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C M, Pasha TY, Rahamathulla M, H P G, B L K, K M G, K N P, Hussain SM, Ahmed MM, Shivanandappa TB, Pasha I. Epidermal growth factor receptors unveiled: a comprehensive survey on mutations, clinical insights of global inhibitors, and emergence of heterocyclic derivatives as EGFR inhibitors. J Drug Target 2025; 33:933-951. [PMID: 39756062 DOI: 10.1080/1061186x.2024.2449495] [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: 09/09/2024] [Revised: 12/09/2024] [Accepted: 12/21/2024] [Indexed: 01/07/2025]
Abstract
Mutations that overexpress the epidermal growth factor receptor (EGFR) are linked to cancers like breast (15-20%), head and neck (10-15%), colorectal (5-8%), and non-small cell lung cancer (10-50%), especially in East Asian populations. EGFR activation stimulates 'RAS/RAF/MEK/ERK, PI3K/Akt, and MAPK' pathways, which enhance cell division, survival, angiogenesis, and tumour growth while inhibiting apoptosis and metastasis. Secondary mutations (e.g. 'T790M', 'C797S'), off-target effects, and resistance due to alternate pathway activation reduce the efficacy of currently available EGFR inhibitors. To address these issues, 'novel heterocyclic inhibitors with structural versatility were developed to improve selectivity and binding affinity for mutant EGFR forms'. These new EGFR reduce side effects, enhance pharmacokinetics, and enhance therapeutic efficacy at low concentrations. This review focuses on 'EGFR mutations in various cancers' detailing the biochemical effects, clinical profiles, and binding interactions of globally approved EGFR inhibitors. Furthermore, it focuses into recent progress in nano-formulations and the development of heterocyclic derivatives that can successfully 'target mutant EGFRs' through varied synthesis methods. These inhibitors have the potential to have better binding affinities, selectivity's, and less side-effect. Further research required to refine the structures and develop nanoformulations of EGFR-targeted therapeutics in order to improve therapeutic efficiency and, provide more effective cancer treatments.
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Affiliation(s)
- Manojmouli C
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - T Y Pasha
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Mohamed Rahamathulla
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Al Faraa 62223, Abha, Saudi Arabia
| | - Gagana H P
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Kavya B L
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Gagana K M
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Purushotham K N
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Shalam M Hussain
- Department of Clinical Pharmacy, College of Nursing and Health Science. Al-Rayyan Medical College, Madinah, Saudi Arabia
| | - Mohammed Muqtader Ahmed
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | | | - Ismail Pasha
- Department of Pharmacology, Orotta College of Medicine and Health Sciences, Asmara University, Asmara, State of Eritrea
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Ryspayeva D, Seyhan AA, MacDonald WJ, Purcell C, Roady TJ, Ghandali M, Verovkina N, El-Deiry WS, Taylor MS, Graff SL. Signaling pathway dysregulation in breast cancer. Oncotarget 2025; 16:168-201. [PMID: 40080721 PMCID: PMC11906143 DOI: 10.18632/oncotarget.28701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/03/2025] [Indexed: 03/15/2025] Open
Abstract
This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special emphasis is placed on the structural dynamics of protein complexes that are integral to the regulation of these signaling cascades. Dysregulation of cellular signaling is a fundamental aspect of BC pathophysiology, with both upstream and downstream signaling cascade activation contributing to cellular process aberrations that not only drive tumor growth, but also contribute to resistance against current treatments. The review explores alterations within these pathways across different BC subtypes and highlights potential therapeutic strategies targeting these pathways. Additionally, the influence of specific mutations on therapeutic decision-making is examined, underscoring their relevance to particular BC subtypes. The article also discusses both approved therapeutic modalities and ongoing clinical trials targeting disrupted signaling pathways. However, further investigation is necessary to fully elucidate the underlying mechanisms and optimize personalized treatment approaches.
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Affiliation(s)
- Dinara Ryspayeva
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
| | - William J. MacDonald
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Connor Purcell
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Tyler J. Roady
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
| | - Maryam Ghandali
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Nataliia Verovkina
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Wafik S. El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
- Department of Medicine, Hematology/Oncology Division, Lifespan Health System and Brown University, RI 02903, USA
| | - Martin S. Taylor
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
- Brown Center on the Biology of Aging, Brown University, RI 02903, USA
| | - Stephanie L. Graff
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Department of Medicine, Hematology/Oncology Division, Lifespan Health System and Brown University, RI 02903, USA
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Premeti K, Tsipa D, Nadalis AE, Papanikolaou MG, Syropoulou V, Karagkiozeli KD, Aggelis G, Iordanidou E, Labrakakis C, Pappas P, Keramidas AD, Antoniou K, Doulias PT, Kabanos TA, Leondaritis G. First generation vanadium-based PTEN inhibitors: Comparative study in vitro and in vivo and identification of a novel mechanism of action. Biochem Pharmacol 2025; 233:116756. [PMID: 39824468 DOI: 10.1016/j.bcp.2025.116756] [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: 09/07/2024] [Revised: 11/29/2024] [Accepted: 01/13/2025] [Indexed: 01/20/2025]
Abstract
PTEN, a tumor suppressor phosphatase, regulates cellular functions by antagonizing the growth promoting PI3K/Akt/mTOR pathway through the dephosphorylation of the second messenger PIP3. Many preclinical cellular and animal studies have used PTEN inhibitors to highlight specific disease contexts where acute activation of PI3K/Akt/mTOR pathway might offer therapeutic advantages. In the present study we have re-evaluated first-generation PTEN inhibitors, including established bisperoxo-vanadium(V) complexes (bpVs). In vitro, all compounds tested inhibited PTEN with IC50 values between 0.2-0.8 μM, although their activity diminished under reducing conditions. bpV(phen) and bpV(HΟpic) significantly increased pSer473Akt levels in PTEN wild-type cells while bpV(phen) induced phosphorylation in PTEN null cells upon re-expression of functional PTEN. bpV(ΗΟpic) was less specific since it also triggered PTEN-independent Erk1/2 phosphorylation. In vivo, bpV(phen) administration in Wistar rats enhanced pS6 levels in kidney and liver tissues, but not in several CNS tissues, and led to reduced locomotion and exploratory behaviour in the open field test. The consensus mechanism of action of first generation PTEN inhibitors appears to be oxidative inhibition, however bpV(phen) does not induce oxidation of cellular endogenous PTEN. Instead, our findings suggest that the inhibition of PTEN by bpV(phen) in cells and in vivo may proceed through a mechanism involving non-specific S-nitrosylation of PTEN. Our study highlights the complexity of PTEN inhibition by first-generation compounds and their limitations, such as low specificity, adverse effects and non-specific mechanisms of action, and emphasizes the need for developing more selective and potent PTEN inhibitors with improved efficacy and well-defined mechanisms of actions.
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Affiliation(s)
- Kyriaki Premeti
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Dimitra Tsipa
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Antonios E Nadalis
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Michael G Papanikolaou
- Department of Chemistry, University of Ioannina, Ioannina 45110, Greece; Department of Chemistry, University of Cyprus, Nicosia 2109, Cyprus
| | - Vasiliki Syropoulou
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Konstantina-Danai Karagkiozeli
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - George Aggelis
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Eleni Iordanidou
- Department of Chemistry, University of Ioannina, Ioannina 45110, Greece
| | - Charalampos Labrakakis
- Department of Biological Applications and Technology, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; Institute of Biosciences, University Research Center Ioannina, University of Ioannina, Ioannina, Greece
| | - Periklis Pappas
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | | | - Katerina Antoniou
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; Institute of Biosciences, University Research Center Ioannina, University of Ioannina, Ioannina, Greece
| | - Paschalis-Thomas Doulias
- Department of Chemistry, University of Ioannina, Ioannina 45110, Greece; Institute of Biosciences, University Research Center Ioannina, University of Ioannina, Ioannina, Greece
| | | | - George Leondaritis
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; Institute of Biosciences, University Research Center Ioannina, University of Ioannina, Ioannina, Greece.
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Azimzadeh M, Cheah PS, Ling KH. Brain insulin resistance in Down syndrome: Involvement of PI3K-Akt/mTOR axis in early-onset of Alzheimer's disease and its potential as a therapeutic target. Biochem Biophys Res Commun 2024; 733:150713. [PMID: 39307112 DOI: 10.1016/j.bbrc.2024.150713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 08/27/2024] [Accepted: 09/16/2024] [Indexed: 10/06/2024]
Abstract
Down syndrome (DS) is the most common genetic cause of intellectual impairment, characterised by an extra copy of chromosome 21. After the age of 40, DS individuals are highly susceptible to accelerated ageing and the development of early-onset Alzheimer-like neuropathology. In the context of DS, the brain presents a spectrum of neuropathological mechanisms and metabolic anomalies. These include heightened desensitisation of brain insulin and insulin-like growth factor-1 (IGF-1) reactions, compromised mitochondrial functionality, escalated oxidative stress, reduced autophagy, and the accumulation of amyloid beta and tau phosphorylation. These multifaceted factors intertwine to shape the intricate landscape of DS-related brain pathology. Altered brain insulin signalling is linked to Alzheimer's disease (AD). This disruption may stem from anomalies in the extracellular aspect (insulin receptor) or the intracellular facet, involving the inhibition of insulin receptor substrate 1 (IRS1). Both domains contribute to the intricate mechanism underlying this dysregulation. The PI3K-Akt/mammalian target of the rapamycin (mTOR) axis is a crucial intracellular element of the insulin signalling pathway that connects numerous physiological processes in the cell cycle. In age-related neurodegenerative disorders like AD, aberrant modulation of the PI3K-Akt signalling cascade is a key factor contributing to their onset. Aberrant and sustained hyperactivation of the PI3K/Akt-mTOR axis in the DS brain is implicated in early symptoms of AD development. Targeting the PI3K-Akt/mTOR pathway may help delay the onset of early-onset AD in individuals with DS, offering a potential way to slow disease progression and enhance their quality of life.
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Affiliation(s)
- Mansour Azimzadeh
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Pike-See Cheah
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Malaysian Research Institute on Ageing (MyAgeing®), Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
| | - King-Hwa Ling
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Malaysian Research Institute on Ageing (MyAgeing®), Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
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Qiang P, Chen Y, Shao Y, Deng Q, Xu S, Zhu W. Deciphering the role of SAMHD1 in endometrial cancer progression. Biol Direct 2024; 19:89. [PMID: 39394602 PMCID: PMC11468744 DOI: 10.1186/s13062-024-00525-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 08/31/2024] [Indexed: 10/13/2024] Open
Abstract
BACKGROUND Endometrial cancer (EC) presents significant clinical challenges due to its heterogeneity and complex pathophysiology. SAMHD1, known for its role as a deoxynucleotide triphosphate triphosphohydrolase, has been implicated in the progression of various cancers, including EC. This study focuses on elucidating the role of SAMHD1 in EC through its impact on TRIM27-mediated PTEN ubiquitination. RESULTS Utilizing a combination of bioinformatics and cellular biology techniques, we investigated the interactions among SAMHD1, TRIM27, and PTEN. Our findings reveal that SAMHD1 modulates PTEN ubiquitination via TRIM27, impacting key pathways involved in EC pathogenesis. These interactions suggest a critical mechanism by which SAMHD1 could influence tumor behavior and progression in EC. CONCLUSIONS The results from this study underscore the potential of targeting the SAMHD1-TRIM27-PTEN axis as a therapeutic strategy in EC. By providing new insights into the molecular mechanisms underlying EC progression, our research supports the development of novel therapeutic approaches that could contribute to improve treatment strategies for patients with EC.
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Affiliation(s)
- Ping Qiang
- Department of Obstetrics and Gynecology, The First People's Hospital of Zhangjiagang City, The Zhangjiagang Affiliated Hospital of Soochow University, Suzhou, 215600, China
| | - Ying Chen
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, Jiangsu Province, 215000, China
| | - Yang Shao
- Department of Obstetrics and Gynecology, The First People's Hospital of Zhangjiagang City, The Zhangjiagang Affiliated Hospital of Soochow University, Suzhou, 215600, China
| | - Qicheng Deng
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, Jiangsu Province, 215000, China
| | - Songyuan Xu
- Department of Obstetrics and Gynecology, The First People's Hospital of Zhangjiagang City, The Zhangjiagang Affiliated Hospital of Soochow University, Suzhou, 215600, China
| | - Weipei Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, Jiangsu Province, 215000, China.
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Samutrtai P, Yingchutrakul Y, Faikhruea K, Vilaivan T, Chaikeeratisak V, Chatwichien J, Krobthong S, Aonbangkhen C. Vernonia amygdalina Leaf Extract Induces Apoptosis in HeLa Cells: A Metabolomics and Proteomics Study. Pharmaceuticals (Basel) 2024; 17:1079. [PMID: 39204184 PMCID: PMC11360076 DOI: 10.3390/ph17081079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 09/03/2024] Open
Abstract
Medicinal plants produce various bioactive molecules with potential anti-cancer properties with favorable safety profiles. We aimed to investigate the comprehensive composition of Vernonia amygdalina leaf extract and its cytotoxic effects via apoptosis in HeLa cells. The metabolomics approach using LC-MS/MS was conducted to gather the metabolite profile of the extract. Proteomics was performed to understand the comprehensive mechanistic pathways of action. The apoptosis was visualized by cellular staining and the apoptotic proteins were evaluated. V. amygdalina leaf extract exhibited dose-dependent cytotoxic effects on both HeLa and Vero cells after 24 h of exposure in the MTT assay with the IC50 values of 0.767 ± 0.0334 and 4.043 ± 0.469 µg mL-1, respectively, which demonstrated a higher concentration required for Vero cell cytotoxicity. The metabolomic profile of 112 known metabolites specified that the majority of them were alkaloids, phenolic compounds, and steroids. Among these metabolites, deacetylvindoline and licochalcone B were suggested to implicate cytotoxicity. The cytotoxic pathways involved the response to stress and cell death which was similar to doxorubicin. The upstream regulatory proteins, phosphatase and tensin homolog deleted on chromosome ten (PTEN) and X-box binding protein 1 (XBP1), were significantly altered, supporting the regulation of apoptosis and cell death. The levels of apoptotic proteins, c-Jun N-terminal kinases (JNK), p53, and caspase-9 were significantly increased. The novel insights gained from the metabolomic profiling and proteomic pathway analysis of V. amygdalina leaf extract have identified crucial components related to apoptosis induction, highlighting its potential to develop future chemotherapy.
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Affiliation(s)
- Pawitrabhorn Samutrtai
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Yodying Yingchutrakul
- National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand;
| | - Kriangsak Faikhruea
- Organic Synthesis Research Unit (OSRU), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; (K.F.); (T.V.)
| | - Tirayut Vilaivan
- Organic Synthesis Research Unit (OSRU), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; (K.F.); (T.V.)
| | - Vorrapon Chaikeeratisak
- Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Jaruwan Chatwichien
- Program in Chemical Sciences, Chulabhorn Graduate Institute (CGI), Bangkok 10210, Thailand;
| | - Sucheewin Krobthong
- Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; (S.K.); (C.A.)
| | - Chanat Aonbangkhen
- Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; (S.K.); (C.A.)
- Center of Excellence on Petrochemical and Materials Technology, Chulalongkorn University, Bangkok 10330, Thailand
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Khorasani ABS, Hafezi N, Sanaei MJ, Jafari-Raddani F, Pourbagheri-Sigaroodi A, Bashash D. The PI3K/AKT/mTOR signaling pathway in breast cancer: Review of clinical trials and latest advances. Cell Biochem Funct 2024; 42:e3998. [PMID: 38561964 DOI: 10.1002/cbf.3998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 03/11/2024] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer mortality in women. As the phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a wide range of physiological functions of cells including growth, proliferation, motility, and angiogenesis, any alteration in this axis could induce oncogenic features; therefore, numerous preclinical and clinical studies assessed agents able to inhibit the components of this pathway in BC patients. To the best of our knowledge, this is the first study that analyzed all the registered clinical trials investigating safety and efficacy of the PI3K/AKT/mTOR axis inhibitors in BC. Of note, we found that the trends of PI3K inhibitors in recent years were superior as compared with the inhibitors of either AKT or mTOR. However, most of the trials entering phase III and IV used mTOR inhibitors (majorly Everolimus) followed by PI3K inhibitors (majorly Alpelisib) leading to the FDA approval of these drugs in the BC context. Despite favorable efficacies, our analysis shows that the majority of trials are utilizing PI3K pathway inhibitors in combination with hormone therapy and chemotherapy; implying monotherapy cannot yield huge clinical benefits, at least partly, due to the activation of compensatory mechanisms. To emphasize the beneficial effects of these inhibitors in combined-modal strategies, we also reviewed recent studies which investigated the conjugation of nanocarriers with PI3K inhibitors to reduce harmful toxicities, increase the local concentration, and improve their efficacies in the context of BC therapy.
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Affiliation(s)
| | - Nasim Hafezi
- Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farideh Jafari-Raddani
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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8
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De D, Ghosh G, Karmakar P. Sumoylation and phosphorylation of PTEN boosts and curtails autophagy respectively by influencing cell membrane localisation. Exp Cell Res 2024; 434:113872. [PMID: 38072303 DOI: 10.1016/j.yexcr.2023.113872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 11/30/2023] [Accepted: 12/03/2023] [Indexed: 12/17/2023]
Abstract
Autophagy is involved in the entirety of cellular survival, homeostasis and death which becomes more self-evident when its dysregulation is implicated in several pathological conditions. PTEN positively regulates autophagy and like other proteins undergo post-translational modifications. It is crucial to investigate the relationship between PTEN and autophagy as it is generally observed to be negligible in PTEN deficient cancer cells. Here, we have shown that such modifications of PTEN namely sumoylation and phosphorylation upregulates and downregulates autophagy respectively. Transfection of plasmid containing full length PTEN in PTEN-negative prostate cancer cell line PC3, induced autophagy on further starvation. When a sumoylation-deficient mutant of PTEN was transfected and cells were put under similar starvation, a decline in autophagy was observed. On the other hand, cells transfected with phosphorylation-deficient mutant of PTEN showed elevated expression of autophagy. Contrarily, transfection with phosphorylation-mimicking mutant caused reduced expression of autophagy. On further analysis, it was detected that PTEN's association with the plasma membrane was under positive and negative influence from its sumoylation and phosphorylation respectively. This association is integral as it is the foremost site for PTEN to oppose PI3K/AKT pathway and consequently upregulate autophagy. Thus, this study indicates that sumoylation and phosphorylation of PTEN can control autophagy via its cell membrane association.
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Affiliation(s)
- Debojyoti De
- Department of Life Science & Biotechnology, Jadavpur University, 188, Raja Subodh Chandra Mallick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
| | - Ginia Ghosh
- Department of Life Science & Biotechnology, Jadavpur University, 188, Raja Subodh Chandra Mallick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
| | - Parimal Karmakar
- Department of Life Science & Biotechnology, Jadavpur University, 188, Raja Subodh Chandra Mallick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
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Maselli FM, Giuliani F, Laface C, Perrone M, Melaccio A, De Santis P, Santoro AN, Guarini C, Iaia ML, Fedele P. Immunotherapy in Prostate Cancer: State of Art and New Therapeutic Perspectives. Curr Oncol 2023; 30:5769-5794. [PMID: 37366915 DOI: 10.3390/curroncol30060432] [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: 04/18/2023] [Revised: 05/22/2023] [Accepted: 06/09/2023] [Indexed: 06/28/2023] Open
Abstract
Prostate cancer (PC) is the most common type of tumor in men. In the early stage of the disease, it is sensitive to androgen deprivation therapy. In patients with metastatic castration-sensitive prostate cancer (mHSPC), chemotherapy and second-generation androgen receptor therapy have led to increased survival. However, despite advances in the management of mHSPC, castration resistance is unavoidable and many patients develop metastatic castration-resistant disease (mCRPC). In the past few decades, immunotherapy has dramatically changed the oncology landscape and has increased the survival rate of many types of cancer. However, immunotherapy in prostate cancer has not yet given the revolutionary results it has in other types of tumors. Research into new treatments is very important for patients with mCRPC because of its poor prognosis. In this review, we focus on the reasons for the apparent intrinsic resistance of prostate cancer to immunotherapy, the possibilities for overcoming this resistance, and the clinical evidence and new therapeutic perspectives regarding immunotherapy in prostate cancer with a look toward the future.
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Affiliation(s)
| | | | - Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Martina Perrone
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Assunta Melaccio
- Medical Oncology, San Paolo Hospital, ASL Bari, 70123 Bari, Italy
| | - Pierluigi De Santis
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | | | - Chiara Guarini
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Maria Laura Iaia
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
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10
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Ke X, Zhang W. Pro-inflammatory activity of long noncoding RNA FOXD2-AS1 in Achilles tendinopathy. J Orthop Surg Res 2023; 18:361. [PMID: 37194076 DOI: 10.1186/s13018-023-03681-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 03/05/2023] [Indexed: 05/18/2023] Open
Abstract
Achilles tendinopathy is a prevalent clinical problem that plagues athletes and general populations. Achilles tendon healing is a complex process, and so far, there is no successful long-term solution to Achilles tendinopathy in the field of microsurgery due to its poor natural regeneration ability. Limitations in understanding the pathogenesis of Achilles tendon development and Achilles tendon injury hinder clinical treatment developments. There is an increasing demand for innovative conservative treatments that can improve Achilles tendon injury. In this study, a Sprague-Dawley rat model of Achilles tendinopathy was established. Lentiviral vectors that interfere with the expression of FOXD2-AS1, miR-21-3p, or PTEN were injected every 3 days. Rats were euthanized after 3 weeks, and the effect of FOXD2-AS1, miR-21-3p, or PTEN on Achilles tendon healing was analyzed by histological observation, biomechanical test, and examinations of inflammatory factors and tendon markers. As measured, downregulating FOXD2-AS1 or upregulating miR-21-3p improved histological structure, suppressed inflammation, promoted the expression of tendon markers, and optimized the biomechanical properties of Achilles tendon. Upregulating PTEN was capable of reversing the promoting effect of inhibition of FOXD2-AS1 on Achilles tendon healing. As concluded, deficiency of FOXD2-AS1 accelerates the healing of Achilles tendon injury and improves tendon degeneration by regulating the miR-21-3p/PTEN axis and promoting the activation of the PI3K/AKT signaling pathway.
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Affiliation(s)
- Xiaoting Ke
- Zhejiang Rehabilitation Medical Center, Hangzhou, 310051, Zhejiang, China
| | - Wenjie Zhang
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China.
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11
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Fu T, Ma Y, Li Y, Wang Y, Wang Q, Tong Y. Mitophagy as a mitochondrial quality control mechanism in myocardial ischemic stress: from bench to bedside. Cell Stress Chaperones 2023; 28:239-251. [PMID: 37093549 PMCID: PMC10167083 DOI: 10.1007/s12192-023-01346-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/25/2023] Open
Abstract
Myocardial ischemia reduces the supply of oxygen and nutrients to cardiomyocytes, leading to an energetic crisis or cell death. Mitochondrial dysfunction is a decisive contributor to the reception, transmission, and modification of cardiac ischemic signals. Cells with damaged mitochondria exhibit impaired mitochondrial metabolism and increased vulnerability to death stimuli due to disrupted mitochondrial respiration, reactive oxygen species overproduction, mitochondrial calcium overload, and mitochondrial genomic damage. Various intracellular and extracellular stress signaling pathways converge on mitochondria, so dysfunctional mitochondria tend to convert from energetic hubs to apoptotic centers. To interrupt the stress signal transduction resulting from lethal mitochondrial damage, cells can activate mitophagy (mitochondria-specific autophagy), which selectively eliminates dysfunctional mitochondria to preserve mitochondrial quality control. Different pharmacological and non-pharmacological strategies have been designed to augment the protective properties of mitophagy and have been validated in basic animal experiments and pre-clinical human trials. In this review, we describe the process of mitophagy in cardiomyocytes under ischemic stress, along with its regulatory mechanisms and downstream effects. Then, we discuss promising therapeutic approaches to preserve mitochondrial homeostasis and protect the myocardium against ischemic damage by inducing mitophagy.
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Affiliation(s)
- Tong Fu
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
- Brandeis University, Waltham, MA, 02453, USA
| | - Yanchun Ma
- Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Yan Li
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Yingwei Wang
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Qi Wang
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Ying Tong
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, China.
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12
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Gu SH, Chen CH, Chang CH, Lin PL. Expression of tyrosine phosphatases in relation to PTTH-stimulated ecdysteroidogenesis in prothoracic glands of the silkworm, Bombyx mori. Gen Comp Endocrinol 2023; 331:114165. [PMID: 36368438 DOI: 10.1016/j.ygcen.2022.114165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 10/19/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022]
Abstract
Protein tyrosine phosphorylation is a reversible, dynamic process regulated by the activities of tyrosine kinases and tyrosine phosphatases. Although the involvement of tyrosine kinases in the prothoracicotropic hormone (PTTH)-stimulated ecdysteroidogenesis in insect prothoracic glands (PGs) has been documented, few studies have been conducted on the involvement of protein tyrosine phosphatases (PTPs) in PTTH-stimulated ecdysteroidogenesis. In the present study, we investigated the correlation between PTPs and PTTH-stimulated ecdysteroidogenesis in Bombyx mori PGs. Our results showed that the basal PTP enzymatic activities exhibited development-specific changes during the last larval instar and pupation stage, with high activities being detected during the later stages of the last larval instar. PTP enzymatic activity was stimulated by PTTH treatment both in vitro and in vivo. Pretreatment with phenylarsine oxide (PAO) and benzylphosphonic acid (BPA), two chemical inhibitors of tyrosine phosphatase, reduced PTTH-stimulated enzymatic activity. Determination of ecdysteroid secretion showed that treatment with PAO and BPA did not affect basal ecdysteroid secretion, but greatly inhibited PTTH-stimulated ecdysteroid secretion, indicating that PTTH-stimulated PTP activity is indeed involved in ecdysteroid secretion. PTTH-stimulated phosphorylation of the extracellular signal-regulated kinase (ERK) and 4E-binding protein (4E-BP) was partially inhibited by pretreatment with either PAO or BPA, indicating the potential link between PTPs and phosphorylation of ERK and 4E-BP. In addition, we also found that in vitro treatment with 20-hydroxyecdysone did not affect PTP enzymatic activity. We further investigated the expressions of two important PTPs (PTP 1B (PTP1B) and the phosphatase and tension homologue (PTEN)) in Bombyx PGs. Our immunoblotting analysis showed that B. mori PGs contained the proteins of PTP1B and PTEN, with PTP1B protein undergoing development-specific changes. Protein levels of PTP1B and PTEN were not affected by PTTH treatment. The gene expression levels of PTP1B and PTEN showed development-specific changes. From these results, we suggest that PTTH-regulated PTP signaling may crosstalk with ERK and target of rapamycin (TOR) signaling pathways and is a necessary component for stimulation of ecdysteroid secretion.
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Affiliation(s)
- Shi-Hong Gu
- Department of Biology, National Museum of Natural Science, 1 Kuan-Chien Road, Taichung 404, Taiwan, ROC.
| | - Chien-Hung Chen
- Chung Hwa University of Medical Technology, 89 Wen-Hwa 1st Road, Jen-Te Township, Tainan County 717, Taiwan, ROC
| | - Chia-Hao Chang
- Department of Biology, National Museum of Natural Science, 1 Kuan-Chien Road, Taichung 404, Taiwan, ROC
| | - Pei-Ling Lin
- Department of Biology, National Museum of Natural Science, 1 Kuan-Chien Road, Taichung 404, Taiwan, ROC
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13
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Cetintas VB, Duzgun Z, Akalin T, Ozgiray E, Dogan E, Yildirim Z, Akinturk N, Biceroglu H, Ertan Y, Kosova B. Molecular dynamic simulation and functional analysis of pathogenic PTEN mutations in glioblastoma. J Biomol Struct Dyn 2023; 41:11471-11483. [PMID: 36591942 DOI: 10.1080/07391102.2022.2162582] [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: 08/17/2022] [Accepted: 12/20/2022] [Indexed: 01/03/2023]
Abstract
PTEN, a dual-phosphatase and scaffold protein, is one of the most commonly mutated tumour suppressor gene across various cancer types in human. The aim of this study therefore was to investigate the stability, structural and functional effects, and pathogenicity of 12 missense PTEN mutations (R15S, E18G, G36R, N49I, Y68H, I101T, C105F, D109N, V133I, C136Y, R173C and N276S) found by next generation sequencing of the PTEN gene in tissue samples obtained from glioblastoma patients. Computational tools and molecular dynamic simulation programs were used to identify the deleterious effects of these mutations. Furthermore, PTEN mRNA and protein expression levels were evaluated by qRT-PCR, Western Blot, and immunohistochemistry staining methods. Various computational tools predicted strong deleterious effects for the G36R, C105F, C136Y and N276S mutations. Molecular dynamic simulation revealed a significant decrease in protein stability for the Y68H and N276S mutations when compared with the wild type protein; whereas, C105F, D109N, V133I and R173C showed partial stability reduction. Significant residual fluctuations were observed in the R15S, N49I and C136Y mutations and radius of gyration graphs revealed the most compact structure for D109N and least for C136Y. In summary, our study is the first one to show the presence of PTEN E18G, N49I, D109N and N276S mutations in glioblastoma patients; where, D109N is neutral and N276S is a damaging and disease-associated mutation.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
| | - Zekeriya Duzgun
- Department of Medical Biology, Giresun University Faculty of Medicine, Giresun, Turkey
| | - Taner Akalin
- Department of Pathology, Ege University Faculty of Medicine, Izmir, Turkey
| | - Erkin Ozgiray
- Department of Neurosurgery, Ege University Faculty of Medicine, Izmir, Turkey
| | - Eda Dogan
- Department of Medical Biology, Ege University Faculty of Medicine, Izmir, Turkey
| | - Zafer Yildirim
- Department of Medical Biology, Ege University Faculty of Medicine, Izmir, Turkey
| | - Nevhis Akinturk
- Department of Neurosurgery, Ege University Faculty of Medicine, Izmir, Turkey
| | - Huseyin Biceroglu
- Department of Neurosurgery, Ege University Faculty of Medicine, Izmir, Turkey
| | - Yesim Ertan
- Department of Pathology, Ege University Faculty of Medicine, Izmir, Turkey
| | - Buket Kosova
- Department of Medical Biology, Ege University Faculty of Medicine, Izmir, Turkey
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14
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The Immunotherapy and Immunosuppressive Signaling in Therapy-Resistant Prostate Cancer. Biomedicines 2022; 10:biomedicines10081778. [PMID: 35892678 PMCID: PMC9394279 DOI: 10.3390/biomedicines10081778] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/12/2022] [Accepted: 07/18/2022] [Indexed: 11/17/2022] Open
Abstract
Prostate cancer is one of the most common malignant tumors in men. Initially, it is androgen-dependent, but it eventually develops into castration-resistant prostate cancer (CRPC), which is incurable with current androgen receptor signaling target therapy and chemotherapy. Immunotherapy, specifically with immune checkpoint inhibitors, has brought hope for the treatment of this type of prostate cancer. Approaches such as vaccines, adoptive chimeric antigen receptor-T (CAR-T) cells, and immune checkpoint inhibitors have been employed to activate innate and adaptive immune responses to treat prostate cancer, but with limited success. Only Sipuleucel-T and the immune checkpoint inhibitor pembrolizumab are approved by the US FDA for the treatment of limited prostate cancer patients. Prostate cancer has a complex tumor microenvironment (TME) in which various immunosuppressive molecules and mechanisms coexist and interact. Additionally, prostate cancer is considered a “cold” tumor with low levels of tumor mutational burden, low amounts of antigen-presenting and cytotoxic T-cell activation, and high levels of immunosuppressive molecules including cytokines/chemokines. Thus, understanding the mechanisms of immunosuppressive signaling activation and immune evasion will help develop more effective treatments for prostate cancer. The purpose of this review is to summarize emerging advances in prostate cancer immunotherapy, with a particular focus on the molecular mechanisms that lead to immune evasion in prostate cancer. At the same time, we also highlight some potential therapeutic targets to provide a theoretical basis for the treatment of prostate cancer.
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15
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Furin extracellularly cleaves secreted PTENα/β to generate C-terminal fragment with a tumor-suppressive role. Cell Death Dis 2022; 13:532. [PMID: 35668069 PMCID: PMC9170693 DOI: 10.1038/s41419-022-04988-2] [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: 02/22/2022] [Revised: 05/23/2022] [Accepted: 05/30/2022] [Indexed: 01/21/2023]
Abstract
PTENα and PTENβ (PTENα/β), two long translational variants of phosphatase and tensin homolog on chromosome 10 (PTEN), exert distinct roles from canonical PTEN, including promoting carcinogenesis and accelerating immune-resistant cancer progression. However, their roles in carcinogenesis remain greatly unknown. Herein, we report that, after secreting into the extracellular space, PTENα/β proteins are efficiently cleaved into a short N-terminal and a long C-terminal fragment by the proprotein convertase Furin at a polyarginine stretch in their N-terminal extensions. Although secreted PTENα/β and their cleaved fragment cannot enter cells, treatment of the purified C-terminal fragment but not cleavage-resistant mutants of PTENα exerts a tumor-suppressive role in vivo. As a result, overexpression of cleavage-resistant PTENα mutants manifest a tumor-promoting role more profound than that of wild-type PTENα. In line with these, the C-terminal fragment is significantly downregulated in liver cancer tissues compared to paired normal tissues, which is consistent with the downregulated expression of Furin. Collectively, we show that extracellular PTENα/β present opposite effects on carcinogenesis from intracellular PTENα/β, and propose that the tumor-suppressive C-terminal fragment of PTENα/β might be used as exogenous agent to treat cancer.
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16
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Hypoxic Microenvironment-Induced Reduction in PTEN-L Secretion Promotes Non-Small Cell Lung Cancer Metastasis through PI3K/AKT Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6683104. [PMID: 35280516 PMCID: PMC8906955 DOI: 10.1155/2022/6683104] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 01/20/2022] [Accepted: 02/07/2022] [Indexed: 11/24/2022]
Abstract
Objective Lung cancer is the leading cause of cancer-related deaths worldwide. The aim of this study was to investigate the effects of hypoxic microenvironment on PTEN-L secretion and the effects of PTEN-L on the metastasis of non-small cell lung cancer (NSCLC) and the potential mechanisms. Methods The expression levels of PTEN-L in NSCLC tissues, cells, and cell culture media were detected. The transfection of PTEN-L overexpression construct or HIF-1α-siRNAs was conducted to manipulate the expression of PTEN-L or HIF-1α. NSCLC cells were introduced into 200 μM CoCl2 medium for 72 hours under 37°C to simulate hypoxia. The proliferation and apoptosis of the A549 cells were determined by the Cell Counting Kit-8 assay and Annexin V-FITC/PI-stained flow cytometry assay, respectively. Wound healing assay and transwell invasion assay were used to measure the migration and invasion of A549 cells. The protein expression of PTEN, PTEN-L, PI3K/AKT pathway-related proteins, and HIF-1α was detected by Western blot. Results PTEN and PTEN-L are downregulated in lung cancer tissues and cells. The protein expression of PTEN-L in the culture medium of lung cancer cell lines is decreased. The hypoxic microenvironment inhibits PTEN-L secretion. The low level of PTEN-L promotes cell proliferation, migration, and invasion, as well as inhibits apoptosis of A549 cells. The overexpression of PTEN-L attenuated the activation of the PI3K/AKT pathway by the hypoxic microenvironment. The knockdown of HIF-1α upregulates PTEN-L secretion under hypoxia. Conclusions The hypoxic microenvironment inhibits PTEN-L secretion and thus activates PI3K/AKT pathway to induce proliferation, migration, and invasion promotion, and apoptosis inhibition in NSCLC cells.
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17
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Rawle DJ, Dumenil T, Tang B, Bishop CR, Yan K, Le TT, Suhrbier A. Microplastic consumption induces inflammatory signatures in the colon and prolongs a viral arthritis. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 809:152212. [PMID: 34890673 DOI: 10.1016/j.scitotenv.2021.152212] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 06/13/2023]
Abstract
Global microplastic (MP) contamination and the effects on the environment are well described. However, the potential for MP consumption to affect human health remains controversial. Mice consuming ≈80 μg/kg/day of 1 μm polystyrene MPs via their drinking water showed no weight loss, nor were MPs detected in internal organs. The microbiome was also not significantly changed. MP consumption did lead to small transcriptional changes in the colon suggesting plasma membrane perturbations and mild inflammation. Mice were challenged with the arthritogenic chikungunya virus, with MP consumption leading to a significantly prolonged arthritic foot swelling that was associated with elevated Th1, NK cell and neutrophil signatures. Immunohistochemistry also showed a significant increase in the ratio of neutrophils to monocyte/macrophages. The picture that emerges is reminiscent of enteropathic arthritis, whereby perturbations in the colon are thought to activate innate lymphoid cells that can inter alia migrate to joint tissues to promote inflammation.
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Affiliation(s)
- Daniel J Rawle
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia
| | - Troy Dumenil
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia
| | - Bing Tang
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia
| | - Cameron R Bishop
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia
| | - Kexin Yan
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia
| | - Thuy T Le
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia
| | - Andreas Suhrbier
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia; Australian Infectious Disease Research Centre, GVN Center of Excellence, Brisbane, Queensland 4029 and 4072, Australia.
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18
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Barzegar Behrooz A, Talaie Z, Jusheghani F, Łos MJ, Klonisch T, Ghavami S. Wnt and PI3K/Akt/mTOR Survival Pathways as Therapeutic Targets in Glioblastoma. Int J Mol Sci 2022; 23:ijms23031353. [PMID: 35163279 PMCID: PMC8836096 DOI: 10.3390/ijms23031353] [Citation(s) in RCA: 130] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is a devastating type of brain tumor, and current therapeutic treatments, including surgery, chemotherapy, and radiation, are palliative at best. The design of effective and targeted chemotherapeutic strategies for the treatment of GBM require a thorough analysis of specific signaling pathways to identify those serving as drivers of GBM progression and invasion. The Wnt/β-catenin and PI3K/Akt/mTOR (PAM) signaling pathways are key regulators of important biological functions that include cell proliferation, epithelial–mesenchymal transition (EMT), metabolism, and angiogenesis. Targeting specific regulatory components of the Wnt/β-catenin and PAM pathways has the potential to disrupt critical brain tumor cell functions to achieve critical advancements in alternative GBM treatment strategies to enhance the survival rate of GBM patients. In this review, we emphasize the importance of the Wnt/β-catenin and PAM pathways for GBM invasion into brain tissue and explore their potential as therapeutic targets.
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Affiliation(s)
- Amir Barzegar Behrooz
- Brain Cancer Department, Asu vanda Gene Industrial Research Company, Tehran 1533666398, Iran; (A.B.B.); (Z.T.)
| | - Zahra Talaie
- Brain Cancer Department, Asu vanda Gene Industrial Research Company, Tehran 1533666398, Iran; (A.B.B.); (Z.T.)
| | - Fatemeh Jusheghani
- Department of Biotechnology, Asu vanda Gene Industrial Research Company, Tehran 1533666398, Iran;
| | - Marek J. Łos
- Biotechnology Center, Silesian University of Technology, 44-100 Gliwice, Poland;
| | - Thomas Klonisch
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada;
- Department of Pathology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Department of Surgery, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Department of Medical Microbiology and Infectious Diseases, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada;
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
- Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Faculty of Medicine, Katowice School of Technology, 40-555 Katowice, Poland
- Correspondence:
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Molecular Signaling to Preserve Mitochondrial Integrity against Ischemic Stress in the Heart: Rescue or Remove Mitochondria in Danger. Cells 2021; 10:cells10123330. [PMID: 34943839 PMCID: PMC8699551 DOI: 10.3390/cells10123330] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular diseases are one of the leading causes of death and global health problems worldwide, and ischemic heart disease is the most common cause of heart failure (HF). The heart is a high-energy demanding organ, and myocardial energy reserves are limited. Mitochondria are the powerhouses of the cell, but under stress conditions, they become damaged, release necrotic and apoptotic factors, and contribute to cell death. Loss of cardiomyocytes plays a significant role in ischemic heart disease. In response to stress, protective signaling pathways are activated to limit mitochondrial deterioration and protect the heart. To prevent mitochondrial death pathways, damaged mitochondria are removed by mitochondrial autophagy (mitophagy). Mitochondrial quality control mediated by mitophagy is functionally linked to mitochondrial dynamics. This review provides a current understanding of the signaling mechanisms by which the integrity of mitochondria is preserved in the heart against ischemic stress.
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Sajjadi E, Venetis K, Piciotti R, Gambini D, Blundo C, Runza L, Ferrero S, Guerini-Rocco E, Fusco N. Combined analysis of PTEN, HER2, and hormone receptors status: remodeling breast cancer risk profiling. BMC Cancer 2021; 21:1152. [PMID: 34706703 PMCID: PMC8555186 DOI: 10.1186/s12885-021-08889-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 10/19/2021] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing is improved by the analysis of PTEN status for the identification of high-risk breast cancer. METHODS A cohort of 608 patients with breast cancer was included in this study. Based on the expression on the neoplastic cells compared to the normal internal controls by immunohistochemistry (IHC), cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on publicly available genomic data and included 4265 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher's exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method. RESULTS Alteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from our group, while genetic aberrations in only 315/4265 (7.4%) cases of the METABRIC and MSK cohorts. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n = 48, 17.1%) compared to PTEN-WT tumors (n = 22, 6.7%; p = 0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival (OS) in PTEN-L but not in PTEN-WT breast cancers (p < .0001). Moreover, PTEN-L protein expression but not gene alterations was related to the outcome, in terms of both OS and disease-free survival (p = 0.002). CONCLUSIONS The combined analysis of PTEN, HER2, and HR status offers relevant information for a more precise risk assessment of patients with breast cancer.
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Affiliation(s)
- Elham Sajjadi
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Konstantinos Venetis
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Roberto Piciotti
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Donatella Gambini
- Division of Medical Oncology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy
| | - Concetta Blundo
- Breast Surgery Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy
| | - Letterio Runza
- Division of Pathology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy
- Department of Biomedical, Surgical, and Dental Sciences, University of Milan, Via della Commenda 10, 20122, Milan, Italy
| | - Elena Guerini-Rocco
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy.
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti 435, 20141, Milan, Italy.
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21
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Zhao M, Yang F, Sang C, Yan C, Wang Z. BGL3 inhibits papillary thyroid carcinoma progression via regulating PTEN stability. J Endocrinol Invest 2021; 44:2165-2174. [PMID: 33543443 DOI: 10.1007/s40618-021-01519-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 01/23/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE BGL3, a novel long non-coding RNA (lncRNA) that plays a crucial role in several human malignancies. However, the clinical significance and biological function of BGL3 in papillary thyroid carcinoma (PTC) have not been explored. Herein, we aimed to investigate the role of BGL3 in human PTC. METHODS A total of 85 pairs of PTC and normal tissues were collected for clinicopathological analysis. Expression of BGL3 was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of BGL3 on PTC cells ware determined by CCK-8, colony formation, EdU and wound healing assays. The molecular mechanism underlying BGL3 was tested by ChIP, Co-IP, RNA pull-down and luciferase reporter assays. In vivo experiments were conducted using xenografts in nude mice. RESULTS BGL3 was significantly decreased in PTC tissues compared to adjacent normal thyroid tissues, and it was transcriptionally repressed by oncogene Myc. Low BGL3 is positively related to larger tumor size, lymph node metastasis, later TNM stage and poor prognosis. Overexpression of BGL3 inhibited PTC cell proliferation and migration in vitro, and reduced tumor size and lung metastasis nodules in vivo. BGL3 was mainly located in the cytoplasm, in which interacted with PTEN and recruited OTUD3, enhancing the de-ubiquitination effect of OTUD3 on PTEN, resulting in increasing PTEN protein stability and inactivating carcinogenic PI3K/AKT signaling. CONCLUSIONS Our data underscore the critical tumor-inhibiting role of BGL3 in PTC via post-translational regulation of PTEN protein stability, which may serve as a novel therapeutic target and prognostic biomarker in human PTC.
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Affiliation(s)
- M Zhao
- Department of General Surgery, Yanqing District Hospital, Beijing and Yanqing Hospital, Peking University Third Hospital, Beijing, People's Republic of China
| | - F Yang
- Department of Orthopedics, Yanqing District Hospital, Beijing and Yanqing Hospital, Peking University Third Hospital, Beijing, People's Republic of China
| | - C Sang
- Department of General Surgery, Yanqing District Hospital, Beijing and Yanqing Hospital, Peking University Third Hospital, Beijing, People's Republic of China
| | - C Yan
- Department of General Surgery, Yanqing District Hospital, Beijing and Yanqing Hospital, Peking University Third Hospital, Beijing, People's Republic of China
| | - Z Wang
- Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China.
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22
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Maadi H, Soheilifar MH, Choi WS, Moshtaghian A, Wang Z. Trastuzumab Mechanism of Action; 20 Years of Research to Unravel a Dilemma. Cancers (Basel) 2021; 13:cancers13143540. [PMID: 34298754 PMCID: PMC8303665 DOI: 10.3390/cancers13143540] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/10/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Trastuzumab as a first HER2-targeted therapy for the treatment of HER2-positive breast cancer patients was introduced in 1998. Although trastuzumab has opened a new avenue to treat patients with HER2-positive breast cancer and other types of cancer, some patients are not responsive or become resistant to this treatment. So far, several mechanisms have been suggested for the mode of action of trastuzumab; however, the findings regarding these mechanisms are controversial. In this review, we aimed to provide a detailed insight into the various mechanisms of action of trastuzumab.
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Affiliation(s)
- Hamid Maadi
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; (H.M.); (W.-S.C.)
| | - Mohammad Hasan Soheilifar
- Department of Medical Laser, Medical Laser Research Center, Yara Institute, ACECR, Tehran 1315795613, Iran;
| | - Won-Shik Choi
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; (H.M.); (W.-S.C.)
| | - Abdolvahab Moshtaghian
- Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar 4741695447, Iran;
- Deputy of Research and Technology, Semnan University of Medical Sciences, Semnan 3514799442, Iran
| | - Zhixiang Wang
- Department of Medical Genetics and Signal, Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
- Correspondence:
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23
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Competing Endogenous RNAs in Cervical Carcinogenesis: A New Layer of Complexity. Processes (Basel) 2021. [DOI: 10.3390/pr9060991] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) regulate gene expression by binding to complementary sequences within target mRNAs. Apart from working ‘solo’, miRNAs may interact in important molecular networks such as competing endogenous RNA (ceRNA) axes. By competing for a limited pool of miRNAs, transcripts such as long noncoding RNAs (lncRNAs) and mRNAs can regulate each other, fine-tuning gene expression. Several ceRNA networks led by different lncRNAs—described here as lncRNA-mediated ceRNAs—seem to play essential roles in cervical cancer (CC). By conducting an extensive search, we summarized networks involved in CC, highlighting the major impacts of such dynamic molecular changes over multiple cellular processes. Through the sponging of distinct miRNAs, some lncRNAs as HOTAIR, MALAT1, NEAT1, OIP5-AS1, and XIST trigger crucial molecular changes, ultimately increasing cell proliferation, migration, invasion, and inhibiting apoptosis. Likewise, several lncRNAs seem to be a sponge for important tumor-suppressive miRNAs (as miR-140-5p, miR-143-3p, miR-148a-3p, and miR-206), impairing such molecules from exerting a negative post-transcriptional regulation over target mRNAs. Curiously, some of the involved mRNAs code for important proteins such as PTEN, ROCK1, and MAPK1, known to modulate cell growth, proliferation, apoptosis, and adhesion in CC. Overall, we highlight important lncRNA-mediated functional interactions occurring in cervical cells and their closely related impact on cervical carcinogenesis.
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24
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Pan J, Xu Z, Xu M, Lin X, Lin B, Lin M. Knockdown of Forkhead box A1 suppresses the tumorigenesis and progression of human colon cancer cells through regulating the phosphatase and tensin homolog/Akt pathway. J Int Med Res 2021; 48:300060520971453. [PMID: 33296605 PMCID: PMC7731712 DOI: 10.1177/0300060520971453] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background This study aimed to evaluate the role and the underlying mechanisms of Forkhead box A1 (encoded by FOXA1) in colon cancer. Methods We analyzed FOXA1 mRNA and protein expression in colon cancer tissues and cell lines. We also silenced FOXA1 expression in HCT116 and SW480 cells to evaluate the effects on cell proliferation, cell cycle, migration, and invasion by using MTT, colony formation, flow cytometry, and the Transwell assay, respectively. Results FOXA1 immunostaining was higher in colon cancer tissues than adjacent healthy tissues. FOXA1 mRNA and protein expression was significantly increased in human colon cancer cells compared with a normal colonic cell line. FOXA1 expression was also significantly higher in colorectal cancer tissues from TCGA data sets and was associated with worse prognosis in the R2 database. FOXA1 expression was negatively correlated with the extent of its methylation, and its knockdown reduced proliferation, migration, and invasion, and induced G2/M phase arrest in HCT116 and SW480 cells by suppressing the phosphatase and tensin homolog/Akt signaling pathway and inhibiting epithelial–mesenchymal transition. Conclusion FOXA1 may act as an oncogene in colon cancer tumorigenesis and development.
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Affiliation(s)
- Jie Pan
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
| | - Zongbin Xu
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
| | - Meifang Xu
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
| | - Xiaoyan Lin
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
| | - Bingqiang Lin
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
| | - Mengxin Lin
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
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25
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Kim SH, Kang BC, Seong D, Lee WH, An JH, Je HU, Cha HJ, Chang HW, Kim SY, Kim SW, Han MW. EPHA3 Contributes to Epigenetic Suppression of PTEN in Radioresistant Head and Neck Cancer. Biomolecules 2021; 11:biom11040599. [PMID: 33919657 PMCID: PMC8073943 DOI: 10.3390/biom11040599] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/12/2021] [Accepted: 04/16/2021] [Indexed: 11/16/2022] Open
Abstract
EPHA3, a member of the EPH family, is overexpressed in various cancers. We demonstrated previously that EPHA3 is associated with radiation resistance in head and neck cancer via the PTEN/Akt/EMT pathway; the inhibition of EPHA3 significantly enhances the efficacy of radiotherapy in vitro and in vivo. In this study, we investigated the mechanisms of PTEN regulation through EPHA3-related signaling. Increased DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2) levels, along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, correlated with decreased levels of PTEN in radioresistant head and neck cancer cells. Furthermore, PTEN is regulated in two ways: DNMT1-mediated DNA methylation, and EZH2-mediated histone methylation through EPHA3/C-myc signaling. Our results suggest that EPHA3 could display a novel regulatory mechanism for the epigenetic regulation of PTEN in radioresistant head and neck cancer cells.
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Affiliation(s)
- Song-Hee Kim
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Byung-Chul Kang
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Daseul Seong
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Won-Hyeok Lee
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Jae-Hee An
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Hyoung-Uk Je
- Department of Radiation Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea;
| | - Hee-Jeong Cha
- Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea;
| | - Hyo-Won Chang
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (H.-W.C.); (S.-Y.K.)
| | - Sang-Yoon Kim
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (H.-W.C.); (S.-Y.K.)
| | - Seong-Who Kim
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Correspondence: (S.-W.K.); (M.-W.H.)
| | - Myung-Woul Han
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
- Correspondence: (S.-W.K.); (M.-W.H.)
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26
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Transferred by exosomes-derived MiR-19b-3p targets PTEN to regulate esophageal cancer cell apoptosis, migration and invasion. Biosci Rep 2021; 40:226893. [PMID: 33146702 PMCID: PMC7685012 DOI: 10.1042/bsr20201858] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
The present study aims to investigate the relationship between miR-19b-3p and esophageal cancer (ESCA), and to detect the effects of miR-19b-3p transferred by exosomes on the phenotype of EC9706 cells. The expression of miR-19b-3p was detected by starBase analysis and real-time quantitative PCR (RT-qPCR). The target genes of miR-19b-3p were predicted by TargetScan and further verified by luciferase analysis. The mRNA and protein expression levels of PTEN and EMT-related genes were detected by RT-qPCR and Western blotting. The effects of miR-19b-3p transferred by exosomes and its target genes on the apoptosis, migration and invasion of EC9706 cells were studied by establishing a co-culture model of donor cells. The expression of miR-19b-3p in ESCA plasma, cells and exosomes was significantly up-regulated. miR-19b-3p transferred by exosomes could significantly reduce EC9706 cells apoptosis rate, promote cell migration and invasion, and could target the inhibition of PTEN expression. PTEN overexpression promoted apoptosis, inhibited cell migration and invasion, down-regulated the expression of MMP-2 and vimentin, and up-regulated E-cadherin expression; however, these effects could be partially reversed by miR-19b-3p. In summary, our results reveal that miR-19b-3p transferred by exosomes can target PTEN to regulate ESCA biological functions in the receptor EC9706 cells.
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27
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Gu SH, Chen CH, Lin PL. Expression of protein tyrosine phosphatases and Bombyx embryonic development. JOURNAL OF INSECT PHYSIOLOGY 2021; 130:104198. [PMID: 33549567 DOI: 10.1016/j.jinsphys.2021.104198] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 11/25/2020] [Accepted: 01/28/2021] [Indexed: 06/12/2023]
Abstract
Protein phosphorylation is an integral component of signal transduction pathways within eukaryotic cells, and it is regulated by coordinated interactions between protein kinases and protein phosphatases. Our previous study demonstrated differential expressions of serine/threonine protein phosphatases (PP2A and calcineurin) between diapause and developing eggs in Bombyx mori. In the present study, we further investigated expression of protein tyrosine phosphatases (PTPs) in relation to the Bombyx embryonic development. An immunoblot analysis showed that eggs contained the proteins of the 51-kDa PTP 1B (PTP1B), the 55-kDa phosphatase and tensin homologue (PTEN), and the 70-kDa Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2), which undergo differential changes between diapause and developing eggs. Protein level of PTP1B and PTEN in eggs whose diapause initiation was prevented by HCl gradually increased toward embryonic development. The protein level of SHP2 also showed a dramatic increase on days 7 and 8 after HCl treatment. However, protein levels of PTP1B, PTEN, and SHP2 in diapause eggs remained at low levels during the first 9 days after oviposition. These differential changing patterns in protein levels were further confirmed using both non-diapause eggs and eggs in which diapause had been terminated by chilling of diapausing eggs at 5 °C for 70 days and then were transferred to 25 °C. Direct determination of PTP enzymatic activities showed higher activities in developing eggs (HCl-treated eggs, non-diapause eggs, and chilled eggs) compared to those in diapause eggs. Examination of temporal changes in mRNA expression levels of PTP1B, PTEN, and SHP2 did not show significant differences between diapause eggs and HCl-treated eggs except high expression in SHP2 variant B during the later embryonic development in HCl-treated eggs. These results demonstrate that higher protein levels of PTP1B, PTEN, and SHP2 and increased tyrosine phosphatase enzymatic activities in developing eggs are likely related to embryonic development of B. mori.
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Affiliation(s)
- Shi-Hong Gu
- Department of Biology, National Museum of Natural Science, 1 Kuan-Chien Road, Taichung 404, Taiwan, ROC.
| | - Chien-Hung Chen
- Chung Hwa University of Medical Technology, 89 Wen-Hwa 1st Road, Jen-Te Township, Tainan County 717, Taiwan, ROC
| | - Pei-Ling Lin
- Department of Biology, National Museum of Natural Science, 1 Kuan-Chien Road, Taichung 404, Taiwan, ROC
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28
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Yao DW, Ma J, Yang CL, Chen LL, He QY, Coleman DN, Wang TZ, Jiang XL, Luo J, Ma Y, Loor JJ. Phosphatase and tensin homolog (PTEN) suppresses triacylglycerol accumulation and monounsaturated fatty acid synthesis in goat mammary epithelial cells. J Dairy Sci 2021; 104:7283-7294. [PMID: 33741170 DOI: 10.3168/jds.2020-18784] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 02/04/2021] [Indexed: 12/30/2022]
Abstract
Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor in nonruminants and regulates various cellular processes including growth through dephosphorylation of phosphoinositide substrates. Although studies with bovine mammary tissue suggested a role for PTEN during lactation, its potential role in lipid metabolism remains unknown. Objectives of the present study were to determine PTEN abundance in goat mammary tissue at 2 stages of lactation (n = 6 Xinong Saanen dairy goats per stage), and to use gene-silencing and adenoviral transfections in vitro with isolated goat mammary epithelial cells (GMEC) to evaluate the role of PTEN abundance of lipid metabolism-related genes. Abundance of PTEN decreased by 51.5% at peak lactation compared with the dry period. The PTEN was overexpressed in isolated GMEC through adenoviral transfection using an adenovirus system with Ad-GFP (recombinant adenovirus of green fluorescent protein) as control, and silenced via targeted small interfering RNA (siRNA) transfection with a scrambled small interfering RNA as a negative control. Cell culture was performed for 48 h before RNA extraction, triacylglycerol (TAG) analysis, and fatty acid analysis. Overexpression of PTEN downregulated abundance of acetyl-coenzyme A carboxylase α (ACACA), fatty acid synthase (FASN), sterol regulatory element binding transcription factor1 (SREBF1), stearoyl-coenzyme A desaturase 1 (SCD1), diacylglycerol acytransferase 1 (DGAT1), 1-acylglycerol-3-phosphate O-acyltransferase 6 (AGPAT6) coupled with an increase in patatin-like-phospholipase domain containing 2 (PNPLA2), hormone-sensitive lipase (LIPE), and carnitine palmitoyltransferase 1 β (CPT1B). Furthermore, overexpressing PTEN in vitro resulted in a significant decrease in TAG concentration and concentration of C16:1. In contrast, interference of PTEN led to an opposite effect on lipid metabolism in GMEC. These changes suggested a shift from lipogenesis and esterification to lipolysis and fatty acid oxidation. Collectively, PTEN seems to play a role in monounsaturated fatty acids synthesis and lipid accumulation in GMEC.
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Affiliation(s)
- D W Yao
- Tianjin Institute of Animal Husbandry and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, P. R. China 300381
| | - J Ma
- Tianjin Institute of Animal Husbandry and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, P. R. China 300381
| | - C L Yang
- Tianjin Institute of Animal Husbandry and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, P. R. China 300381
| | - L L Chen
- Tianjin Institute of Animal Husbandry and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, P. R. China 300381
| | - Q Y He
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China 712100
| | - D N Coleman
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - T Z Wang
- Tianjin Institute of Animal Husbandry and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, P. R. China 300381
| | - X L Jiang
- Tianjin Institute of Animal Husbandry and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, P. R. China 300381
| | - J Luo
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China 712100
| | - Y Ma
- Tianjin Institute of Animal Husbandry and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, P. R. China 300381.
| | - J J Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801.
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29
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Li Q, Li H, Liang J, Mei J, Cao Z, Zhang L, Luo J, Tang Y, Huang R, Xia H, Zhang Q, Xiang Q, Yang Y, Huang Y. Sertoli cell-derived exosomal MicroRNA-486-5p regulates differentiation of spermatogonial stem cell through PTEN in mice. J Cell Mol Med 2021; 25:3950-3962. [PMID: 33608983 PMCID: PMC8051706 DOI: 10.1111/jcmm.16347] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/24/2020] [Accepted: 01/12/2021] [Indexed: 12/14/2022] Open
Abstract
Self‐renewal and differentiation of spermatogonial stem cell (SSC) are critical for male fertility and reproduction, both of which are highly regulated by testicular microenvironment. Exosomal miRNAs have emerged as new components in intercellular communication. However, their roles in the differentiation of SSC remain unclear. Here, we observed miR‐486‐5p enriched in Sertoli cell and Sertoli cell‐derived exosomes. The exosomes mediate the transfer of miR‐486‐5p from Sertoli cells to SSCs. Exosomes release miR‐486‐5p, thus up‐regulate expression of Stra8 (stimulated by retinoic acid 8) and promote differentiation of SSC. And PTEN was identified as a target of miR‐486‐5p. Overexpression of miR‐486‐5p in SSCs down‐regulates PTEN expression, which up‐regulates the expression of STRA8 and SYCP3, promotes SSCs differentiation. In addition, blocking the exosome‐mediated transfer of miR‐486‐5p inhibits differentiation of SSC. Our findings demonstrate that miR‐486‐5p acts as a communication molecule between Sertoli cells and SSCs in modulating differentiation of SSCs. This provides a new insight on molecular mechanisms that regulates SSC differentiation and a basis for the diagnosis, treatment, and prevention of male infertility.
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Affiliation(s)
- Quan Li
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Hanhao Li
- Department of Pharmacology, Jinan University, Guangzhou, China
| | - Jinlian Liang
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Jiaxin Mei
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Zhen Cao
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Lei Zhang
- Guangdong Provincial Institute of Biological Products and Materia Medica, Guangzhou, China
| | - Jiao Luo
- Institute for Translational Medicine, Shenzhen Second People's Hospital / The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Yan Tang
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Rufei Huang
- Department of Pharmacology, Jinan University, Guangzhou, China
| | - Huan Xia
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Qihao Zhang
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
| | - Qi Xiang
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China.,Biopharmaceutical Research & Development Center of Jinan University, Guangzhou, China
| | - Yan Yang
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
| | - Yadong Huang
- Department of Cell Biology & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China.,Department of Pharmacology, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
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30
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Serttas R, Koroglu C, Erdogan S. Eupatilin Inhibits the Proliferation and Migration of Prostate Cancer Cells through Modulation of PTEN and NF-κB Signaling. Anticancer Agents Med Chem 2021; 21:372-382. [PMID: 32781972 DOI: 10.2174/1871520620666200811113549] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/29/2020] [Accepted: 07/09/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Despite advances in the treatment of prostate cancer, side effects and the risks of developing drug resistance require new therapeutic agents. Eupatilin is a secondary metabolite of Artemisia asiatica and has shown potential anti-tumor activity in some cancers, but its potential in prostate cancer treatment has not yet been evaluated. OBJECTIVE The aim of the study was to investigate the effectiveness of eupatilin on prostate cancer cell proliferation and migration. METHODS Human prostate cancer PC3 and LNCaP cells were exposed to eupatilin and its efficacy on cell survival was determined by the MTT test. Apoptosis and cell cycle phases were evaluated by an image-based cytometer. Cell migration and invasion were evaluated by wound healing and matrigel migration assays; the expression of mRNA and protein was assessed by RT-qPCR and Western blot, respectively. RESULTS Eupatilin time- and dose-dependently reduced the viability of prostate cancer cells. Exposure of PC3 cells to 12.5μM-50μM eupatilin resulted in apoptosis by upregulating the expression of caspase 3, Bax and cytochrome c. Annexin V assessment also confirmed that eupatilin causes apoptosis. The treatment significantly upregulated the mRNA expression of p53, p21, and p27, causing cell cycle arrest in the G1 phase. Administration of eupatilin inhibited migration and invasion of the cells by downregulating the expression of Twist, Slug and MMP-2, -7. In addition, the agent increased protein expression of tumor suppressor PTEN, while transcription factor NF-κB expression was reduced. CONCLUSION Eupatilin strongly prevents the proliferation of prostate cancer cells, and suppresses migration and invasion. Due to its therapeutic potential, the clinical use of eupatilin in prostate cancer should also be supported by in vivo studies.
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Affiliation(s)
- Riza Serttas
- Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey
| | - Cagla Koroglu
- Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey
| | - Suat Erdogan
- Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey
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31
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Li F, Wang S, Niu M. Scutellarin Inhibits the Growth and EMT of Gastric Cancer Cells through Regulating PTEN/PI3K Pathway. Biol Pharm Bull 2021; 44:780-788. [PMID: 34078809 DOI: 10.1248/bpb.b20-00822] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Gastric cancer is one of the most common malignancies with a high mortality rate world. This study intends to make clear the role and mechanism of the Scutellarin (Scu), a flavonoid isolated from Erigeron breviscapus (Vant.) Hand.-Mazz, in regulating the evolvement of gastric cancer. We selected different doses of Scu to treat gastric cancer cells (MGC-803 and AGS). Then, cell counting kit-8 (CCK8) assay was conducted to verify the proliferation of tumor cells, while flow cytometry was adopted to test the apoptosis rate. Meanwhile, Western blot was conducted to examine epithelial-mesenchymal transition (EMT) markers and the expression of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K) and apoptosis-related proteins (Bax, Bcl2 and Caspase3). Moreover, xenograft tumor experiment in nude mice was established to verify the effect of Scu on tumor growth. Furthermore, the knockdown model of PTEN was constructed, and the influence of PTEN on the anti-tumor effect of Scu was investigated. As a result, Scu inhibited cell proliferation, EMT and promoted the apoptosis in gastric cancer dose-dependently. Additionally, Scu attenuated tumor cell growth in vivo. Besides, Scu enhanced the expression of PTEN while reduced the phosphorylated level of PI3K. Moreover, the mechanistic study proved that Scu inactivated PI3K by up-regulating PTEN, thus dampening tumor progression. In conclusion, Scu dampened the growth and EMT of gastric cancer by regulating the PTEN/PI3K pathway.
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Affiliation(s)
- Fu Li
- Department of Gastroenterology, Shanxian Dongda Hospital
| | - Suping Wang
- Department of Gastroenterology, Shanxian Dongda Hospital
| | - Manxiang Niu
- Department of General Surgery, Shanxian Dongda Hospital
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32
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Shao R, Yang Y, Fan K, Wu X, Jiang R, Tang L, Li L, Shen Y, Liu G, Zhang L. REV-ERBα Agonist GSK4112 attenuates Fas-induced Acute Hepatic Damage in Mice. Int J Med Sci 2021; 18:3831-3838. [PMID: 34790059 PMCID: PMC8579287 DOI: 10.7150/ijms.52011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 10/07/2021] [Indexed: 12/04/2022] Open
Abstract
Fas-induced apoptosis is a central mechanism of hepatocyte damage during acute and chronic hepatic disorders. Increasing evidence suggests that circadian clock plays critical roles in the regulation of cell fates. In the present study, the potential significance of REV-ERBα, a core ingredient of circadian clock, in Fas-induced acute liver injury has been investigated. The anti-Fas antibody Jo2 was injected intraperitoneally in mice to induce acute liver injury and the REV-ERBα agonist GSK4112 was administered. The results indicated that treatment of GSK4112 decreased the level of plasma ALT and AST, attenuated the liver histological changes, and promoted the survival rate in Jo2-insulted mice. Treatment with GSK4112 also downregulated the activities of caspase-3 and caspase-8, suppressed hepatocyte apoptosis. In addition, treatment with GSK4112 decreased the level of Fas and enhanced the phosphorylation of Akt. In conclusion, treatment with GSK4112 alleviated Fas-induced apoptotic liver damage in mice, suggesting that REV-ERBα agonist might have potential value in pharmacological intervention of Fas-associated liver injury.
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Affiliation(s)
- Ruyue Shao
- Clinical Medical School, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China.,Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing 401331, China
| | - Yongqiang Yang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Kerui Fan
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Xicheng Wu
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Rong Jiang
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Li Tang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Longjiang Li
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Yi Shen
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Gang Liu
- Department of Emergency, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Li Zhang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
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33
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Miricescu D, Totan A, Stanescu-Spinu II, Badoiu SC, Stefani C, Greabu M. PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. Int J Mol Sci 2020; 22:E173. [PMID: 33375317 PMCID: PMC7796017 DOI: 10.3390/ijms22010173] [Citation(s) in RCA: 450] [Impact Index Per Article: 90.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is a serious health problem worldwide, representing the second cause of death through malignancies among women in developed countries. Population, endogenous and exogenous hormones, and physiological, genetic and breast-related factors are involved in breast cancer pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is a signaling pathway involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair. In breast tumors, PIK3CA somatic mutations have been reported, located in exon 9 and exon 20. Up to 40% of PIK3CA mutations are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) -negative in primary and metastatic breast cancer. HER2 is overexpressed in 20-30% of breast cancers. HER1, HER2, HER3 and HER4 are membrane receptor tyrosine kinases involved in HER signaling to which various ligands can be attached, leading to PI3K/AKT activation. Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy.
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Affiliation(s)
- Daniela Miricescu
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (D.M.); (A.T.); (M.G.)
| | - Alexandra Totan
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (D.M.); (A.T.); (M.G.)
| | - Iulia-Ioana Stanescu-Spinu
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (D.M.); (A.T.); (M.G.)
| | - Silviu Constantin Badoiu
- Department of Anatomy and Embryology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Constantin Stefani
- Department of Family Medicine and Clinical Base, Dr. Carol Davila Central Military Emergency University Hospital, 134 Calea Plevnei, 010825 Bucharest, Romania;
| | - Maria Greabu
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (D.M.); (A.T.); (M.G.)
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34
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Miasaki FY, Fuziwara CS, de Carvalho GA, Kimura ET. Genetic Mutations and Variants in the Susceptibility of Familial Non-Medullary Thyroid Cancer. Genes (Basel) 2020; 11:E1364. [PMID: 33218058 PMCID: PMC7698903 DOI: 10.3390/genes11111364] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 11/11/2020] [Accepted: 11/16/2020] [Indexed: 12/17/2022] Open
Abstract
Thyroid cancer is the most frequent endocrine malignancy with the majority of cases derived from thyroid follicular cells and caused by sporadic mutations. However, when at least two or more first degree relatives present thyroid cancer, it is classified as familial non-medullary thyroid cancer (FNMTC) that may comprise 3-9% of all thyroid cancer. In this context, 5% of FNMTC are related to hereditary syndromes such as Cowden and Werner Syndromes, displaying specific genetic predisposition factors. On the other hand, the other 95% of cases are classified as non-syndromic FNMTC. Over the last 20 years, several candidate genes emerged in different studies of families worldwide. Nevertheless, the identification of a prevalent polymorphism or germinative mutation has not progressed in FNMTC. In this work, an overview of genetic alteration related to syndromic and non-syndromic FNMTC is presented.
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Affiliation(s)
- Fabíola Yukiko Miasaki
- Department of Endocrinology and Metabolism (SEMPR), Hospital de Clínicas, Federal University of Paraná, Curitiba 80030-110, Brazil; (F.Y.M.); (G.A.d.C.)
| | - Cesar Seigi Fuziwara
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil;
| | - Gisah Amaral de Carvalho
- Department of Endocrinology and Metabolism (SEMPR), Hospital de Clínicas, Federal University of Paraná, Curitiba 80030-110, Brazil; (F.Y.M.); (G.A.d.C.)
| | - Edna Teruko Kimura
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil;
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35
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Liu B, Gao TT, Fu XY, Xu ZH, Ren H, Zhao P, Qi ZT, Qin ZL. PTEN Lipid Phosphatase Activity Enhances Dengue Virus Production through Akt/FoxO1/Maf1 Signaling. Virol Sin 2020; 36:412-423. [PMID: 33044659 DOI: 10.1007/s12250-020-00291-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 07/31/2020] [Indexed: 01/19/2023] Open
Abstract
Dengue virus (DENV) is an arthropod-borne viral pathogen and a global health burden. Knowledge of the DENV-host interactions that mediate virus pathogenicity remains limited. Host lipid metabolism is hijacked by DENV for virus replication in which lipid droplets (LDs) play a key role during the virus lifecycle. In this study, we reveal a novel role for phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in LDs-mediated DENV infection. We demonstrate that PTEN expression is downregulated upon DENV infection through post-transcriptional regulation and, in turn, PTEN overexpression enhances DENV replication. PTEN lipid phosphatase activity was found to decrease cellular LDs area and number through Akt/FoxO1/Maf1 signaling, which, together with autophagy, enhanced DENV replication and virus production. We therefore provide mechanistic insight into the interaction between lipid metabolism and the DENV replication cycle.
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Affiliation(s)
- Bin Liu
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Ting-Ting Gao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.,Department of Nephrology, The Air Force Hospital from Northern Theater of PLA, Shenyang 110042, China
| | - Xiao-Yu Fu
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Zhen-Hao Xu
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Hao Ren
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Ping Zhao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Zhong-Tian Qi
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Zhao-Ling Qin
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
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36
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Fusco N, Sajjadi E, Venetis K, Gaudioso G, Lopez G, Corti C, Rocco EG, Criscitiello C, Malapelle U, Invernizzi M. PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine? Genes (Basel) 2020; 11:E719. [PMID: 32605290 PMCID: PMC7397204 DOI: 10.3390/genes11070719] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/27/2020] [Accepted: 06/27/2020] [Indexed: 12/15/2022] Open
Abstract
Alterations in the tumor suppressor phosphatase and tensin homolog (PTEN) occur in a substantial proportion of solid tumors. These events drive tumorigenesis and tumor progression. Given its central role as a downregulator of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, PTEN is deeply involved in cell growth, proliferation, and survival. This gene is also implicated in the modulation of the DNA damage response and in tumor immune microenvironment modeling. Despite the actionability of PTEN alterations, their role as biomarkers remains controversial in clinical practice. To date, there is still a substantial lack of validated guidelines and/or recommendations for PTEN testing. Here, we provide an update on the current state of knowledge on biologic and genetic alterations of PTEN across the most frequent solid tumors, as well as on their actual and/or possible clinical applications. We focus on possible tailored schemes for cancer patients' clinical management, including risk assessment, diagnosis, prognostication, and treatment.
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Affiliation(s)
- Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (K.V.); (E.G.R.)
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
| | - Elham Sajjadi
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
| | - Konstantinos Venetis
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (K.V.); (E.G.R.)
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
- Doctoral Program in Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Gabriella Gaudioso
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20131 Milan, Italy; (G.G.); (G.L.); (C.C.)
| | - Gianluca Lopez
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20131 Milan, Italy; (G.G.); (G.L.); (C.C.)
| | - Chiara Corti
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20131 Milan, Italy; (G.G.); (G.L.); (C.C.)
| | - Elena Guerini Rocco
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (K.V.); (E.G.R.)
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
| | - Carmen Criscitiello
- New Drugs and Early Drug Development for Innovative Therapies Division, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
| | - Umberto Malapelle
- Department of Public Health, University Federico II, 80138 Naples, Italy;
| | - Marco Invernizzi
- Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy;
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Venniyoor A. PTEN: A Thrifty Gene That Causes Disease in Times of Plenty? Front Nutr 2020; 7:81. [PMID: 32582754 PMCID: PMC7290048 DOI: 10.3389/fnut.2020.00081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/06/2020] [Indexed: 12/15/2022] Open
Abstract
The modern obesity epidemic with associated disorders of metabolism and cancer has been attributed to the presence of "thrifty genes". In the distant past, these genes helped the organism to improve energy efficiency and store excess energy safely as fat to survive periods of famine, but in the present day obesogenic environment, have turned detrimental. I propose PTEN as the likely gene as it has functions that span metabolism, cancer and reproduction, all of which are deranged in obesity and insulin resistance. The activity of PTEN can be calibrated in utero by availability of nutrients by the methylation arm of the epigenetic pathway. Deficiency of protein and choline has been shown to upregulate DNA methyltransferases (DNMT), especially 1 and 3a; these can then methylate promoter region of PTEN and suppress its expression. Thus, the gene is tuned like a metabolic rheostat proportional to the availability of specific nutrients, and the resultant "dose" of the protein, which sits astride and negatively regulates the insulin-PI3K/AKT/mTOR pathway, decides energy usage and proliferation. This "fixes" the metabolic capacity of the organism periconceptionally to a specific postnatal level of nutrition, but when faced with a discordant environment, leads to obesity related diseases.
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Affiliation(s)
- Ajit Venniyoor
- Department of Medical Oncology, National Oncology Centre, The Royal Hospital, Muscat, Oman
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38
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Russo LC, Farias JO, Forti FL. DUSP3 maintains genomic stability and cell proliferation by modulating NER pathway and cell cycle regulatory proteins. Cell Cycle 2020; 19:1545-1561. [PMID: 32380926 DOI: 10.1080/15384101.2020.1762043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The DUSP3 phosphatase regulates cell cycle, proliferation, apoptosis and senescence of different cell types, lately shown as a mediator of DNA repair processes. This work evaluated the impact of DUSP3 loss of function (lof) on DNA repair-proficient fibroblasts (MRC-5), NER-deficient cell lines (XPA and XPC) and translesion DNA synthesis (TLS)-deficient cells (XPV), after UV-radiation stress. The levels of DNA strand breaks, CPDs and 6-4-PPs have accumulated over time in all cells under DUSP3 lof, with a significant increase in NER-deficient lines. The inefficient repair of these lesions increased sub-G1 population of XPA and XPC cells 24 hours after UV treatment, notably marked by DUSP3 lof, which is associated with a reduced cell population in G1, S and G2/M phases. It was also detected an increase in S and G2/M populations of XPV and MRC-5 cells after UV-radiation exposure, which was slightly attenuated by DUSP3 lof due to a discrete increase in sub-G1 cells. The cell cycle progression was accompanied by changes in the levels of the main Cyclins (A1, B1, D1 or E1), CDKs (1, 2, 4 or 6), and the p21 Cip1 inhibitor, in a DUSP3-dependent manner. DUSP3 lof affected the proliferation of MRC-5 and XPA cells, with marked worsening of the XP phenotype after UV radiation. This work highlights the roles of DUSP3 in DNA repair fitness and in the fine control of regulatory proteins of cell cycle, essential mechanisms to maintenance of genomic stability.
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Affiliation(s)
- Lilian Cristina Russo
- Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo , São Paulo-SP, Brazil
| | - Jessica Oliveira Farias
- Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo , São Paulo-SP, Brazil
| | - Fabio Luis Forti
- Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo , São Paulo-SP, Brazil
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Xu F, Na L, Li Y, Chen L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci 2020; 10:54. [PMID: 32266056 PMCID: PMC7110906 DOI: 10.1186/s13578-020-00416-0] [Citation(s) in RCA: 389] [Impact Index Per Article: 77.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism and angiogenesis. Compared with those of other signalling pathways, the components of the PI3K/AKT/mTOR signalling pathway are complicated. The regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway are important in many human diseases, including ischaemic brain injury, neurodegenerative diseases, and tumours. PI3K/AKT/mTOR signalling pathway inhibitors include single-component and dual inhibitors. Numerous PI3K inhibitors have exhibited good results in preclinical studies, and some have been clinically tested in haematologic malignancies and solid tumours. In this review, we briefly summarize the results of research on the PI3K/AKT/mTOR pathway and discuss the structural composition, activation, communication processes, regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway in the pathogenesis of neurodegenerative diseases and tumours.
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Affiliation(s)
- Fei Xu
- Department of Microbiology and Immunology, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Rd, Shanghai, 201318 China
- Collaborative Innovation Center of Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China
| | - Lixin Na
- Collaborative Innovation Center of Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China
- Department of Inspection and Quarantine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China
| | - Yanfei Li
- Department of Inspection and Quarantine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China
| | - Linjun Chen
- Department of Inspection and Quarantine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China
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40
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Zhang L, Li Y, Wang Q, Chen Z, Li X, Wu Z, Hu C, Liao D, Zhang W, Chen ZS. The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer. Mol Cancer 2020; 19:10. [PMID: 31952518 PMCID: PMC6966863 DOI: 10.1186/s12943-019-1112-1] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 11/29/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. METHODS The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP. RESULTS By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. CONCLUSIONS The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Cell Proliferation
- Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors
- Drug Resistance, Multiple/drug effects
- Drug Resistance, Neoplasm/drug effects
- Gene Expression Regulation, Neoplastic
- Humans
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Protein Kinase Inhibitors/pharmacology
- Tumor Cells, Cultured
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Affiliation(s)
- Lei Zhang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Yidong Li
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qianchao Wang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, China
| | - Zhuo Chen
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, China.
| | - Xiaoyun Li
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
- College of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Zhuoxun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Chaohua Hu
- College of Agriculture, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Dan Liao
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
- Key Laboratory of Complementary and Alternative Medicine Experimental Animal Models of Guangxi, Guangxi University of Chinese Medicine, Nanning, 530200, China
| | - Wei Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
- Institute of Plastic Surgery, Weifang Medical University, Weifang, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
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Freeberg MAT, Easa A, Lillis JA, Benoit DS, van Wijnen AJ, Awad HA. Transcriptomic Analysis of Cellular Pathways in Healing Flexor Tendons of Plasminogen Activator Inhibitor 1 (PAI-1/Serpine1) Null Mice. J Orthop Res 2020; 38:43-58. [PMID: 31424116 PMCID: PMC7364818 DOI: 10.1002/jor.24448] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 08/07/2019] [Indexed: 02/04/2023]
Abstract
Injuries to flexor tendons can be complicated by fibrotic adhesions, which severely impair the function of the hand. Plasminogen activator inhibitor 1 (PAI-1/SERPINE1), a master suppressor of fibrinolysis and protease activity, is associated with adhesions. Here, we used next-generation RNA sequencing (RNA-Seq) to assess genome-wide differences in messenger RNA expression due to PAI-1 deficiency after zone II flexor tendon injury. We used the ingenuity pathway analysis to characterize molecular pathways and biological drivers associated with differentially expressed genes (DEG). Analysis of hundreds of overlapping and DEG in PAI-1 knockout (KO) and wild-type mice (C57Bl/6J) during tendon healing revealed common and distinct biological processes. Pathway analysis identified cell proliferation, survival, and senescence, as well as chronic inflammation as potential drivers of fibrotic healing and adhesions in injured tendons. Importantly, we identified the activation of PTEN signaling and the inhibition of FOXO1-associated biological processes as unique transcriptional signatures of the healing tendon in the PAI-1/Serpine1 KO mice. Further, transcriptomic differences due to the genetic deletion of PAI-1 were mechanistically linked to PI3K/Akt/mTOR, PKC, and MAPK signaling cascades. These transcriptional observations provide novel insights into the biological roles of PAI-1 in tendon healing and could identify therapeutic targets to achieve scar-free regenerative healing of tendons. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:43-58, 2020.
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Affiliation(s)
- Margaret A. T. Freeberg
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, United States,Center for Musculoskeletal Research, University of Rochester, Rochester, NY, United States
| | - Anas Easa
- Center for Musculoskeletal Research, University of Rochester, Rochester, NY, United States
| | - Jacquelyn A. Lillis
- Genomics Research Center, University of Rochester, Rochester, NY, United States
| | - Danielle S.W. Benoit
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, United States,Center for Musculoskeletal Research, University of Rochester, Rochester, NY, United States
| | | | - Hani A. Awad
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, United States,Center for Musculoskeletal Research, University of Rochester, Rochester, NY, United States,Department of Orthopedics, University of Rochester, Rochester, NY, United States
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Eisemann T, Pascal JM. Poly(ADP-ribose) polymerase enzymes and the maintenance of genome integrity. Cell Mol Life Sci 2020; 77:19-33. [PMID: 31754726 PMCID: PMC11104942 DOI: 10.1007/s00018-019-03366-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 10/11/2019] [Accepted: 10/31/2019] [Indexed: 01/15/2023]
Abstract
DNA damage response (DDR) relies on swift and accurate signaling to rapidly identify DNA lesions and initiate repair. A critical DDR signaling and regulatory molecule is the posttranslational modification poly(ADP-ribose) (PAR). PAR is synthesized by a family of structurally and functionally diverse proteins called poly(ADP-ribose) polymerases (PARPs). Although PARPs share a conserved catalytic domain, unique regulatory domains of individual family members endow PARPs with unique properties and cellular functions. Family members PARP-1, PARP-2, and PARP-3 (DDR-PARPs) are catalytically activated in the presence of damaged DNA and act as damage sensors. Family members tankyrase-1 and closely related tankyrase-2 possess SAM and ankyrin repeat domains that regulate their diverse cellular functions. Recent studies have shown that the tankyrases share some overlapping functions with the DDR-PARPs, and even perform novel functions that help preserve genomic integrity. In this review, we briefly touch on DDR-PARP functions, and focus on the emerging roles of tankyrases in genome maintenance. Preservation of genomic integrity thus appears to be a common function of several PARP family members, depicting PAR as a multifaceted guardian of the genome.
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Affiliation(s)
- Travis Eisemann
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - John M Pascal
- Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada.
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Zhao D, Zhang S, Wang X, Gao D, Liu J, Cao K, Chen L, Liu R, Liu J, Long J. ATG7 regulates hepatic Akt phosphorylation through the c-JUN/PTEN pathway in high fat diet-induced metabolic disorder. FASEB J 2019; 33:14296-14306. [PMID: 31645130 DOI: 10.1096/fj.201901414rr] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 09/17/2019] [Indexed: 12/12/2022]
Abstract
Growing evidence has suggested that autophagy-related protein 7 (ATG7) plays an important role in insulin signaling, but the mechanism of ATG7 in hepatic insulin sensitivity is not fully understood. The purpose of the present study is to clarify the underlying molecular mechanisms of ATG7 in obesity development. Serum and liver samples from mice fed a high fat diet (HFD) were evaluated for metabolic profile data and ATG expressions during obesity development. We found that compared with other ATGs, ATG7 expression increased earlier with lower hepatic insulin sensitivity in the 4-wk HFD-fed mice. For in vitro analyses, silencing ATG7 significantly up-regulated insulin-stimulated phosphorylation of protein kinase B (Akt) and down-regulated phosphatase and tension homolog deleted on chromosome ten (PTEN) in HepG2 cells. Replenishing PTEN to ATG7-silenced hepatocytes restored the phosphorylated Akt level. Furthermore, ATG7 silencing led to higher c-JUN expression, which transcriptionally reduced PTEN expression. These results reveal a novel mechanism by which ATG7 regulates Akt phosphorylation via the c-JUN/PTEN pathway at the early stage of HFD-induced metabolic disorder.-Zhao, D., Zhang, S., Wang, X., Gao, D., Liu, J., Cao, K., Chen, L., Liu, R., Liu, J., Long, J. ATG7 regulates hepatic Akt phosphorylation through the c-JUN/PTEN pathway in high fat diet-induced metabolic disorder.
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Affiliation(s)
- Daina Zhao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Shuangxi Zhang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Xueqiang Wang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Dan Gao
- Department of Anatomy, Histology, and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Jing Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Ke Cao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Lei Chen
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Run Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiangang Long
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
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Fernández-Acero T, Bertalmio E, Luna S, Mingo J, Bravo-Plaza I, Rodríguez-Escudero I, Molina M, Pulido R, Cid VJ. Expression of Human PTEN-L in a Yeast Heterologous Model Unveils Specific N-Terminal Motifs Controlling PTEN-L Subcellular Localization and Function. Cells 2019; 8:cells8121512. [PMID: 31779149 PMCID: PMC6952770 DOI: 10.3390/cells8121512] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/21/2019] [Accepted: 11/22/2019] [Indexed: 12/21/2022] Open
Abstract
The tumour suppressor PTEN is frequently downregulated, mutated or lost in several types of tumours and congenital disorders including PHTS (PTEN Hamartoma Tumour Syndrome) and ASD (Autism Spectrum Disorder). PTEN is a lipid phosphatase whose activity over the lipid messenger PIP3 counteracts the stimulation of the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway. Recently, several extended versions of PTEN produced in the cell by alternative translation initiation have been described, among which, PTEN-L and PTEN-M represent the longest isoforms. We previously developed a humanized yeast model in which the expression of PI3K in Saccharomyces cerevisiae led to growth inhibition that could be suppressed by co-expression of PTEN. Here, we show that the expression of PTEN-L and PTEN-M in yeast results in robust counteracting of PI3K-dependent growth inhibition. N-terminally tagged GFP-PTEN-L was sharply localized at the yeast plasma membrane. Point mutations of a putative membrane-binding helix located at the PTEN-L extension or its deletion shifted localization to nuclear. Also, a shift from plasma membrane to nucleus was observed in mutants at basic amino acid clusters at the PIP2-binding motif, and at the Cα2 and CBR3 loops at the C2 domain. In contrast, C-terminally tagged PTEN-L-GFP displayed mitochondrial localization in yeast, which was shifted to plasma membrane by removing the first 22 PTEN-L residues. Our results suggest an important role of the N-terminal extension of alternative PTEN isoforms on their spatial and functional regulation.
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Affiliation(s)
- Teresa Fernández-Acero
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM) & Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS). Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain; (T.F.-A.); (E.B.); (I.B.-P.); (I.R.-E.); (M.M.)
| | - Eleonora Bertalmio
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM) & Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS). Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain; (T.F.-A.); (E.B.); (I.B.-P.); (I.R.-E.); (M.M.)
| | - Sandra Luna
- Instituto de Investigación Sanitaria Biocruces Bizkaia, 48903 Barakaldo, Spain; (S.L.); (J.M.)
| | - Janire Mingo
- Instituto de Investigación Sanitaria Biocruces Bizkaia, 48903 Barakaldo, Spain; (S.L.); (J.M.)
| | - Ignacio Bravo-Plaza
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM) & Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS). Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain; (T.F.-A.); (E.B.); (I.B.-P.); (I.R.-E.); (M.M.)
| | - Isabel Rodríguez-Escudero
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM) & Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS). Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain; (T.F.-A.); (E.B.); (I.B.-P.); (I.R.-E.); (M.M.)
| | - María Molina
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM) & Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS). Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain; (T.F.-A.); (E.B.); (I.B.-P.); (I.R.-E.); (M.M.)
| | - Rafael Pulido
- Instituto de Investigación Sanitaria Biocruces Bizkaia, 48903 Barakaldo, Spain; (S.L.); (J.M.)
- IKERBASQUE, Fundación Vasca para la Ciencia, 48011 Bilbao, Spain
- Correspondence: (R.P.); (V.J.C.)
| | - Víctor J. Cid
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM) & Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS). Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain; (T.F.-A.); (E.B.); (I.B.-P.); (I.R.-E.); (M.M.)
- Correspondence: (R.P.); (V.J.C.)
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PTENα and PTENβ promote carcinogenesis through WDR5 and H3K4 trimethylation. Nat Cell Biol 2019; 21:1436-1448. [DOI: 10.1038/s41556-019-0409-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 09/20/2019] [Indexed: 12/18/2022]
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Liu Y, Wang M, Marcora EM, Zhang B, Goate AM. Promoter DNA hypermethylation - Implications for Alzheimer's disease. Neurosci Lett 2019; 711:134403. [PMID: 31351091 PMCID: PMC6759378 DOI: 10.1016/j.neulet.2019.134403] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 07/12/2019] [Accepted: 07/23/2019] [Indexed: 12/31/2022]
Abstract
Recent methylome-wide association studies (MWAS) in humans have solidified the concept that aberrant DNA methylation is associated with Alzheimer's disease (AD). We summarize these findings to improve the understanding of mechanisms governing DNA methylation pertinent to transcriptional regulation, with an emphasis of AD-associated promoter DNA hypermethylation, which establishes an epigenetic barrier for transcriptional activation. By considering brain cell type specific expression profiles that have been published only for non-demented individuals, we detail functional activities of selected neuron, microglia, and astrocyte-enriched genes (AGAP2, DUSP6 and GPR37L1, respectively), which are DNA hypermethylated at promoters in AD. We highlight future directions in MWAS including experimental confirmation, functional relevance to AD, cell type-specific temporal characterization, and mechanism investigation.
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Affiliation(s)
- Yiyuan Liu
- Department of Neuroscience and Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA
| | - Minghui Wang
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
| | - Edoardo M Marcora
- Department of Neuroscience and Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA
| | - Alison M Goate
- Department of Neuroscience and Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA
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Le Guevelou J, Lebars S, Kammerer E, de Gabory L, Vergez S, Janot F, Baujat B, Righini C, Jegoux F, Dufour X, Merol JC, Mauvais O, Lasne-Cardon A, Selleret L, Thariat J. Head and neck cancer during pregnancy. Head Neck 2019; 41:3719-3732. [PMID: 31329334 DOI: 10.1002/hed.25877] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 06/28/2019] [Accepted: 07/03/2019] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND The incidence of cancer during pregnancy is low but is slightly increasing. Data on incidence and etiology of head and neck (HN) cancers in pregnant women are rare. We evaluated the frequency, tumor type, associated factors, and specific biomarkers in HN cancers occurring in pregnant (and peripartum) women. METHODS A systematic literature search was performed on PubMed, for any HN tumor site occurring in pregnant women. RESULTS Sixty cases of HN cancers occurring during pregnancy were identified. Most of them were oral cavity cancers. Relationships with oncogenic viruses, hormonal disturbance, and shift in maternal immunity profile were identified. CONCLUSION Carcinogenesis of HN cancers in pregnant women may be led by different cancer type-specific hallmarks. Relevance of these etiological factors with respect to treatments and birth control recommendations is being investigated by the REFCOR in an ambispective study.
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Affiliation(s)
| | | | | | - Ludovic de Gabory
- Service de Chirurgie ORL, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France
| | - Sebastien Vergez
- Service de Chirurgie ORL, Centre Hospitalier Universitaire Rangueil-Larrey, Toulouse, France
| | - François Janot
- Service de Chirurgie ORL, Centre Gustave Roussy, Villejuif, France
| | - Bertrand Baujat
- Service de Chirurgie ORL, Hopital Tenon, Université Paris-Est, Paris, France
| | - Christian Righini
- Service de Chirurgie ORL, Centre Hospitalier Universitaire de Grenoble, Grenoble, France
| | - Franck Jegoux
- Service de Chirurgie ORL, Centre Hospitalier Universitaire Pontchaillou, Rennes, France
| | - Xavier Dufour
- Service de Chirurgie ORL, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Jean-Claude Merol
- Service de Chirurgie ORL, Centre Hospitalier Universitaire de Reims, Reims, France
| | - Olivier Mauvais
- Service de Chirurgie ORL, Centre Hospitalier Universitaire de Besançon, Besançon, France
| | - Audrey Lasne-Cardon
- Service de Chirurgie ORL Centre François Baclesse, Normandie Université-Unicaen, Caen, France
| | - Lise Selleret
- Service de Gynécologie Obstetrique, Hopital Tenon, Paris, France
| | - Juliette Thariat
- Service de Radiothérapie, Centre François Baclesse, Caen, France
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RSRC1 suppresses gastric cancer cell proliferation and migration by regulating PTEN expression. Mol Med Rep 2019; 20:1747-1753. [PMID: 31257492 PMCID: PMC6625388 DOI: 10.3892/mmr.2019.10409] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 05/10/2019] [Indexed: 12/15/2022] Open
Abstract
Arginine/serine-rich coiled coil 1 (RSRC1) is a gene which plays a significant role in the constitutive and alternative splicing of mRNA and transcriptional regulation. It has been implicated in various neurological disorders, as well as in cancer. However, its role in gastric cancer (GC) remains unknown. Thus, the present study aimed to investigate the role of RSRC1 in GC. RSRC1 expression in GC tissues was determined by RT-qPCR and immunohistochemical staining. The effects of RSRC1 on cell proliferation and migration were detected using a Cell Counting Kit-8 assay, 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay and a Transwell migration assay. Western blot analysis and RT-qPCR were used to explore the molecular mechanisms of of action of RSRC1 in GC. The results indicated that RSRC1 expression was downregulated in GC tissues compared to paired normal tissues and the reduced expression of RSRC1 was shown to contribute to a poor prognosis of patients with GC. RSRC1 knockdown promoted the proliferation and migration of GC cells. In addition, the knockdown of RSRC1 decreased the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a potent tumor suppressor gene controlling cellular growth and viability. On the whole, the findings of the present study indicate that RSRC1 functions as a tumor suppressor gene in GC and that it may exert its effects by regulating PTEN expression.
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Abstract
INTRODUCTION 3-Phosphoinositide-dependent kinase 1 (PDK1), the 'master kinase of the AGC protein kinase family', plays a key role in cancer development and progression. Although it has been rather overlooked, in the last decades a growing number of molecules have been developed to effectively modulate the PDK1 enzyme. AREAS COVERED This review collects different PDK1 inhibitors patented from October 2014 to December 2018. The molecules have been classified on the basis of the chemical structure/type of inhibition, and for each general structure, examples have been discussed in extenso. EXPERT OPINION The role of PDK1 in cancer development and progression as well as in metastasis formation and in chemoresistance has been confirmed by many studies. Therefore, the pharmaceutical discovery in both public and private institutions is still ongoing despite the plentiful molecules already published. The majority of the new molecules synthetized interact with binding sites different from the ATP binding site (i.e. PIF pocket or DFG-out conformation). However, many researchers are still looking for innovative PDK1 modulation strategy such as combination of well-known inhibitory agents or multitarget ligands, aiming to block, together with PDK1, other different critical players in the wide panorama of proteins involved in tumor pathways.
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Affiliation(s)
- Simona Sestito
- a Department of Pharmacy , University of Pisa , Pisa , Italy
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Genetic Testing to Guide Risk-Stratified Screens for Breast Cancer. J Pers Med 2019; 9:jpm9010015. [PMID: 30832243 PMCID: PMC6462925 DOI: 10.3390/jpm9010015] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/18/2019] [Accepted: 02/22/2019] [Indexed: 12/14/2022] Open
Abstract
Breast cancer screening modalities and guidelines continue to evolve and are increasingly based on risk factors, including genetic risk and a personal or family history of cancer. Here, we review genetic testing of high-penetrance hereditary breast and ovarian cancer genes, including BRCA1 and BRCA2, for the purpose of identifying high-risk individuals who would benefit from earlier screening and more sensitive methods such as magnetic resonance imaging. We also consider risk-based screening in the general population, including whether every woman should be genetically tested for high-risk genes and the potential use of polygenic risk scores. In addition to enabling early detection, the results of genetic screens of breast cancer susceptibility genes can be utilized to guide decision-making about when to elect prophylactic surgeries that reduce cancer risk and the choice of therapeutic options. Variants of uncertain significance, especially missense variants, are being identified during panel testing for hereditary breast and ovarian cancer. A finding of a variant of uncertain significance does not provide a basis for increased cancer surveillance or prophylactic procedures. Given that variant classification is often challenging, we also consider the role of multifactorial statistical analyses by large consortia and functional tests for this purpose.
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