open
Abstract
The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.
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Affiliation(s)
- Brian Lam
- Angiogenesis Research Group, School of Kinesiology and Health Sciences, Muscle Health Research Center, Faculty of Health, York University, Toronto, ON, Canada
| | - Emilie Roudier
- Angiogenesis Research Group, School of Kinesiology and Health Sciences, Muscle Health Research Center, Faculty of Health, York University, Toronto, ON, Canada
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Hypoxia in the Initiation and Progression of Neuroblastoma Tumours. Int J Mol Sci 2019; 21:ijms21010039. [PMID: 31861671 PMCID: PMC6982287 DOI: 10.3390/ijms21010039] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/16/2019] [Accepted: 12/17/2019] [Indexed: 12/16/2022] Open
Abstract
Neuroblastoma is the most frequent extracranial solid tumour in children, causing 10% of all paediatric oncology deaths. It arises in the embryonic neural crest due to an uncontrolled behaviour of sympathetic nervous system progenitors, giving rise to heterogeneous tumours. Low local or systemic tissue oxygen concentration has emerged as a cellular stimulus with important consequences for tumour initiation, evolution and progression. In neuroblastoma, several evidences point towards a role of hypoxia in tumour initiation during development, tumour cell differentiation, survival and metastatic spreading. However, the heterogeneous nature of the disease, its developmental origin and the lack of suitable experimental models have complicated a clear understanding of the effect of hypoxia in neuroblastoma tumour progression and the molecular mechanisms implicated. In this review, we have compiled available evidences to try to shed light onto this important field. In particular, we explore the effect of hypoxia in neuroblastoma cell transformation and differentiation. We also discuss the experimental models available and the emerging alternatives to study this problem, and we present hypoxia-related therapeutic avenues being explored in the field.
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Zhang D, Yang L, Liu X, Gao J, Liu T, Yan Q, Yang X. Hypoxia modulates stem cell properties and induces EMT through N-glycosylation of EpCAM in breast cancer cells. J Cell Physiol 2019; 235:3626-3633. [PMID: 31584203 DOI: 10.1002/jcp.29252] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 08/26/2019] [Indexed: 12/11/2022]
Abstract
Epithelial cell adhesion molecule (EpCAM), which is a transmembrane glycoprotein, is related to tumor progression. We demonstrated that EpCAM plays important roles in proliferation, apoptosis, and metastasis during breast cancer (BC) progression. But the role of N-glycosylation in EpCAM in tumor aggressiveness is not clear. Here, we evaluated the role of N-glycosylation of EpCAM in stemness and epithelial-mesenchymal transition (EMT) characteristics. EpCAM overexpression increases the expression of stemness markers (NANOG，SOX2, and OCT4) and EMT markers (N-cadherin and vimentin) under the condition of hypoxia in BC. Knockdown of EpCAM and mutation of N-glycosylation of EpCAM maintained in severe hypoxia lead to a significant reduction of stemness/EMT markers. In addition, we found that N-glycosylation of EpCAM is a crucial factor during this process. This demonstrates that EpCAM has a novel regulatory role in stemness/EMT dependence of hypoxia-inducible factor 1-alpha via regulating nuclear factor kappa B in BC cells. Hence, our study reveals EpCAM glycosylation modification as a new regulator of stemness/EMT under hypoxic in BC and points out EpCAM as a potential therapeutic target.
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Affiliation(s)
- Dandan Zhang
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
| | - Liu Yang
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
| | - Xue Liu
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
| | - Jiujiao Gao
- Department of Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
| | - Tingjiao Liu
- Section of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian, China
| | - Qiu Yan
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
| | - Xuesong Yang
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
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Tang JC, Zhao J, Long F, Chen JY, Mu B, Jiang Z, Ren Y, Yang J. Efficacy of Shikonin against Esophageal Cancer Cells and its possible mechanisms in vitro and in vivo. J Cancer 2018; 9:32-40. [PMID: 29290767 PMCID: PMC5743709 DOI: 10.7150/jca.21224] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Accepted: 08/22/2017] [Indexed: 02/06/2023] Open
Abstract
Increasing evidences indicate that shikonin can suppress the tumor growth. However, the mechanisms remain elusive. In the present study, we investigated the effects and mechanisms of shikonin against esophageal cancer. The expression of hypoxia inducible factor 1α (HIF1α) and pyruvate kinase M2 (PKM2) in esophageal cancer tissues and cells was detected by immunohistochemistry and Western blot. CCK-8 was used to examine the esophageal cancer cell viability. Apoptosis and cell cycle were analyzed by flow cytometry. The expression of EGFR, PI3K, Akt, p-AKT, mTOR, HIF1α and PKM2 was detected by Western blot. EC109/pkm2 was established by lentivirus transducer. Ec109 tumor model was founded to observe the antitumor effect of shikonin in vivo. We found that HIF1α and PKM2 protein expression levels were higher in esophageal cancer tissues and cells than normal esophageal tissues and cells. Shikonin reduced esophageal cancer cells viability and induced cell cycle arrest and apoptosis. Shikonin decreased EGFR, PI3K, p-AKT, HIF1α and PKM2 expression. Overexpression of PKM2 could enhance resistance of esophageal cancer cells to shikonin. In vivo we found that shikonin reduced tumor burden, inducing cell arrest and apoptosis. Taken together, shikonin has a significant antitumor effect in the esophageal cancer by regulating HIF1α/PKM2 signal pathway.
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Affiliation(s)
| | | | - Feng Long
- Department of Pharmacy, Nan Chong Central Hospital
| | | | - Bo Mu
- Department of Biochemistry
| | | | | | - Jian Yang
- Pathogenic Biology and Immunology Experiment Teaching Center, North of Si Chuan Medical University, China
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Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K, Miyoshi N, Takahashi H, Nishida N, Haraguchi N, Sakai D, Kudo T, Hata T, Matsuda C, Mizushima T, Satoh T, Doki Y, Mori M, Ishii H. Hypoxia stimulates the cytoplasmic localization of oncogenic long noncoding RNA LINC00152 in colorectal cancer. Int J Oncol 2017; 52:453-460. [PMID: 29345294 DOI: 10.3892/ijo.2017.4218] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 10/19/2017] [Indexed: 11/05/2022] Open
Abstract
Recent studies have indicated that long noncoding RNAs (lncRNAs) play a pivotal role in almost all physiological cellular processes, including every stage of cancer development. Given that hypoxia in the tumor microenvironment is involved in the malignant behavior of tumors, such as invasion and metastasis, we investigated the cytoplasmic and nuclear localization of lncRNAs in colorectal cancer cells. A cell culture under hypoxic conditions revealed several lncRNAs, such as LINC00152, whose levels were increased in the cytoplasm of colorectal cancer cells. A database study indicated that LINC00152 shares microRNA-binding sites, such as miR-138 and miR-193, with the hypoxia-inducible factor 1 (HIF1), thus suggesting that LINC00152 could possibly function as a competing endogenous RNA that can augment Hif1 translation in the cytoplasm of hypoxic colorectal cancer cells. Moreover, the data presented in the studies of surgically resected samples showed that patients with colorectal cancer exhibiting high LINC00152 expression were associated with a worsened survival rate; this supports the suggested oncogenic function of LINC00152 in the cytoplasm under hypoxic conditions. The present study demonstrated that lncRNA networks could provide diagnostic tools and novel therapeutic targets against colorectal cancer cells.
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Affiliation(s)
- Yujiro Nishizawa
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Ayumu Asai
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Jun Koseki
- Department of Disease Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Naohiro Nishida
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Naotsugu Haraguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Daisuke Sakai
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Toshihiro Kudo
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Taishi Hata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Chu Matsuda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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11
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Zhang X, Cheng Q, Yin H, Yang G. Regulation of autophagy and EMT by the interplay between p53 and RAS during cancer progression (Review). Int J Oncol 2017; 51:18-24. [PMID: 28560457 DOI: 10.3892/ijo.2017.4025] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 05/05/2017] [Indexed: 11/06/2022] Open
Abstract
Cellular autophagy and epithelial-mesenchymal transition (EMT) are key events mostly resulted from the interplay of tumor suppressors and oncogenes during cancer progression. The master tumor suppressor p53 may control tumor cell autophagy and EMT through the transcriptional induction of multiple target genes, while the activated oncogene RAS may also play a critical role in regulating mitogenic signaling to tumor cell autophagy and EMT. Although the fundamental functions of p53 and RAS are well understood, the interactive effects of p53 and RAS on autophagy and EMT are still unclear. In this review, we highlight the recent advances in the regulation of autophagy and EMT by p53 and RAS, aiming to explore novel therapeutic targets and biomarkers in cancer treatment and prevention.
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Affiliation(s)
- Xiaofei Zhang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Qian Cheng
- Department of Orthopedics, the Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Huijing Yin
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Gong Yang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
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12
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Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma. Oncotarget 2016; 7:873-84. [PMID: 26621849 PMCID: PMC4808039 DOI: 10.18632/oncotarget.6418] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 11/16/2015] [Indexed: 12/16/2022] Open
Abstract
Overexpression of hypoxia-induced factor 1α (HIF-1α) has been shown to be involved in the development and progression of hepatocellular carcinoma (HCC). HIF-1α should therefore be a promising molecular target for the development of anti-HCC agents. Metformin, an established antidiabetic drug, has proved to also be effective in treating cancer although the precise underlying mechanisms of this activity are not fully elucidated. The aim of this study was to investigate the effects of metformin on the expression of HIF-1α and oxygen metabolism in HCC. The results showed that metformin inhibited hypoxia-induced HIF-1α accumulation and activation independent of AMP-activated protein kinase (AMPK). Moreover, this decrease in HIF-1α accumulation was accompanied by promotion of HIF-1α protein degradation. In addition, metformin significantly decreased oxygen consumption, ultimately leading to increased intracellular oxygen tension and decreased staining with the hypoxia marker pimonidazole. In vivo studies demonstrated that metformin delayed tumor growth and attenuated the expression of HIF-1α in HCC tumor xenografts. Together, these findings suggest that metformin decreases hypoxia-induced HIF-1α accumulation by actively suppressing mitochondrial oxygen consumption and enhancing cellular oxygenation ability, providing a fundamental mechanism of metformin activity against HCC.
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13
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Bredell MG, Ernst J, El-Kochairi I, Dahlem Y, Ikenberg K, Schumann DM. Current relevance of hypoxia in head and neck cancer. Oncotarget 2016; 7:50781-50804. [PMID: 27434126 PMCID: PMC5226620 DOI: 10.18632/oncotarget.9549] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 04/28/2016] [Indexed: 01/23/2023] Open
Abstract
Head and Neck cancer (HNC) is a complex mix of cancers and one of the more common cancers with a relatively poor prognosis. One of the factors that may assist us in predicting survival and allow us to adjust our treatment strategies is the presence of tumor hypoxia. In this overview we aim to evaluate the current evidence and potential clinical relevance of tumor hypoxia in head and neck cancer according to an extensive search of current literature.An abundance of evidence and often contradictory evidence is found in the literature. Even the contradictory evidence and comparisons are difficult to judge as criteria and methodologies differ greatly, furthermore few prospective observational studies exist for verification of the pre-clinical studies. Despite these discrepancies there is clear evidence of associations between prognosis and poor tumor oxygenation biomarkers such as HIF-1α, GLUT-1 and lactate, though these associations are not exclusive. The use of genetic markers is expanding and will probably lead to significantly more and complex evidence. The lack of oxygenation in head and neck tumors is of paramount importance for the prediction of treatment outcomes and prognosis. Despite the wide array of conflicting evidence, the drive towards non-invasive prediction of tumor hypoxia should continue.
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Affiliation(s)
- Marius G. Bredell
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Jutta Ernst
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Ilhem El-Kochairi
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Yuliya Dahlem
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Kristian Ikenberg
- Department of Pathology, University Hospital of Zürich, Zürich, Switzerland
| | - Desiree M. Schumann
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
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14
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Aiken J, Roudier E, Ciccone J, Drouin G, Stromberg A, Vojnovic J, Olfert IM, Haas T, Gustafsson T, Grenier G, Birot O. Phosphorylation of murine double minute‐2 on Ser
166
is downstream of VEGF‐A in exercised skeletal muscle and regulates primary endothelial cell migration and
FoxO
gene expression. FASEB J 2015; 30:1120-34. [DOI: 10.1096/fj.15-276964] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 11/09/2015] [Indexed: 12/13/2022]
Affiliation(s)
- Julian Aiken
- Faculty of HealthSchool of Kinesiology and Health ScienceAngiogenesis Research GroupYork UniversityTorontoOntarioCanada
| | - Emilie Roudier
- Faculty of HealthSchool of Kinesiology and Health ScienceAngiogenesis Research GroupYork UniversityTorontoOntarioCanada
| | - Joseph Ciccone
- Faculty of HealthSchool of Kinesiology and Health ScienceAngiogenesis Research GroupYork UniversityTorontoOntarioCanada
| | - Genevieve Drouin
- Department of SurgeryUniversite de SherbrookeSherbrookeQuébecCanada
| | - Anna Stromberg
- Department of Laboratory MedicineDivision of Clinical PhysiologyKarolinska InstitutetKarolinska University HospitalStockholmSweden
| | - Jovana Vojnovic
- Faculty of HealthSchool of Kinesiology and Health ScienceAngiogenesis Research GroupYork UniversityTorontoOntarioCanada
| | - I. Mark Olfert
- Center for Cardiovascular and Respiratory Sciences and Division of Exercise PhysiologyWest Virginia UniversityMorgantownWest VirginiaUSA
| | - Tara Haas
- Faculty of HealthSchool of Kinesiology and Health ScienceAngiogenesis Research GroupYork UniversityTorontoOntarioCanada
| | - Thomas Gustafsson
- Department of Laboratory MedicineDivision of Clinical PhysiologyKarolinska InstitutetKarolinska University HospitalStockholmSweden
| | | | - Olivier Birot
- Faculty of HealthSchool of Kinesiology and Health ScienceAngiogenesis Research GroupYork UniversityTorontoOntarioCanada
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