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He N, Wei X, Sun R, Zhang G, Zhao J, Jiang X, Long B, Yu Z, Shi W, Jiao Z. Targeting Eg5 using Arry520 combats gastric cancer by inducing monopolar spindles. Gene 2025; 955:149458. [PMID: 40187619 DOI: 10.1016/j.gene.2025.149458] [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: 12/21/2024] [Revised: 03/12/2025] [Accepted: 03/28/2025] [Indexed: 04/07/2025]
Abstract
Eg5, also known as KIF11, is a motor protein essential for establishing a bipolar spindle and ensuring proper chromosome congression during mitosis. It is amplified in various human cancers and serves as a critical oncogene driving tumour progression. However, the role and clinical significance of Eg5 in gastric cancer has remained elusive. In this study, we showed that Eg5 is upregulation in gastric cancer tissues and is negatively associated with patient prognosis. The ablation of Eg5 inhibits the proliferation and migration of gastric cancer cells and suppresses tumour growth in xenograft mice. Mechanistically, Eg5 ablation induces the formation of monopolar spindle, leading to cell apoptosis and consequent inhibition of tumour growth. Furthermore, Arry520 is demonstrated as a potent Eg5 inhibitor which blocks tumour growth by increasing the formation of cell monopolar spindle and inducing apoptosis. Arry520 exhibits efficiently therapeutic effects on gastric cancer in tumour organoid models, cell-derived xenografts and patient-derived xenografts (PDX) in mice. Collectively, our findings provide evidence for the oncogenic properties of the mitotic protein Eg5 and identify Arry520 as a promising strategy to combat gastric cancer.
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Affiliation(s)
- Na He
- Department of Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, China; The Second Clinical Medical College, Lanzhou University, Gansu, China
| | - Xinyuan Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Ruofei Sun
- Department of Oncology, Dingxi People's Hospital, Gansu, China
| | - Gengyuan Zhang
- The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, People's Republic of China
| | - Jie Zhao
- Department of Pathology, Gansu Provincial Maternity and Chlid-care Hospital, Lanzhou, Gansu, China
| | - Xiangyan Jiang
- The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, People's Republic of China
| | - Bo Long
- The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, People's Republic of China
| | - Zeyuan Yu
- The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, People's Republic of China
| | - Wengui Shi
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, People's Republic of China; Biobank of Tumors from Plateau of Gansu Province, Lanzhou University Second Hospital, Lanzhou, People's Republic of China.
| | - Zuoyi Jiao
- The Second Clinical Medical College, Lanzhou University, Gansu, China; The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, People's Republic of China; Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, People's Republic of China; Biobank of Tumors from Plateau of Gansu Province, Lanzhou University Second Hospital, Lanzhou, People's Republic of China.
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Guo W, Gao Y, Du D, Sanchez JE, Li Y, Qiu W, Li L. Elucidating the interactions between Kinesin-5/BimC and the microtubule: insights from TIRF microscopy and molecular dynamics simulations. Brief Bioinform 2025; 26:bbaf144. [PMID: 40172259 PMCID: PMC11962974 DOI: 10.1093/bib/bbaf144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 03/07/2025] [Accepted: 03/11/2025] [Indexed: 04/04/2025] Open
Abstract
Kinesin-5 s are bipolar motor proteins that contribute to cell division by crosslinking and sliding apart antiparallel microtubules inside the mitotic spindle. However, the mechanism underlying the interactions between kinesin-5 and the microtubule remains poorly understood. In this study, we investigated the binding of BimC, a kinesin-5 motor from Aspergillus nidulans, to the microtubule using a combination of total internal reflection fluorescence (TIRF) microscopy and molecular dynamics (MD) simulations. TIRF microscopy experiments revealed that increasing the concentration of KCl in the motility buffer from 0 mM to 150 mM completely abolishes the ability of BimC to bind to the microtubule. Consistent with this experimental finding, MD simulations demonstrated a significant reduction in the strength of electrostatic interactions between BimC and microtubules at 150 mM KCl compared to 0 mM KCl. Furthermore, we identified several salt bridges at the BimC-microtubule interface, with positively charged residues on BimC interacting with negatively charged residues on the tubulin heterodimer. These results provide mechanistic insights into the role of electrostatic interactions in kinesin-5-microtubule binding, advancing our understanding of the molecular underpinnings of kinesin-5 motility.
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Affiliation(s)
- Wenhan Guo
- Department of Physics, University of Texas at El Paso, 500 W University Ave, El Paso, TX 79968, United States
| | - Yuan Gao
- Department of Physics, Oregon State University, 1500 Jefferson Way, Corvallis, OR 97330, United States
| | - Dan Du
- Computational Science Program, University of Texas at El Paso, 500 W University Ave, El Paso, TX 79968, United States
| | - Jason E Sanchez
- Computational Science Program, University of Texas at El Paso, 500 W University Ave, El Paso, TX 79968, United States
| | - Yupeng Li
- Department of Pharmaceutical Sciences, University of Texas at El Paso, 500 W University Ave, El Paso, TX 79968, United States
- Border Biomedical Research Center, University of Texas at El Paso, 500 W University Ave, El Paso, TX 79968, United States
| | - Weihong Qiu
- Department of Physics, Oregon State University, 1500 Jefferson Way, Corvallis, OR 97330, United States
| | - Lin Li
- Department of Physics, University of Texas at El Paso, 500 W University Ave, El Paso, TX 79968, United States
- Computational Science Program, University of Texas at El Paso, 500 W University Ave, El Paso, TX 79968, United States
- Border Biomedical Research Center, University of Texas at El Paso, 500 W University Ave, El Paso, TX 79968, United States
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Lengerli D, Çalışkan ÖA, Çalışkan K, Saatci Ö, Lim C, Vempati S, Çalışkan B, Şahin Ö, Banoglu E. Isoxazole-pyrimidine derivatives as TACC3 inhibitors: A novel modality to targeted cancer therapy. Bioorg Chem 2025; 156:108204. [PMID: 39889548 DOI: 10.1016/j.bioorg.2025.108204] [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: 12/10/2024] [Revised: 01/10/2025] [Accepted: 01/21/2025] [Indexed: 02/03/2025]
Abstract
Inhibiting the function of transforming acidic coiled-coil 3 (TACC3) offers a promising therapeutic approach for various cancers, such as breast, ovarian, and lung cancers.Our previous work introduced BO-264 as a novel chemotype for inhibiting TACC3 function, though it exhibited relatively low metabolic stability. In this study, sixty-two compounds were designed and synthesized to modify the structure of BO-264 to improve its metabolic stability while maintaining its potency. The tractable SAR results obtained by these novel analogs indicated that appropriate substitutions on the left-end phenyl-isoxazole and right-end morpholine groups improved metabolic stability while preserving potency. Among these, compound 13b exhibited approximately sevenfold improvement in metabolic stability and bioavailability while maintaining strong potency and a favorable safety profile. 13b markedly increased the levels of p-Histone H3 (Ser10), cleaved PARP, and p-H2AX (Ser139), indicative of mitotic arrest, apoptosis, and DNA damage, respectively. In addition, the protein-drug binding assay, DARTS, identified TACC3 as a biologically significant target of 13b, positioning it as an advanced lead compound for further development of clinically relevant TACC3 inhibitors in cancers with elevated TACC3 expression.
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Affiliation(s)
- Deniz Lengerli
- Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06560 Ankara, Turkey
| | - Özge Akbulut Çalışkan
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Kübra Çalışkan
- Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06560 Ankara, Turkey
| | - Özge Saatci
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Chaemin Lim
- A2A Pharmaceuticals, Inc., 1185 Avenue of the Americas, New York, NY 10036, USA
| | - Sridhar Vempati
- A2A Pharmaceuticals, Inc., 1185 Avenue of the Americas, New York, NY 10036, USA
| | - Burcu Çalışkan
- Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06560 Ankara, Turkey
| | - Özgür Şahin
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Erden Banoglu
- Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06560 Ankara, Turkey.
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Saadh MJ, Ghnim ZS, Mahdi MS, Chandra M, Ballal S, Bareja L, Chaudhary K, Sharma RSK, Gupta S, Taher WM, Alwan M, Jawad MJ, Hamad AK. Decoding the Role of Kinesin Superfamily Proteins in Glioma Progression. J Mol Neurosci 2025; 75:10. [PMID: 39847238 DOI: 10.1007/s12031-025-02308-9] [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: 12/05/2024] [Accepted: 01/04/2025] [Indexed: 01/24/2025]
Abstract
Glioma is a highly aggressive and invasive brain tumor with limited treatment options, highlighting the need for novel therapeutic approaches. Kinesin superfamily proteins (KIFs) are a diverse group of motor proteins that play essential roles in cellular processes such as mitosis, intracellular transport, and signal transduction, all of which are crucial for tumorigenesis. This review focuses on the multifaceted role of KIFs in glioma, examining their clinical relevance, contribution to tumor progression, and potential as therapeutic targets. We discuss how KIFs influence key aspects of glioma biology, including cell proliferation, invasion, migration, and metastasis. Furthermore, we explore the regulation of the cell cycle and critical signaling pathways associated with glioma, such as PI3K-Akt, Wnt/β-catenin, and Hedgehog signaling by KIFs. The review also addresses the emerging interplay between KIFs and non-coding RNAs, including circular RNAs (circRNAs) and microRNAs (miRNAs), in glioma progression. Finally, we examine current therapeutic strategies targeting KIFs, including immunotherapy, chemotherapy, and small-molecule inhibitors, and their potential to improve treatment outcomes for glioma patients. By synthesizing these insights, this review underscores the significance of KIFs in glioma pathogenesis and their promise as novel therapeutic targets in the fight against glioma.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan.
| | | | | | - Muktesh Chandra
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - R S K Sharma
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Sofia Gupta
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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Nturubika BDD, Logan J, Johnson IRD, Moore C, Li KL, Tang J, Lam G, Parkinson-Lawrence E, Williams DB, Chakiris J, Hindes M, Brooks RD, Miles MA, Selemidis S, Gregory P, Weigert R, Butler L, Ward MP, Waugh DJJ, O’Leary JJ, Brooks DA. Components of the Endosome-Lysosome Vesicular Machinery as Drivers of the Metastatic Cascade in Prostate Cancer. Cancers (Basel) 2024; 17:43. [PMID: 39796673 PMCID: PMC11718918 DOI: 10.3390/cancers17010043] [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: 11/21/2024] [Revised: 12/16/2024] [Accepted: 12/22/2024] [Indexed: 01/13/2025] Open
Abstract
Prostate cancer remains a significant global health concern, with over 1.4 million new cases diagnosed and more than 330,000 deaths each year. The primary clinical challenge that contributes to poor patient outcomes involves the failure to accurately predict and treat at the onset of metastasis, which remains an incurable stage of the disease. This review discusses the emerging paradigm that prostate cancer metastasis is driven by a dysregulation of critical molecular machinery that regulates endosome-lysosome homeostasis. Endosome and lysosome compartments have crucial roles in maintaining normal cellular function but are also involved in many hallmarks of cancer pathogenesis, including inflammation, immune response, nutrient sensing, metabolism, proliferation, signalling, and migration. Here we discuss new insight into how alterations in the complex network of trafficking machinery, responsible for the microtubule-based transport of endosomes and lysosomes, may be involved in prostate cancer progression. A better understanding of endosome-lysosome dynamics may facilitate the discovery of novel strategies to detect and manage prostate cancer metastasis and improve patient outcomes.
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Affiliation(s)
- Bukuru Dieu-Donne Nturubika
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Jessica Logan
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Ian R. D. Johnson
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Courtney Moore
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Ka Lok Li
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Jingying Tang
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Giang Lam
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia; (G.L.); (P.G.); (D.J.J.W.)
| | - Emma Parkinson-Lawrence
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Desmond B. Williams
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - James Chakiris
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Madison Hindes
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Robert D. Brooks
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
| | - Mark A. Miles
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia; (M.A.M.); (S.S.)
| | - Stavros Selemidis
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia; (M.A.M.); (S.S.)
| | - Philip Gregory
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia; (G.L.); (P.G.); (D.J.J.W.)
| | - Roberto Weigert
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Lisa Butler
- South Australian ImmunoGENomics Cancer Institute, Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA 5000, Australia;
- Solid Tumour Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Mark P. Ward
- Department of Pathology, The Coombe Women and Infants University Hospital, Trinity College Dublin, D08 XW7X Dublin, Ireland;
| | - David J. J. Waugh
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia; (G.L.); (P.G.); (D.J.J.W.)
| | - John J. O’Leary
- Department of Histopathology, Trinity College Dublin, D08 XW7X Dublin, Ireland;
| | - Douglas A. Brooks
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia; (J.L.); (C.M.); (K.L.L.); (J.T.); (E.P.-L.); (D.B.W.); (J.C.); (M.H.); (R.D.B.)
- Department of Histopathology, Trinity College Dublin, D08 XW7X Dublin, Ireland;
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Advani D, Kumar P. Uncovering Cell Cycle Dysregulations and Associated Mechanisms in Cancer and Neurodegenerative Disorders: A Glimpse of Hope for Repurposed Drugs. Mol Neurobiol 2024; 61:8600-8630. [PMID: 38532240 DOI: 10.1007/s12035-024-04130-7] [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: 12/25/2023] [Accepted: 03/19/2024] [Indexed: 03/28/2024]
Abstract
The cell cycle is the sequence of events orchestrated by a complex network of cell cycle proteins. Unlike normal cells, mature neurons subsist in a quiescent state of the cell cycle, and aberrant cell cycle activation triggers neuronal death accompanied by neurodegeneration. The periodicity of cell cycle events is choreographed by various mechanisms, including DNA damage repair, oxidative stress, neurotrophin activity, and ubiquitin-mediated degradation. Given the relevance of cell cycle processes in cancer and neurodegeneration, this review delineates the overlapping cell cycle events, signaling pathways, and mechanisms associated with cell cycle aberrations in cancer and the major neurodegenerative disorders. We suggest that dysregulation of some common fundamental signaling processes triggers anomalous cell cycle activation in cancer cells and neurons. We discussed the possible use of cell cycle inhibitors for neurodegenerative disorders and described the associated challenges. We propose that a greater understanding of the common mechanisms driving cell cycle aberrations in cancer and neurodegenerative disorders will open a new avenue for the development of repurposed drugs.
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Affiliation(s)
- Dia Advani
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), Shahbad Daulatpur, Bawana Road, New Delhi, Delhi, 110042, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), Shahbad Daulatpur, Bawana Road, New Delhi, Delhi, 110042, India.
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7
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Ghnim ZS, Mahdi MS, Ballal S, Chahar M, Verma R, Al-Nuaimi AMA, Kumar MR, Al-Hussein RKA, Adil M, Jawad MJ. The role of kinesin superfamily proteins in hepatocellular carcinoma. Med Oncol 2024; 41:271. [PMID: 39400594 DOI: 10.1007/s12032-024-02497-0] [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: 07/29/2024] [Accepted: 09/04/2024] [Indexed: 10/15/2024]
Abstract
The most prevalent form of primary liver cancer, hepatocellular carcinoma (HCC) poses a significant global health challenge due to its limited therapeutic options. Researchers are currently focused on the complex molecular landscape that governs the initiation and progression of HCC in order to identify new avenues for diagnosis, prognosis, and treatment. In the context of HCC, the Kinesin Superfamily Proteins (KIFs) have become critical regulators of cellular processes, prompting a growing interest in their function among the diverse array of molecular actors implicated in cancer. The KIFs, a family of microtubule-based molecular motors, are renowned for their essential roles in the dynamics of mitotic spindles and intracellular transport. Beyond their well-established functions in normal cellular physiology, emerging evidence indicates that dysregulation of KIFs significantly contributes to the pathogenesis of HCC. Novel therapeutic targets and diagnostic markers are revealed through the unique opportunity to comprehend the complex interplay between KIFs and the molecular events that drive HCC.
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Affiliation(s)
| | | | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India.
| | - Mamata Chahar
- Department of Chemistry, NIMS Institute of Engineering & Technology, NIMS University, Jaipur, Rajasthan, India
| | - Rajni Verma
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges, Jhanjeri, Mohali, Amritsar, Punjab, 140307, India
| | | | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | | | - Mohaned Adil
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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8
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Wang T, Wang RX, Colgan SP. Physiologic hypoxia in the intestinal mucosa: a central role for short-chain fatty acids. Am J Physiol Cell Physiol 2024; 327:C1087-C1093. [PMID: 39159391 PMCID: PMC11482044 DOI: 10.1152/ajpcell.00472.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 08/21/2024]
Abstract
The intestinal mucosa is a dynamic surface that facilitates interactions between the host and an outside world that includes trillions of microbes, collectively termed the microbiota. This fine balance is regulated by an energetically demanding physical and biochemical barrier that is formed by the intestinal epithelial cells. In addition, this homeostasis exists at an interface between the anaerobic colonic lumen and a highly oxygenated, vascularized lamina propria. The resultant oxygen gradient within the intestine establishes "physiologic hypoxia" as a central metabolic feature of the mucosa. Although oxygen is vital for energy production to meet cellular metabolism needs, the availability of oxygen has far-reaching influences beyond just energy provision. Recent studies have shown that the intestinal mucosa has purposefully adapted to use differential oxygen levels largely through the presence of short-chain fatty acids (SCFAs), particularly butyrate (BA). Intestinal epithelial cells use butyrate for a multitude of functions that promote mucosal homeostasis. In this review, we explore how the physiologic hypoxia profile interfaces with SCFAs to benefit host mucosal tissues.
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Affiliation(s)
- Timothy Wang
- Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Department of Healthcare Studies, University of Texas Dallas, Richardson, Texas, United States
| | - Ruth X Wang
- Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Department of Dermatology, University of California San Diego, San Diego, California, United States
| | - Sean P Colgan
- Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado, United States
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9
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Yao Z, Chen J, Wang Y, Cao L. Bioinformatics analysis and validation of HAUS6 as a key prognostic gene in squamous cell carcinoma of the tongue. Arch Oral Biol 2024; 164:106000. [PMID: 38759391 DOI: 10.1016/j.archoralbio.2024.106000] [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: 01/31/2024] [Revised: 05/01/2024] [Accepted: 05/07/2024] [Indexed: 05/19/2024]
Abstract
OBJECTIVE To explore the expression of HAUS6 in squamous cell carcinoma of the tongue (TSCC) and its relationship with the clinicopathological features of patients, and to further provide new ideas and therapeutic targets for curing TSCC. DESIGN The Cancer Genome Atlas (TCGA) database was used to screen for differentially expressed genes (DEGs) between TSCC and normal tissues and survival analysis. DEGs of HAUS6 were screened and analyzed for GO, KEGG and GSEA enrichment. Exploring the correlation of HAUS6 with immune cell infiltration and immune checkpoint-related genes. The expression of HAUS6 in tumor and paraneoplastic tissues was confirmed by immunohistochemistry and Western Blot. RESULTS Analysis of the TCGA database results showed that expression of HAUS6 mRNA was significantly enhanced and correlated with overall survival (OS, p < 0.05) in TSCC. HAUS6 expression correlated with the level of immune cell infiltration and immune checkpoint-related genes. Immunohistochemistry and Western Blot confirmed that the expression level of HAUS6 protein was significantly higher in tumor tissues than in paraneoplastic tissues, and that tumor size and hypo-differentiation were higher in the HAUS6 high expression group than in the low expression group in TSCC (p < 0.05). CONCLUSIONS In conclusion, these analyses suggest that HAUS6 can act as an independent predictor of prognosis (p < 0.05) and high HAUS6 expression is strongly associated with poor prognosis.
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Affiliation(s)
- Zhuoyue Yao
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China
| | - Jing Chen
- Pathology Teaching and Research Laboratory, Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Yue Wang
- Pathology Teaching and Research Laboratory, Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Liyu Cao
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China; Pathology Teaching and Research Laboratory, Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China.
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10
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Guo W, Gao Y, Du D, Sanchez JE, Visootsat A, Li Y, Qiu W, Li L. How does the ion concentration affect the functions of kinesin BimC. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.31.596855. [PMID: 38853942 PMCID: PMC11160742 DOI: 10.1101/2024.05.31.596855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
BimC family proteins are bipolar motor proteins belonging to the kinesin superfamily which promote mitosis by crosslinking and sliding apart antiparallel microtubules. Understanding the binding mechanism between the kinesin and the microtubule is crucial for researchers to make advances in the treatment of cancer and other malignancies. Experimental research has shown that the ion concentration affects the function of BimC significantly. But the insights of the ion-dependent function of BimC remain unclear. By combining molecular dynamics (MD) simulations with a series of computational approaches, we studied the electrostatic interactions at the binding interfaces of BimC and the microtubule under different KCl concentrations. We found the electrostatic interaction between BimC and microtubule is stronger at 0 mM KCl compared to 150 mM KCl, which is consistent with experimental conclusions. Furthermore, important salt bridges and residues at the binding interfaces of the complex were identified, which illustrates the details of the BimC-microtubule interactions. Molecular dynamics analyses of salt bridges identified that the important residues on the binding interface of BimC are positively charged, while those residues on the binding interface of the tubulin heterodimer are negatively charged. The finding in this work reveals some important mechanisms of kinesin-microtubule binding, which helps the future drug design for cancer therapy.
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Nejabat M, Hadizadeh F, Sahebkar A. The Application of Kinesin Inhibitors in Medical Issues. Curr Rev Clin Exp Pharmacol 2024; 19:370-378. [PMID: 38275041 DOI: 10.2174/0127724328277623231204064614] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/27/2023] [Accepted: 11/01/2023] [Indexed: 01/27/2024]
Abstract
Kinesins are a group of motor proteins in charge of several crucial functions in the cell. These proteins often bind to microtubules and perform their functions using the energy produced by ATP hydrolysis. One function of mitotic kinesin, a subclass of kinesin that is expressed during cell division at the mitotic phase, is to create the mitotic spindle. Uncontrolled cell growth is one trait of cancerous cells. Traditional anticancer medications still used in clinics include taxanes (paclitaxel) and vinca alkaloids (vincristine, vinblastine), which interfere with microtubule dynamics. However, because non-dividing cells like post-mitotic neurons contain microtubules, unwanted side effects like peripheral neuropathy are frequently found in patients taking these medications. More than ten members of the mitotic kinesin family play distinct or complementary roles during mitosis. The mitotic kinesin family's KSP, or Eg5, is regarded as its most dramatic target protein. The current work systematically reviews the use of kinesin inhibitors in the medical field. The challenges of KSP and the practical solutions are also examined, and the outcomes of the previous works are reported. The significant gaps and shortcomings of the related works are also highlighted, which can be an onset topic for future works.
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Affiliation(s)
- Mojgan Nejabat
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzin Hadizadeh
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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12
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Timofeeva AV, Fedorov IS, Asaturova AV, Sannikova MV, Tregubova AV, Mayboroda OA, Khabas GN, Frankevich VE, Sukhikh GT. Blood Plasma Small Non-Coding RNAs as Diagnostic Molecules for the Progesterone-Receptor-Negative Phenotype of Serous Ovarian Tumors. Int J Mol Sci 2023; 24:12214. [PMID: 37569592 PMCID: PMC10419267 DOI: 10.3390/ijms241512214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
The expression level of the progesterone receptor (PGR) plays a crucial role in determining the biological characteristics of serous ovarian carcinoma. Low PGR expression is associated with chemoresistance and a poorer outcome. In this study, our objective was to explore the relationship between tumor progesterone receptor levels and RNA profiles (miRNAs, piwiRNAs, and mRNAs) to understand their biological characteristics and behavior. To achieve this, we employed next-generation sequencing of small non-coding RNAs, quantitative RT-PCR, and immunohistochemistry to analyze both FFPE and frozen tumor samples, as well as blood plasma from patients with benign cystadenoma (BSC), serous borderline tumor (SBT), low-grade serous ovarian carcinoma (LGSOC), and high-grade serous ovarian carcinoma (HGSOC). Our findings revealed significant upregulation of MMP7 and MUC16, along with downregulation of PGR, in LGSOC and HGSOC compared to BSC. We observed significant correlations of PGR expression levels in tumor tissue with the contents of miR-199a-5p, miR-214-3p, miR-424-3p, miR-424-5p, and miR-125b-5p, which potentially target MUC16, MMP7, and MMP9, as well as with the tissue content of miR-16-5p, miR-17-5p, miR-20a-5p, and miR-93-5p, which are associated with the epithelial-mesenchymal transition (EMT) of cells. The levels of EMT-associated miRNAs were significantly correlated with the content of hsa_piR_022437, hsa_piR_009295, hsa_piR_020813, hsa_piR_004307, and hsa_piR_019914 in tumor tissues. We developed two optimal logistic regression models using the quantitation of hsa_piR_020813, miR-16-5p, and hsa_piR_022437 or hsa_piR_004307, hsa_piR_019914, and miR-93-5p in the tumor tissue, which exhibited a significant ability to diagnose the PGR-negative tumor phenotype with 93% sensitivity. Of particular interest, the blood plasma levels of miR-16-5p and hsa_piR_022437 could be used to diagnose the PGR-negative tumor phenotype with 86% sensitivity even before surgery and chemotherapy. This knowledge can help in choosing the most effective treatment strategy for this aggressive type of ovarian cancer, such as neoadjuvant chemotherapy followed by cytoreduction in combination with hyperthermic intraperitoneal chemotherapy and targeted therapy, thus enhancing the treatment's effectiveness and the patient's longevity.
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Affiliation(s)
- Angelika V. Timofeeva
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Ivan S. Fedorov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Aleksandra V. Asaturova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Maya V. Sannikova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Anna V. Tregubova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Oleg A. Mayboroda
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands;
| | - Grigory N. Khabas
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Vladimir E. Frankevich
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
- Laboratory of Translational Medicine, Siberian State Medical University, 634050 Tomsk, Russia
| | - Gennady T. Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
- Department of Obstetrics, Gynecology, Perinatology and Reproductology, First Moscow State Medical University Named after I.M. Sechenov, 119991 Moscow, Russia
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13
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Weaver N, Hammonds J, Ding L, Lerner G, Dienger-Stambaugh K, Spearman P. KIF16B Mediates Anterograde Transport and Modulates Lysosomal Degradation of the HIV-1 Envelope Glycoprotein. J Virol 2023; 97:e0025523. [PMID: 37358446 PMCID: PMC10373548 DOI: 10.1128/jvi.00255-23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/08/2023] [Indexed: 06/27/2023] Open
Abstract
The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) is incorporated into virions at the site of particle assembly on the plasma membrane (PM). The route taken by Env to reach the site of assembly and particle incorporation remains incompletely understood. Following initial delivery to the PM through the secretory pathway, Env is rapidly endocytosed, suggesting that recycling is required for particle incorporation. Endosomes marked by the small GTPase Rab14 have been previously shown to play a role in Env trafficking. Here, we examined the role of KIF16B, the molecular motor protein that directs outward movement of Rab14-dependent cargo, in Env trafficking. Env colocalized extensively with KIF16B+ endosomes at the cellular periphery, while expression of a motor-deficient mutant of KIF16B redistributed Env to a perinuclear location. The half-life of Env labeled at the cell surface was markedly reduced in the absence of KIF16B, while a normal half-life was restored through inhibition of lysosomal degradation. In the absence of KIF16B, Env expression on the surface of cells was reduced, leading to a reduction in Env incorporation into particles and a corresponding reduction in particle infectivity. HIV-1 replication in KIF16B knockout cells was substantially reduced compared to that in wild-type cells. These results indicated that KIF16B regulates an outward sorting step involved in Env trafficking, thereby limiting lysosomal degradation and enhancing particle incorporation. IMPORTANCE The HIV-1 envelope glycoprotein is an essential component of HIV-1 particles. The cellular pathways that contribute to incorporation of envelope into particles are not fully understood. Here, we have identified KIF16B, a motor protein that directs movement from internal compartments toward the plasma membrane, as a host factor that prevents envelope degradation and enhances particle incorporation. This is the first host motor protein identified that contributes to HIV-1 envelope incorporation and replication.
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Affiliation(s)
- Nicholas Weaver
- Immunobiology Division, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
- Infectious Diseases, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Jason Hammonds
- Infectious Diseases, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Lingmei Ding
- Infectious Diseases, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Grigoriy Lerner
- Immunobiology Division, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
- Infectious Diseases, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Krista Dienger-Stambaugh
- Infectious Diseases, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Paul Spearman
- Infectious Diseases, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
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14
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Zhang J, An L, Zhao R, Shi R, Zhou X, Wei S, Zhang Q, Zhang T, Feng D, Yu Z, Wang H. KIF4A promotes genomic stability and progression of endometrial cancer through regulation of TPX2 protein degradation. Mol Carcinog 2023; 62:303-318. [PMID: 36468837 DOI: 10.1002/mc.23487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 10/07/2022] [Accepted: 11/04/2022] [Indexed: 12/12/2022]
Abstract
Kinesin family member 4A (KIF4A) belongs to the kinesin superfamily proteins, which are closely associated with mitophagy. Nonetheless, the role of KIF4A in endometrial cancer (EC) remains poorly characterized. The present study showed that KIF4A not only was upregulated but also predicted poor prognosis in patients with EC. KIF4A knockdown in EC cells resulted in attenuated proliferative capacity in vitro and in vivo. Transcriptome sequencing and gene function analysis revealed that KIF4A contributed to the maintenance of EC cells' genomic stability and that KIF4A knockdown induced the DNA damage response, cell cycle arrest, and apoptosis. Mechanistically, KIF4A interacted with TPX2 (a protein involved in DNA damage repair to cope with the replication pressure) to enhance its stability via inhibition of TPX2 ubiquitination and eventually ensured the genomic stability of EC cells during mitosis. Taken together, our results indicated that KIF4A functions as a tumor oncogene that facilitates EC progression via the maintenance of genomic stability. Therefore, targeting the KIF4A/TPX2 axis may provide new concepts and strategies for the treatment of patients with EC.
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Affiliation(s)
- Jun Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lanfen An
- Division of Life Science and Medicine, Clinical Center of Reproductive Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Rong Zhao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rui Shi
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xing Zhou
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sitian Wei
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qi Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tangansu Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dilu Feng
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhicheng Yu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hongbo Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Clinical Research Center of Cancer Immunotherapy, Wuhan, Hubei, China
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15
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Zhang C, Guo C, Russell RW, Quinn CM, Li M, Williams JC, Gronenborn AM, Polenova T. Magic-angle-spinning NMR structure of the kinesin-1 motor domain assembled with microtubules reveals the elusive neck linker orientation. Nat Commun 2022; 13:6795. [PMID: 36357375 PMCID: PMC9649657 DOI: 10.1038/s41467-022-34026-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 10/10/2022] [Indexed: 11/12/2022] Open
Abstract
Microtubules (MTs) and their associated proteins play essential roles in maintaining cell structure, organelle transport, cell motility, and cell division. Two motors, kinesin and cytoplasmic dynein link the MT network to transported cargos using ATP for force generation. Here, we report an all-atom NMR structure of nucleotide-free kinesin-1 motor domain (apo-KIF5B) in complex with paclitaxel-stabilized microtubules using magic-angle-spinning (MAS) NMR spectroscopy. The structure reveals the position and orientation of the functionally important neck linker and how ADP induces structural and dynamic changes that ensue in the neck linker. These results demonstrate that the neck linker is in the undocked conformation and oriented in the direction opposite to the KIF5B movement. Chemical shift perturbations and intensity changes indicate that a significant portion of ADP-KIF5B is in the neck linker docked state. This study also highlights the unique capability of MAS NMR to provide atomic-level information on dynamic regions of biological assemblies.
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Affiliation(s)
- Chunting Zhang
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Changmiao Guo
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Ryan W Russell
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Caitlin M Quinn
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Mingyue Li
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - John C Williams
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA.
| | - Angela M Gronenborn
- Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA.
| | - Tatyana Polenova
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA.
- Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA.
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16
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Synthesis, crystal structure and molecular docking study of new monastrol analogues as inhibitors of epidermal growth factor receptor tyrosine kinase. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.134508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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17
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Apaza Ticona L, Rumbero Sánchez Á, Humanes Bastante M, Serban AM, Hernáiz MJ. Antitumoral activity of 1,2,4-oxadiazoles compounds isolated from the Neowerdermannia vorwerkii in liver and colon human cancer cells. PHYTOCHEMISTRY 2022; 201:113259. [PMID: 35662550 DOI: 10.1016/j.phytochem.2022.113259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 06/15/2023]
Abstract
Two unknown 1,2,4-oxadiazoles (3-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,4-oxadiazole and 5-(3-hydroxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole) and one known 1,2,4-oxadiazole (5-(3-methoxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole) were isolated from tubers of Neowerdermannia vorwerkii, collected from the San Juan Huancollo, Ingavi province, La Paz, Bolivia. The chemical structures of these compounds were elucidated through NMR and HRMS spectroscopic analyses. All compounds showed apoptotic capacity against the SK-HEP-1 and Caco-2 tumour cells. 5-(3-methoxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole and 5-(3-hydroxyphenyl)-3-(pyridin-3-yl)-1,2, 4-oxadiazole showed slight apoptotic capacities, with an IC50 between 17.46 ± 0.75 to 15.91 ± 0.62 μM and 39.29 ± 0.98 to 34.81 ± 0.70 μM, respectively. 3-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,4-oxadiazole showed a higher apoptotic capacity with an IC50 in the range of 0.98 ± 0.11 to 0.76 ± 0.03 μM, similar to that of the positive control (Dimethylenastron).
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Affiliation(s)
- Luis Apaza Ticona
- Organic Chemistry Unit, Department of Chemistry in Pharmaceutical Sciences, Faculty of Pharmacy, Universidad Complutense de Madrid, Plza. Ramón y Cajal s/n, 28040, Madrid, Spain; Department of Organic Chemistry, Faculty of Sciences, University Autónoma of Madrid, Cantoblanco, 28049, Madrid, Spain.
| | - Ángel Rumbero Sánchez
- Department of Organic Chemistry, Faculty of Sciences, University Autónoma of Madrid, Cantoblanco, 28049, Madrid, Spain
| | - Marcos Humanes Bastante
- Department of Organic Chemistry, Faculty of Sciences, University Autónoma of Madrid, Cantoblanco, 28049, Madrid, Spain
| | - Andreea Madalina Serban
- Maria Sklodowska Curie University Hospital for Children. Constantin Brancoveanu Boulevard, 077120, Bucharest, Romania
| | - María J Hernáiz
- Organic Chemistry Unit, Department of Chemistry in Pharmaceutical Sciences, Faculty of Pharmacy, Universidad Complutense de Madrid, Plza. Ramón y Cajal s/n, 28040, Madrid, Spain
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Wang LB, Zhang XB, Liu J, Liu QJ. The Proliferation of Glioblastoma Is Contributed to Kinesin Family Member 18A and Medical Data Analysis of GBM. Front Genet 2022; 13:858882. [PMID: 35464837 PMCID: PMC9033168 DOI: 10.3389/fgene.2022.858882] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 01/26/2022] [Indexed: 11/23/2022] Open
Abstract
Background: Glioblastoma (GBM) is widely known as a classical kind of malignant tumor originating in the brain with high morbidity and mortality. Targeted therapy has shown great promise in treating glioblastoma, but more promising targets, including effective therapeutic targets, remain to be identified. 18A (KIF18A) is a microtubule-based motor protein that is dysregulated and involved in the progression of multiple human cancers. However, the possible effects of KIF18A on GBM progression are still unclear. Methods: We performed DEG analysis, medical data analysis, and network analysis to identify critical genes affecting glioma progression. We also performed immunohistochemical analysis of the KIF18A levels in 94 patients with glioblastoma and the associated surrounding tissues. Patients were divided into two groups according to the high and low expression. Using a clinical analysis, we showed the potential associations between KIF18A expression and clinical characteristics of 94 GBM patients. We then investigated the effects of KIF18A on GBM cell proliferation by colony establishment, MTT, and immune blogging. The possible effect of KIF18A on GBM tumor growth was determined in mice. Results: We identified KIF18A as a potential gene affecting GBM progression. We further demonstrated that GBM tissues expressed KIF18A much higher, and its presentation was associated with recurrence in glioblastoma patients. We believe KIF18A promotes GBM cell proliferation. Conclusion: We demonstrated that KIF18A could be a promising target in treating GBM.
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Affiliation(s)
- Lei-Bo Wang
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Xue-Bin Zhang
- Department of Pathology, Tianjin Huanhu Hospital, Tianjin, China
| | - Jun Liu
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Qing-Jun Liu
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
- *Correspondence: Qing-Jun Liu,
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NAT10 regulates mitotic cell fate by acetylating Eg5 to control bipolar spindle assembly and chromosome segregation. Cell Death Differ 2022; 29:846-860. [PMID: 35210604 PMCID: PMC8989979 DOI: 10.1038/s41418-021-00899-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 02/07/2023] Open
Abstract
Cell fate of mitotic cell is controlled by spindle assembly. Deficient spindle assembly results in mitotic catastrophe leading to cell death to maintain cellular homeostasis. Therefore, inducing mitotic catastrophe provides a strategy for tumor therapy. Nucleolar acetyltransferase NAT10 has been found to regulate various cellular processes to maintain cell homeostasis. Here we report that NAT10 regulates mitotic cell fate by acetylating Eg5. NAT10 depletion results in multinuclear giant cells, which is the hallmark of mitotic catastrophe. Live-cell imaging showed that knockdown of NAT10 dramatically prolongs the mitotic time and induces defective chromosome segregation including chromosome misalignment, bridge and lagging. NAT10 binds and co-localizes with Eg5 in the centrosome during mitosis. Depletion of NAT10 reduces the centrosome loading of Eg5 and impairs the poleward movement of centrosome, leading to monopolar and asymmetrical spindle formation. Furthermore, NAT10 stabilizes Eg5 through its acetyltransferase function. NAT10 acetylates Eg5 at K771 to control Eg5 stabilization. We generated K771-Ac specific antibody and showed that Eg5 K771-Ac specifically localizes in the centrosome during mitosis. Additionally, K771 acetylation is required for the motor function of Eg5. The hyper-acetylation mimic Flag-Eg5 K771Q but not Flag-Eg5 rescued the NAT10 depletion-induced defective spindle formation and mitotic catastrophe, demonstrating that NAT10 controls mitosis through acetylating Eg5 K771. Collectively, we identify Eg5 as an important substrate of NAT10 in the control of mitosis and provide K771 as an essential acetylation site in the stabilization and motor function of Eg5. Our findings reveal that targeting the NAT10-mediated Eg5 K771 acetylation provides a potential strategy for tumor therapy.
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20
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Liu B, Qiang L, Guan B, Ji Z. Targeting kinesin family member 21B by miR-132-3p represses cell proliferation, migration and invasion in gastric cancer. Bioengineered 2022; 13:9006-9018. [PMID: 35341446 PMCID: PMC9161970 DOI: 10.1080/21655979.2022.2054755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Recently, kinesin family member 21B (KIF21B) has been reported to be an oncogene in non-small cell lung cancer and hepatocellular carcinoma. However, the functional role of KIF21B and related molecular mechanisms in gastric cancer (GC) remain largely uncovered. In this study, online bioinformatics analysis showed that KIF21B was overexpression in GC and predicted poor prognosis. Consistently, we found that the protein expression of KIF21B was upregulated in GC tissues compared with adjacent tissues by immunohistochemistry. Knockdown of KIF21B significantly suppressed cell proliferation, migration and invasion in GC cell lines (AGS and SNU-5) using Cell counting kit‑8 (CCK-8) assay, colony formation and transwell assay. KIF21B was confirmed as the target of miR-132-3p in GC cells by luciferase reporter assay. Moreover, miR-132-3p was down-regulated and KIF21B expression was upregulated in GC tissues. Overexpression of KIF21B reversed the miR-132-3p-mediated suppressive effects on GC cell proliferation, migration and invasion. Furthermore, miR-132-3p overexpression downregulated the protein levels of Wnt1, c-Myc, β-catenin, proliferating cell nuclear antigen (PCNA) and N-cadherin, and upregulated E-cadherin expression in GC cells, which were all alleviated after KIF21B overexpression. In conclusion, our findings indicate that down-regulation of KIF21B by miR-132-3p suppresses cellular functions in GC, which might be linked to reduced Wnt/β-catenin signaling.
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Affiliation(s)
- Bingtian Liu
- Department of Gastrointestinal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ling Qiang
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Bingxin Guan
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhipeng Ji
- Department of Gastrointestinal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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21
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Kinesin spindle protein inhibitors in cancer: from high throughput screening to novel therapeutic strategies. Future Sci OA 2022; 8:FSO778. [PMID: 35251692 PMCID: PMC8890118 DOI: 10.2144/fsoa-2021-0116] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 12/14/2021] [Indexed: 11/23/2022] Open
Abstract
Bringing to a halt the cell cycle in mitosis and interfering with its normal progression is one of the most successful anti-cancer strategies used nowadays. Classically, several kinds of anti-cancer drugs like taxanes and vinca alkaloids directly inhibit microtubules during cell division. These drugs exhibit serious side effects, most importantly, severe peripheral neuropathies. Alternatively, KSP inhibitors are grasping a lot of research attention as less toxic mitotic inhibitors. In this review, we track the medicinal chemistry developmental stages of KSP inhibitors. Moreover, we address the challenges that are faced during the development of KSP inhibitor therapy for cancer and future insights for the latest advances in research that are directed to find active KSP inhibitor drugs. Scientists have recognized the importance of selective KSP inhibitors in the early 2000s and so various KSP protein inhibitors have been investigated. Only ten of these have been clinically evaluated for cancer treatment. Ispinesib (SB-715992) and filanesib (Arry-520) were the most promising small molecules in clinical trials against the KSP protein. Many challenges are faced during the development of an active anti-KSP drug; most importantly are the unsatisfactory clinical trial results. Designing dual inhibitors, antibody–drug conjugates, combination therapy and gene therapy approach are among the main strategies that are being investigated nowadays to find new effective KSP inhibitors. The scientific research efforts are still devoted to find an effective and tolerable KSP inhibitor drug that can gain US FDA approval.
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22
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Gao T, Yu L, Fang Z, Liu J, Bai C, Li S, Xue R, Zhang L, Tan Z, Fan Z. KIF18B promotes tumor progression in osteosarcoma by activating β-catenin. Cancer Biol Med 2021; 17:371-386. [PMID: 32587775 PMCID: PMC7309474 DOI: 10.20892/j.issn.2095-3941.2019.0452] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 04/01/2020] [Indexed: 01/01/2023] Open
Abstract
Objective: Osteosarcoma is a common primary highly malignant bone tumor. Kinesin family member 18B (KIF18B) has been identified as a potential oncogene involved in the development and metastasis of several cancer types. While KIF18B overexpression in osteosarcoma tissue is clearly detected, its specific function in the disease process remains to be established. Methods:KIF18B expression was assessed in osteosarcoma tissues and cells. We additionally evaluated the effects of KIF18B on proliferation, migration, and invasion of osteosarcoma cells, both in vitro and in vivo. Results: Our results showed overexpression of KIF18B in osteosarcoma tissues and cells. Knockdown of KIF18B induced G1/S phase arrest and significantly inhibited proliferation, migration, and invasion of osteosarcoma cells, both in vitro and in vivo. KIF18B regulated β-catenin expression at the transcriptional level by controlling nuclear aggregation of ATF2 and at the post-transcriptional level by interacting with the adenomatous polyposis coli (APC) tumor suppressor gene in osteosarcoma cells. Conclusions: KIF18B plays a carcinogenic role in osteosarcoma by regulating expression of β-catenin transcriptionally via decreasing nuclear aggregation of ATF2 or post-transcriptionally through interactions with APC. Our collective findings support the potential utility of KIF18B as a novel prognostic biomarker for osteosarcoma.
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Affiliation(s)
- Tian Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Ling Yu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zhiwei Fang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jiayong Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Chujie Bai
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Shu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Ruifeng Xue
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Lu Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhichao Tan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhengfu Fan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Eg5 as a Prognostic Biomarker and Potential Therapeutic Target for Hepatocellular Carcinoma. Cells 2021; 10:cells10071698. [PMID: 34359867 PMCID: PMC8303881 DOI: 10.3390/cells10071698] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The kinesin Eg5, a mitosis-associated protein, is overexpressed in many cancers. Here we explored the clinical significance of Eg5 in hepatocellular carcinoma (HCC). METHODS HCC tissues from surgical resection were collected. Total RNA was prepared from tumorous and nontumorous parts. Eg5 expression levels were correlated with overall survival (OS) and disease-free survival (DFS). In vitro efficacy of LGI-147, a specific Eg5 inhibitor, was tested in HCC cell lines. In vivo efficacy of Eg5 inhibition was investigated in a xenograft model. RESULTS A total of 108 HCC samples were included. The patients were divided into three tertile groups with high, medium, and low Eg5 expression levels. OS of patients with low Eg5 expression was better than that of patients with medium and high Eg5 expression (median, 155.6 vs. 75.3 vs. 57.7 months, p = 0.002). DFS of patients with low Eg5 expression was also better than that of patients with medium and high Eg5 expression (median, 126.3 vs. 46.2 vs. 39.4 months, p = 0.001). In multivariate analyses, the associations between Eg5 expression and OS (p < 0.001) or DFS remained (p < 0.001). LGI-147 reduced cell growth via cell cycle arrest and apoptosis and induced accumulation of abnormal mitotic cells. In the xenograft model, the tumor growth rate under LGI-147 treatment was significantly slower than under the control. CONCLUSION High Eg5 expression was associated with poor HCC prognosis. In vitro and in vivo evidence suggests that Eg5 may be a reasonable therapeutic target for HCC.
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24
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Pandey H, Popov M, Goldstein-Levitin A, Gheber L. Mechanisms by Which Kinesin-5 Motors Perform Their Multiple Intracellular Functions. Int J Mol Sci 2021; 22:6420. [PMID: 34203964 PMCID: PMC8232732 DOI: 10.3390/ijms22126420] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/07/2021] [Indexed: 11/16/2022] Open
Abstract
Bipolar kinesin-5 motor proteins perform multiple intracellular functions, mainly during mitotic cell division. Their specialized structural characteristics enable these motors to perform their essential functions by crosslinking and sliding apart antiparallel microtubules (MTs). In this review, we discuss the specialized structural features of kinesin-5 motors, and the mechanisms by which these features relate to kinesin-5 functions and motile properties. In addition, we discuss the multiple roles of the kinesin-5 motors in dividing as well as in non-dividing cells, and examine their roles in pathogenetic conditions. We describe the recently discovered bidirectional motility in fungi kinesin-5 motors, and discuss its possible physiological relevance. Finally, we also focus on the multiple mechanisms of regulation of these unique motor proteins.
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Affiliation(s)
| | | | | | - Larisa Gheber
- Department of Chemistry and Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel; (H.P.); (M.P.); (A.G.-L.)
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25
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Almacellas E, Pelletier J, Day C, Ambrosio S, Tauler A, Mauvezin C. Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability. Autophagy 2021; 17:796-813. [PMID: 32573315 PMCID: PMC8032240 DOI: 10.1080/15548627.2020.1764727] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 01/01/2023] Open
Abstract
Lysosomes, as primary degradative organelles, are the endpoint of different converging pathways, including macroautophagy. To date, lysosome degradative function has been mainly studied in interphase cells, while their role during mitosis remains controversial. Mitosis dictates the faithful transmission of genetic material among generations, and perturbations of mitotic division lead to chromosomal instability, a hallmark of cancer. Heretofore, correct mitotic progression relies on the orchestrated degradation of mitotic factors, which was mainly attributed to ubiquitin-triggered proteasome-dependent degradation. Here, we show that mitotic transition also relies on lysosome-dependent degradation, as impairment of lysosomes increases mitotic timing and leads to mitotic errors, thus promoting chromosomal instability. Furthermore, we identified several putative lysosomal targets in mitotic cells. Among them, WAPL, a cohesin regulatory protein, emerged as a novel SQSTM1-interacting protein for targeted lysosomal degradation. Finally, we characterized an atypical nuclear phenotype, the toroidal nucleus, as a novel biomarker for genotoxic screenings. Our results establish lysosome-dependent degradation as an essential event to prevent chromosomal instability.Abbreviations: 3D: three-dimensional; APC/C: anaphase-promoting complex; ARL8B: ADP ribosylation factor like GTPase 8B; ATG: autophagy-related; BORC: BLOC-one-related complex; CDK: cyclin-dependent kinase; CENPE: centromere protein E; CIN: chromosomal instability; ConcA: concanamycin A; CQ: chloroquine; DAPI: 4,6-diamidino-2-penylinole; FTI: farnesyltransferase inhibitors; GFP: green fluorescent protein; H2B: histone 2B; KIF: kinesin family member; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; PDS5B: PDS5 cohesin associated factor B; SAC: spindle assembly checkpoint; PLEKHM2: pleckstrin homology and RUN domain containing M2; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; v-ATPase: vacuolar-type H+-translocating ATPase; WAPL: WAPL cohesion release factor.
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Affiliation(s)
- Eugènia Almacellas
- Department of Biochemistry and Physiology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain
- Metabolism and Cancer Laboratory, Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell, Institut d’Investigació Biomèdica de Bellvitge ‐ IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Joffrey Pelletier
- Metabolism and Cancer Laboratory, Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell, Institut d’Investigació Biomèdica de Bellvitge ‐ IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Charles Day
- Hormel Institute, University of Minnesota, Austin, MN, USA
- Neuro-Oncology Program, Mayo Clinic, Rochester, MN, USA
| | - Santiago Ambrosio
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Albert Tauler
- Department of Biochemistry and Physiology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain
- Metabolism and Cancer Laboratory, Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell, Institut d’Investigació Biomèdica de Bellvitge ‐ IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Caroline Mauvezin
- Metabolism and Cancer Laboratory, Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell, Institut d’Investigació Biomèdica de Bellvitge ‐ IDIBELL, L'Hospitalet de Llobregat, Spain
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26
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Das T, Anand U, Pandey SK, Ashby CR, Assaraf YG, Chen ZS, Dey A. Therapeutic strategies to overcome taxane resistance in cancer. Drug Resist Updat 2021; 55:100754. [PMID: 33691261 DOI: 10.1016/j.drup.2021.100754] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 12/17/2022]
Abstract
One of the primary causes of attenuated or loss of efficacy of cancer chemotherapy is the emergence of multidrug resistance (MDR). Numerous studies have been published regarding potential approaches to reverse resistance to taxanes, including paclitaxel (PTX) and docetaxel, which represent one of the most important classes of anticancer drugs. Since 1984, following the FDA approval of paclitaxel for the treatment of advanced ovarian carcinoma, taxanes have been extensively used as drugs that target tumor microtubules. Taxanes, have been shown to affect an array of oncogenic signaling pathways and have potent cytotoxic efficacy. However, the clinical success of these drugs has been restricted by the emergence of cancer cell resistance, primarily caused by the overexpression of MDR efflux transporters or by microtubule alterations. In vitro and in vivo studies indicate that the mechanisms underlying the resistance to PTX and docetaxel are primarily due to alterations in α-tubulin and β-tubulin. Moreover, resistance to PTX and docetaxel results from: 1) alterations in microtubule-protein interactions, including microtubule-associated protein 4, stathmin, centriole, cilia, spindle-associated protein, and kinesins; 2) alterations in the expression and activity of multidrug efflux transporters of the ABC superfamily including P-glycoprotein (P-gp/ABCB1); 3) overexpression of anti-apoptotic proteins or inhibition of apoptotic proteins and tumor-suppressor proteins, as well as 4) modulation of signal transduction pathways associated with the activity of several cytokines, chemokines and transcription factors. In this review, we discuss the abovementioned molecular mechanisms and their role in mediating cancer chemoresistance to PTX and docetaxel. We provide a detailed analysis of both in vitro and in vivo experimental data and describe the application of these findings to therapeutic practice. The current review also discusses the efficacy of different pharmacological modulations to achieve reversal of PTX resistance. The therapeutic roles of several novel compounds, as well as herbal formulations, are also discussed. Among them, many structural derivatives had efficacy against the MDR phenotype by either suppressing MDR or increasing the cytotoxic efficacy compared to the parental drugs, or both. Natural products functioning as MDR chemosensitizers offer novel treatment strategies in patients with chemoresistant cancers by attenuating MDR and increasing chemotherapy efficacy. We broadly discuss the roles of inhibitors of P-gp and other efflux pumps, in the reversal of PTX and docetaxel resistance in cancer cells and the significance of using a nanomedicine delivery system in this context. Thus, a better understanding of the molecular mechanisms mediating the reversal of drug resistance, combined with drug efficacy and the application of target-based inhibition or specific drug delivery, could signal a new era in modern medicine that would limit the pathological consequences of MDR in cancer patients.
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Affiliation(s)
- Tuyelee Das
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India
| | - Uttpal Anand
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Swaroop Kumar Pandey
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India.
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27
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Ji Z, Mi A, Li M, Li Q, Qin C. Aberrant KIF23 expression is associated with adverse clinical outcome and promotes cellular malignant behavior through the Wnt/β-catenin signaling pathway in Colorectal Cancer. J Cancer 2021; 12:2030-2040. [PMID: 33754001 PMCID: PMC7974518 DOI: 10.7150/jca.51565] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 12/29/2020] [Indexed: 01/11/2023] Open
Abstract
Purpose: The aim of the present study was to reveal the clinicopathological significance and prognostic role of kinesin family member 23 (KIF23) in colorectal cancer (CRC) and characterize its biological function and the underlying mechanisms. Methods: Bioinformatics analysis, immunohistochemistry, Western blot and qRT-PCR were utilized to investigate the expression of KIF23 in CRC tissues. The CCK-8 assay, wound healing assay and Matrigel assay were used to detect cell proliferation, migration and invasion in vitro. Western blot, immunofluorescence staining and cell function experiment were performed to explore the underlying mechanism. Results: The overexpression of KIF23 was associated with T stage, N stage, M stage and TNM stage, and CRC patients with high KIF23 expression had a worse prognosis. KIF23 knockdown inhibits CRC cells proliferation, migration and invasion in vitro. The mechanism study determined that KIF23 activates the Wnt/β-catenin signaling pathway by promoting the nuclear translocation of β-catenin to regulate the malignant behavior of CRC cells. Conclusion: These results suggest that KIF23 may act as a putative oncogene and a potential therapeutic target in CRC.
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Affiliation(s)
- Zhiyu Ji
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Aoning Mi
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Mengmeng Li
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Quanying Li
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Changjiang Qin
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
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28
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Sun S, Karki C, Xie Y, Xian Y, Guo W, Gao BZ, Li L. Hybrid method for representing ions in implicit solvation calculations. Comput Struct Biotechnol J 2021; 19:801-811. [PMID: 33598096 PMCID: PMC7847951 DOI: 10.1016/j.csbj.2021.01.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 01/09/2021] [Accepted: 01/14/2021] [Indexed: 12/16/2022] Open
Abstract
Fast and accurate calculations of the electrostatic features of highly charged biomolecules such as DNA, RNA, and highly charged proteins are crucial and challenging tasks. Traditional implicit solvent methods calculate the electrostatic features quickly, but these methods are not able to balance the high net biomolecular charges effectively. Explicit solvent methods add unbalanced ions to neutralize the highly charged biomolecules in molecular dynamic simulations, which require more expensive computing resources. Here we report developing a novel method, Hybridizing Ions Treatment (HIT), which hybridizes the implicit solvent method with an explicit method to realistically calculate the electrostatic potential for highly charged biomolecules. HIT utilizes the ionic distribution from an explicit method to predict the bound ions. The bound ions are then added in the implicit solvent method to perform the electrostatic potential calculations. In this study, two training sets were developed to optimize parameters for HIT. The performance on the testing set demonstrates that HIT significantly improves the electrostatic calculations. Results on molecular motors myosin and kinesin reveal some mechanisms and explain some previous experimental findings. HIT can be widely used to study highly charged biomolecules, including DNA, RNA, molecular motors, and other highly charged biomolecules. The HIT package is available at http://compbio.utep.edu/static/downloads/download_hit.zip.
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Affiliation(s)
- Shengjie Sun
- Computational Science Program, University of Texas at El Paso, 500 W University Ave, TX 79968, USA
| | - Chitra Karki
- Computational Science Program, University of Texas at El Paso, 500 W University Ave, TX 79968, USA
| | - Yixin Xie
- Computational Science Program, University of Texas at El Paso, 500 W University Ave, TX 79968, USA
| | - Yuejiao Xian
- Department of Chemistry, University of Texas at El Paso, 500 W University Ave, TX 79968, USA
| | - Wenhan Guo
- Computational Science Program, University of Texas at El Paso, 500 W University Ave, TX 79968, USA
| | - Bruce Z Gao
- Department of Bioengineering, Clemson University, Clemson, SC 29634, USA
| | - Lin Li
- Computational Science Program, University of Texas at El Paso, 500 W University Ave, TX 79968, USA.,Department of Physics, University of Texas at El Paso, 500 W University Ave, TX 79968, USA
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29
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Xian Y, Xie Y, Silva SM, Karki CB, Qiu W, Li L. StructureMan: A Structure Manipulation Tool to Study Large Scale Biomolecular Interactions. Front Mol Biosci 2021; 7:627087. [PMID: 33505991 PMCID: PMC7831659 DOI: 10.3389/fmolb.2020.627087] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 12/10/2020] [Indexed: 11/22/2022] Open
Abstract
Studying biomolecular interactions is a crucial but challenging task. Due to their large scales, many biomolecular interactions are difficult to be simulated via all atom models. An effective approach to investigate the biomolecular interactions is highly demanded in many areas. Here we introduce a Structure Manipulation (StructureMan) program to operate the structures when studying the large-scale biomolecular interactions. This novel StructureMan tool provides comprehensive operations which can be utilized to study the interactions in various large biological systems. Combining with electrostatic calculation programs such as DelPhi and DelPhiForce, StructureMan was implemented to reveal the detailed electrostatic features in two large biological examples, the viral capsid and molecular motor-microtubule complexes. Applications on these two examples revealed interesting binding mechanisms in the viral capsid and molecular motor. Such applications demonstrated that the StructureMan can be widely used when studying the biomolecular interactions in large scale biological problems. This novel tool provides an alternative approach to efficiently study the biomolecular interactions, especially for large scale biology systems. The StructureMan tool is available at our website: http://compbio.utep.edu/static/downloads/script-for-munipulation2.zip.
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Affiliation(s)
- Yuejiao Xian
- Department of Chemistry and Biochemistry, University of Texas at El Paso, El Paso, TX, United States
| | - Yixin Xie
- Computational Science Program, University of Texas at El Paso, El Paso, TX, United States
| | - Sebastian Miki Silva
- Department of Physics, University of Texas at El Paso, El Paso, TX, United States
| | - Chitra B Karki
- Computational Science Program, University of Texas at El Paso, El Paso, TX, United States
| | - Weihong Qiu
- Department of Physics, Oregon State University, Corvallis, OR, United States.,Department of Biochemistry & Biophysics, Oregon State University, Corvallis, OR, United States
| | - Lin Li
- Computational Science Program, University of Texas at El Paso, El Paso, TX, United States.,Department of Physics, University of Texas at El Paso, El Paso, TX, United States
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30
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Shi A, Kasumova GG, Michaud WA, Cintolo-Gonzalez J, Díaz-Martínez M, Ohmura J, Mehta A, Chien I, Frederick DT, Cohen S, Plana D, Johnson D, Flaherty KT, Sullivan RJ, Kellis M, Boland GM. Plasma-derived extracellular vesicle analysis and deconvolution enable prediction and tracking of melanoma checkpoint blockade outcome. SCIENCE ADVANCES 2020; 6:6/46/eabb3461. [PMID: 33188016 PMCID: PMC7673759 DOI: 10.1126/sciadv.abb3461] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 09/28/2020] [Indexed: 05/02/2023]
Abstract
Immune checkpoint inhibitors (ICIs) show promise, but most patients do not respond. We identify and validate biomarkers from extracellular vesicles (EVs), allowing non-invasive monitoring of tumor- intrinsic and host immune status, as well as a prediction of ICI response. We undertook transcriptomic profiling of plasma-derived EVs and tumors from 50 patients with metastatic melanoma receiving ICI, and validated with an independent EV-only cohort of 30 patients. Plasma-derived EV and tumor transcriptomes correlate. EV profiles reveal drivers of ICI resistance and melanoma progression, exhibit differentially expressed genes/pathways, and correlate with clinical response to ICI. We created a Bayesian probabilistic deconvolution model to estimate contributions from tumor and non-tumor sources, enabling interpretation of differentially expressed genes/pathways. EV RNA-seq mutations also segregated ICI response. EVs serve as a non-invasive biomarker to jointly probe tumor-intrinsic and immune changes to ICI, function as predictive markers of ICI responsiveness, and monitor tumor persistence and immune activation.
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Affiliation(s)
- Alvin Shi
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | | | - William A Michaud
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | | | | | - Jacqueline Ohmura
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Arnav Mehta
- Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Isabel Chien
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
| | | | - Sonia Cohen
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Deborah Plana
- Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Douglas Johnson
- Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | | | - Ryan J Sullivan
- Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Manolis Kellis
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Genevieve M Boland
- Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
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Liang WT, Liu XF, Huang HB, Gao ZM, Li K. Prognostic significance of KIF23 expression in gastric cancer. World J Gastrointest Oncol 2020; 12:1104-1118. [PMID: 33133380 PMCID: PMC7579732 DOI: 10.4251/wjgo.v12.i10.1104] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/29/2020] [Accepted: 08/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Kinesin super family 23 (KIF23) is a member of the KIF family, and it plays an important role in mitosis and cytokinesis. Loss of expression can cause mitotic arrest. The Oncomine database is one of the largest oncogene chip databases in the world, and is an integrated data mining platform for cancer gene information. By querying the database, differences in expression between tumor tissue and normal tissue can be determined.
AIM To study the expression and prognostic significance of KIF23 in gastric cancer (GC).
METHODS We used immunohistochemistry to compare the expression of KIF23 in GC and normal gastric tissues. We mined the data on the expression and prognosis of KIF23 in GC using Oncomine and Kaplan–Meier plotter database.
RESULTS Compared with normal gastric tissues, KIF23 expression was increased in GC tissues, and correlated with T, N, and tumor–node–metastasis stages. Survival analysis showed that patients with high expression of KIF23 had a poor overall survival. There were five studies in the Oncomine database in which expression of KIF23 was significantly higher in GC tissues than in normal gastric tissues (P < 0.05). Kaplan–Meier plotter database analysis showed that recurrence-free survival, overall survival, distant metastasis free survival, and post progression survival of patients with high expression of KIF23 were lower than those of patients with low expression. Further stratified analysis found that prognostic survival indicators worsened in patients with T2 and T3 poorly differentiated adenocarcinoma with high expression of KIF23.
CONCLUSION KIF23 is highly expressed in GC and is associated with a poor prognosis of patients. It may be of great significance in the diagnosis, treatment, and prognostic evaluation of GC.
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Affiliation(s)
- Wei-Tian Liang
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiao-Fang Liu
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hai-Bo Huang
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Zi-Ming Gao
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Kai Li
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Škubník J, Jurášek M, Ruml T, Rimpelová S. Mitotic Poisons in Research and Medicine. Molecules 2020; 25:E4632. [PMID: 33053667 PMCID: PMC7587177 DOI: 10.3390/molecules25204632] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one of the most common causes of human death in the world, mainly in low and middle-income countries. According to the World Health Organization (WHO), cancer treatment services are not available in more then 70% of low-income countries (90% of high-income countries have them available), and also approximately 70% of cancer deaths are reported in low-income countries. Various approaches on how to combat cancer diseases have since been described, targeting cell division being among them. The so-called mitotic poisons are one of the cornerstones in cancer therapies. The idea that cancer cells usually divide almost uncontrolled and far more rapidly than normal cells have led us to think about such compounds that would take advantage of this difference and target the division of such cells. Many groups of such compounds with different modes of action have been reported so far. In this review article, the main approaches on how to target cancer cell mitosis are described, involving microtubule inhibition, targeting aurora and polo-like kinases and kinesins inhibition. The main representatives of all groups of compounds are discussed and attention has also been paid to the presence and future of the clinical use of these compounds as well as their novel derivatives, reviewing the finished and ongoing clinical trials.
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Affiliation(s)
- Jan Škubník
- Department of Biochemistry and Microbiology, University of Chemistry and Technology in Prague, Technická 3, 166 28, Prague 6, Czech Republic; (J.Š.); (T.R.)
| | - Michal Jurášek
- Department of Chemistry of Natural Compounds, University of Chemistry and Technology in Prague, Technická 3, 166 28, Prague 6, Czech Republic;
| | - Tomáš Ruml
- Department of Biochemistry and Microbiology, University of Chemistry and Technology in Prague, Technická 3, 166 28, Prague 6, Czech Republic; (J.Š.); (T.R.)
| | - Silvie Rimpelová
- Department of Biochemistry and Microbiology, University of Chemistry and Technology in Prague, Technická 3, 166 28, Prague 6, Czech Republic; (J.Š.); (T.R.)
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FAM64A: A Novel Oncogenic Target of Lung Adenocarcinoma Regulated by Both Strands of miR-99a ( miR-99a-5p and miR-99a-3p). Cells 2020; 9:cells9092083. [PMID: 32932948 PMCID: PMC7564711 DOI: 10.3390/cells9092083] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 08/28/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023] Open
Abstract
Lung adenocarcinoma (LUAD) is the most aggressive cancer and the prognosis of these patients is unfavorable. We revealed that the expression levels of both strands of miR-99a (miR-99a-5p and miR-99a-3p) were significantly suppressed in several cancer tissues. Analyses of large The Cancer Genome Atlas (TCGA) datasets showed that reduced miR-99a-5p or miR-99a-3p expression is associated with worse prognoses in LUAD patients (disease-free survival (DFS): p = 0.1264 and 0.0316; overall survival (OS): p = 0.0176 and 0.0756, respectively). Ectopic expression of these miRNAs attenuated LUAD cell proliferation, suggesting their tumor-suppressive roles. Our in silico analysis revealed 23 putative target genes of pre-miR-99a in LUAD cells. Among these targets, high expressions of 19 genes were associated with worse prognoses in LUAD patients (OS: p < 0.05). Notably, FAM64A was regulated by both miR-99a-5p and miR-99a-3p in LUAD cells, and its aberrant expression was significantly associated with poor prognosis in LUAD patients (OS: p = 0.0175; DFS: p = 0.0276). FAM64A knockdown using siRNAs suggested that elevated FAM64A expression contributes to cancer progression. Aberrant FAM64A expression was detected in LUAD tissues by immunostaining. Taken together, our miRNA-based analysis might be effective for identifying prognostic and therapeutic molecules in LUAD.
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Inhibition of kinesin motor protein KIFC1 by AZ82 induces multipolar mitosis and apoptosis in prostate cancer cell. Gene 2020; 760:144989. [PMID: 32717307 DOI: 10.1016/j.gene.2020.144989] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/28/2020] [Accepted: 07/21/2020] [Indexed: 12/14/2022]
Abstract
Kinesin 14 family member KIFC1 is a mitotic kinesin which contains a C-terminal motor domain and plays a vital role for clustering the amplified centrosomes. Overexpression of KIFC1 in prostate cancer (PCa) cells showed resistance to docetaxel (DTX). The present study revealed that small KIFC1 inhibitor AZ82 suppresed the transcription and translation of KIFC1 significantly in PCa cells. AZ82 inhibited the KIFC1 expression both in the cytoplasm and nucleus of PCa cells. Inhibition of KIFC1 by AZ82 caused multipolar mitosis in PCa cells via de-clustering the amplified centrosomes and decreased the rate of cancer cell growth and proliferation. Moreover, depletion of KIFC1 reduced cells entering the cell cycle and caused PCa cells death through apoptosis by increasing the expression of Bax and Cytochrome C. Thereby, KIFC1 silencing and inhibition decreased the PCa cells survival by inducing multipolar mitosis as well as apoptosis, suggesting inhibition of KIFC1 using AZ82 might be a strategy to treat PCa by controlling the cancer cell proliferation.
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Sun ZG, Pan F, Shao JB, Yan QQ, Lu L, Zhang N. Kinesin superfamily protein 21B acts as an oncogene in non-small cell lung cancer. Cancer Cell Int 2020; 20:233. [PMID: 32536821 PMCID: PMC7291654 DOI: 10.1186/s12935-020-01323-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 06/04/2020] [Indexed: 12/25/2022] Open
Abstract
Background Kinesin superfamily proteins (KIFs) serve as microtubule-dependent molecular motors, and are involved in the progression of many malignant tumors. In this study, we aimed to investigate the expression pattern and precise role of kinesin family member 21B (KIF21B) in non-small cell lung cancer (NSCLC). Methods KIF21B expression in 72 cases of NSCLC tissues was measured by immunohistochemical staining (IHC). We used shRNA-KIF21B interference to silence KIF21B in NSCLC H1299 and A549 cells and normal lung epithelial bronchus BEAS-2B cells. The biological roles of KIF21B in the growth and metastasis abilities of NSCLC cells were measured by Cell Counting Kit-8 (CCK8), colony formation and Hoechst 33342/PI, wound-healing, and Transwell assays, respectively. Expression of apoptosis-related proteins was determined using western blot. The effect of KIF21B on tumor growth in vivo was examined using nude mice model. Results KIF21B was up-regulated in NSCLC tissues, and correlated with pathological lymph node and pTNM stage, its high expression was predicted a poor prognosis of patients with NSCLC. Silencing of KIF21B mediated by lentivirus-delivered shRNA significantly inhibited the proliferation ability of H1299 and A549 cells. KIF21B knockdown increased apoptosis in H1299 and A549 cells, down-regulated the expression of Bcl-2 and up-regulated the expression of Bax and active Caspase 3. Moreover, KIF21B knockdown decreased the level of phosphorylated form of Akt (p-Akt) and Cyclin D1 expression in H1299 and A549 cells. In addition, silencing of KIF21B impeded the migration and invasion of H1299 and A549 cells. Further, silencing of KIF 21B dramatically inhibited xenograft growth in BALB/c nude mice. However, silencing of KIF21B did not affect the proliferation, migration and invasion of BEAS-2B cells. Conclusions These results reveal that KIF21B is up-regulated in NSCLC and acts as an oncogene in the growth and metastasis of NSCLC, which may function as a potential therapeutic target and a prognostic biomarker for NSCLC.
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Affiliation(s)
- Zhi-Gang Sun
- Department of Thoracic Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013 People's Republic of China
| | - Feng Pan
- Department of Ethics Committee, Central Hospital Affiliated to Shandong University, Jinan, 250012 People's Republic of China
| | - Jing-Bo Shao
- Weifang Medical University, Weifang, 261053 People's Republic of China
| | - Qian-Qian Yan
- Department of Oncology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012 People's Republic of China
| | - Lu Lu
- Shandong First Medical University, Jinan, 250013 Shandong China
| | - Nan Zhang
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013 People's Republic of China
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Wang RX, Lee JS, Campbell EL, Colgan SP. Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin. Proc Natl Acad Sci U S A 2020; 117:11648-11657. [PMID: 32398370 PMCID: PMC7260972 DOI: 10.1073/pnas.1917597117] [Citation(s) in RCA: 188] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The intestinal mucosa exists in dynamic balance with trillions of luminal microbes. Disruption of the intestinal epithelial barrier, commonly observed in mucosal inflammation and diseases such as inflammatory bowel diseases (IBDs), is often associated with dysbiosis, particularly decreases in species producing short-chain fatty acids (SCFAs), such as butyrate. It remains unclear to what extent microbiota-derived factors contribute to the overall maintenance of intestinal homeostasis. Initial studies revealed that butyrate selectively promotes epithelial barrier function and wound healing. We aimed to define the specific mechanism(s) through which butyrate contributes to these epithelial responses. Guided by an unbiased profiling approach, we identified the dominant regulation of the actin-binding protein synaptopodin (SYNPO). Extensions of this work revealed a role for SYNPO in intestinal epithelial barrier function and wound healing. SYNPO was localized to the intestinal epithelial tight junction and within F-actin stress fibers where it is critical for barrier integrity and cell motility. Butyrate, but not other SCFAs, induced SYNPO in epithelial cell lines and murine colonic enteroids through mechanisms possibly involving histone deacetylase inhibition. Moreover, depletion of the microbiota abrogated expression of SYNPO in the mouse colon, which was rescued with butyrate repletion. Studies in Synpo-deficient mice demonstrated exacerbated disease susceptibility and increased intestinal permeability in a dextran sulfate sodium colitis model. These findings establish a critical role for the microbiota and their products, specifically butyrate, in the regulated expression of SYNPO for intestinal homeostasis and reveal a direct mechanistic link between microbiota-derived butyrate and barrier restoration.
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Affiliation(s)
- Ruth X Wang
- Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
- Medical Scientist Training Program, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - J Scott Lee
- Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Eric L Campbell
- Centre for Experimental Medicine, Queens University Belfast, Belfast BT9 7BL, Northern Ireland
| | - Sean P Colgan
- Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
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How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter. Cells 2020; 9:cells9051154. [PMID: 32392819 PMCID: PMC7290485 DOI: 10.3390/cells9051154] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/01/2020] [Accepted: 05/04/2020] [Indexed: 12/13/2022] Open
Abstract
The bipolar mitotic spindle drives accurate chromosome segregation by capturing the kinetochore and pulling each set of sister chromatids to the opposite poles. In this review, we describe recent findings on the multiple pathways leading to bipolar spindle formation in fission yeast and discuss these results from a broader perspective. The roles of three mitotic kinesins (Kinesin-5, Kinesin-6 and Kinesin-14) in spindle assembly are depicted, and how a group of microtubule-associated proteins, sister chromatid cohesion and the kinetochore collaborate with these motors is shown. We have paid special attention to the molecular pathways that render otherwise essential Kinesin-5 to become non-essential: how cells build bipolar mitotic spindles without the need for Kinesin-5 and where the alternate forces come from are considered. We highlight the force balance for bipolar spindle assembly and explain how outward and inward forces are generated by various ways, in which the proper fine-tuning of microtubule dynamics plays a crucial role. Overall, these new pathways have illuminated the remarkable plasticity and adaptability of spindle mechanics. Kinesin molecules are regarded as prospective targets for cancer chemotherapy and many specific inhibitors have been developed. However, several hurdles have arisen against their clinical implementation. This review provides insight into possible strategies to overcome these challenges.
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38
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Ding L, Li B, Yu X, Li Z, Li X, Dang S, Lv Q, Wei J, Sun H, Chen H, Liu M, Li G. KIF15 facilitates gastric cancer via enhancing proliferation, inhibiting apoptosis, and predict poor prognosis. Cancer Cell Int 2020; 20:125. [PMID: 32322172 PMCID: PMC7160940 DOI: 10.1186/s12935-020-01199-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 03/31/2020] [Indexed: 12/19/2022] Open
Abstract
Background Kinesin superfamily proteins (KIFs) can transport membranous organelles and protein complexes in an ATP-dependent manner. Kinesin family member 15 (KIF15) is overexpressed in various cancers. However, the function of KIF15 in gastric cancer (GC) is still unclear. Methods GC patients’ data from The Cancer Genome Atlas (TCGA) were analyzed by bioinformatics methods. The expression of KIF15 was examined in GC and paracarcinoma tissues from 41 patients to verify the analysis results. The relationship between KIF15 expression and clinical characteristics were also observed by bioinformatics methods. Kaplan–Meier survival analysis of 122 GC patients in our hospital was performed to explore the relationship between KIF15 expression levels and GC patients’ prognosis. KIF15 was downregulated in GC cell lines AGS and SGC-7901 by transfecting a lentivirus-mediated shRNA plasmid targeting KIF15. In vitro, GC cell proliferation and apoptosis were detected by MTT assay, colony formation assay, and Annexin V-APC staining. In vivo, xenograft experiments were used to verify the in vitro results. Furthermore, Human Apoptosis Antibody Array kit was used to screen possible targets of KIF15 in GC cell lines. Results The bioinformatics results showed that KIF15 expression levels were higher in GC tissues than in normal tissues. IHC showed same results. High expression of KIF15 was statistical correlated with high age and early histologic stage. Kaplan–Meier curves indicated that high KIF15 expression predict poor prognosis in patients with GC. MTT assay and colony formation assay showed that KIF15 promote GC cell proliferation. Annexin V-APC staining found that KIF15 can inhibit GC cell apoptosis. Xenograft experiments reveal that downregulating KIF15 can inhibit GC tumor growth and promote GC apoptosis. Through detection of 43 anti-apoptotic proteins by the Human Apoptosis Antibody Array kit, it was confirmed that knocking down KIF15 can reduce seven anti-apoptotic proteins expression. Conclusions Taken together, our study revealed a critical role for KIF15 to inhibit GC cell apoptosis and promote GC cell proliferation. KIF15 may decrease anti-apoptotic proteins expression by regulating apoptosis pathways. High expression of KIF15 predicts a poor prognosis in patients with GC. KIF15 might be a novel prognostic biomarker and a therapeutic target for GC.
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Affiliation(s)
- Lixian Ding
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Bin Li
- 3Department of Clinical Laboratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang China
| | - Xiaotong Yu
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Zhongsheng Li
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Xinglong Li
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Shuwei Dang
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Qiang Lv
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Jiufeng Wei
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Haixia Sun
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Hongsheng Chen
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Ming Liu
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
| | - Guodong Li
- 1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China.,2Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001 Heilongjiang China
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Suppression of KIF22 Inhibits Cell Proliferation and Xenograft Tumor Growth in Tongue Squamous Cell Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6387545. [PMID: 32090103 PMCID: PMC6996685 DOI: 10.1155/2020/6387545] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 10/26/2019] [Accepted: 11/12/2019] [Indexed: 01/24/2023]
Abstract
Background Oral carcinoma is the sixth most common cancer and is a serious public health problem, and tongue squamous cell carcinoma (TSCC) is the most common type of oral carcinoma. Kinesin family member 22 (KIF22), also called as kinesin-like DNA binding protein (KID), is a microtubule-based motor protein and binds to both microtubules and chromosomes, transporting organelles, protein, and mRNA. This research aimed at investigating the prognostic significance of KIF22 in TSCC. Patients and Methods. This retrospective research collected 82 paired tissues with TSCC. KIF22 protein expression level was detected by immunohistochemical staining. Suppression of KIF22 with shRNA in CAL-27 and SCC-15 cells was to observe cell proliferation in vitro and xenograft tumor growth in vivo. Results In TSCC tissues, the protein expression level of KIF22 was increased and correlated with tumor stage, clinical stage, and lymphatic metastasis (P=0.013, P=0.013, P=0.013, Conclusion KIF22 might play an important role in the progression of TSCC and could serve as a therapeutic target for TSCC.
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Zhang H, Zou J, Yin Y, Zhang B, Hu Y, Wang J, Mu H. Bioinformatic analysis identifies potentially key differentially expressed genes in oncogenesis and progression of clear cell renal cell carcinoma. PeerJ 2019; 7:e8096. [PMID: 31788359 PMCID: PMC6883955 DOI: 10.7717/peerj.8096] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 10/24/2019] [Indexed: 12/12/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is one of the most common and lethal types of cancer within the urinary system. Great efforts have been made to elucidate the pathogeny. However, the molecular mechanism of ccRCC is still not well understood. The aim of this study is to identify key genes in the carcinogenesis and progression of ccRCC. The mRNA microarray dataset GSE53757 was downloaded from the Gene Expression Omnibus database. The GSE53757 dataset contains tumor and matched paracancerous specimens from 72 ccRCC patients with clinical stage I to IV. The linear model of microarray data (limma) package in R language was used to identify differentially expressed genes (DEGs). The protein–protein interaction (PPI) network of the DEGs was constructed using the search tool for the retrieval of interacting genes (STRING). Subsequently, we visualized molecular interaction networks by Cytoscape software and analyzed modules with MCODE. A total of 1,284, 1,416, 1,610 and 1,185 up-regulated genes, and 932, 1,236, 1,006 and 929 down-regulated genes were identified from clinical stage I to IV ccRCC patients, respectively. The overlapping DEGs among the four clinical stages contain 870 up-regulated and 645 down-regulated genes. The enrichment analysis of DEGs in the top module was carried out with DAVID. The results showed the DEGs of the top module were mainly enriched in microtubule-based movement, mitotic cytokinesis and mitotic chromosome condensation. Eleven up-regulated genes and one down-regulated gene were identified as hub genes. Survival analysis showed the high expression of CENPE, KIF20A, KIF4A, MELK, NCAPG, NDC80, NUF2, TOP2A, TPX2 and UBE2C, and low expression of ACADM gene could be involved in the carcinogenesis, invasion or recurrence of ccRCC. Literature retrieval results showed the hub gene NDC80, CENPE and ACADM might be novel targets for the diagnosis, clinical treatment and prognosis of ccRCC. In conclusion, the findings of present study may help us understand the molecular mechanisms underlying the carcinogenesis and progression of ccRCC, and provide potential diagnostic, therapeutic and prognostic biomarkers.
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Affiliation(s)
- Haiping Zhang
- Department of Derma Science Laboratory, Wuxi NO.2 People's Hospital affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Jian Zou
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.,Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, China
| | - Ying Yin
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.,Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, China
| | - Bo Zhang
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.,Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, China
| | - Yaling Hu
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.,Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, China
| | - Jingjing Wang
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.,Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, China
| | - Huijun Mu
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.,Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, China
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Marconi GD, Carradori S, Ricci A, Guglielmi P, Cataldi A, Zara S. Kinesin Eg5 Targeting Inhibitors as a New Strategy for Gastric Adenocarcinoma Treatment. Molecules 2019; 24:molecules24213948. [PMID: 31683688 PMCID: PMC6864856 DOI: 10.3390/molecules24213948] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 10/26/2019] [Accepted: 10/30/2019] [Indexed: 01/30/2023] Open
Abstract
The Kinesins are proteins involved in several biological processes such as mitosis, intracellular transport, and microtubule movement. The mitotic process is allowed by the correct formation of the mitotic spindle which consists of microtubules originating from the spindle poles. In recent years, kinesin Eg5 inhibitors were studied as new chemotherapeutic drugs, due to the lack of side effects and resistance mechanisms. The aim of this work was to investigate the molecular signaling underlying the administration of novel kinesis Eg5 inhibitors in an in vitro model of gastric adenocarcinoma. Data obtained from analogues of K858 led us to select compounds 2 and 41, due to their lower IC50 values. The ability of kinesin inhibitors to induce apoptosis was investigated by evaluating Bax and Caspase-3 protein expression, evidencing that compound 41 and K858 markedly raise Bax expression, while only compounds 2 and 41 co-administrated with K858 trigger Caspase-3 activation. The inhibition of mitotic spindle was measured by β-tubulin immunofluorescence analysis revealing monopolar spindles formation in gastric cancer cells treated with compounds 2, 41, and K858. Nitric Oxide Synthase (NOS-2) and Matrix Metalloproteinase 9 (MMP-9) expression levels were measured finding a NOS-2-mediated downregulation of MMP-9 when compound 41 and K858 are co-administered. However, this is in contrast to what was reported by migration assay in which both novel compounds and K858 in monotherapy markedly reduce cell migration. This work remarks the importance of understanding and exploring the biological effects of different novel Eg5 kinesin inhibitors administered in monotherapy and in combination with K858 as potential strategy to counteract gastric cancer.
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Affiliation(s)
- Guya Diletta Marconi
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
| | - Simone Carradori
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
| | - Alessia Ricci
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
| | - Paolo Guglielmi
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
| | - Amelia Cataldi
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
| | - Susi Zara
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
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Li B, Zhu FC, Yu SX, Liu SJ, Li BY. Suppression of KIF22 Inhibits Cell Proliferation and Xenograft Tumor Growth in Colon Cancer. Cancer Biother Radiopharm 2019; 35:50-57. [PMID: 31657617 DOI: 10.1089/cbr.2019.3045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background: Kinesin family member 22 (KIF22) is known as a regulator of cell mitosis and cellular vesicle transport. The alterations of KIF22 are associated with a series of tumors; however, its possible role in the progression of colon cancer is still unclear. Materials and Methods: This retrospective research collected 82 paired tissues with colon cancer. KIF22 protein and mRNA expression levels were detected by immunohistochemistry assays and Immunoblot assays, respectively. Short hairpin RNA (shRNA) plasmids were used to suppress the expression of KIF22 in HCT116 and HT29 cells, and the silencing efficiencies of shRNA plasmids targeted KIF22 were detected by quantitative PCR assays and immunoblot assays. In addition, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays and xenograft tumor growth assays were performed to observe cell proliferation in vitro and in vivo. Results: In human colon cancer tissues, the expression level of KIF22 was increased and correlated with clinical pathological features, including tumor stage and clinical stage (p = 0.034, and p = 0.015, respectively). Suppression of KIF22 inhibited cell proliferation and xenograft tumor growth. Conclusion: KIF22 might play an important role in the regulation of cell proliferation in colon cancer and might therefore serve as a promising therapeutic target.
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Affiliation(s)
- Bing Li
- Department of Anorectal Surgery, Tangxian People's Hospital in Hebei Province, Baoding, China
| | - Feng-Chi Zhu
- Department of Anorectal Surgery, Baoding Second Hospital, Baoding, China
| | - Su-Xiang Yu
- Department of Pathology, Tangxian People's Hospital in Hebei Province, Baoding, China
| | - Sheng-Jia Liu
- Medical Record Room, Tangxian People's Hospital in Hebei Province, Baoding, China
| | - Bao-Yu Li
- Department of General Surgery, The Secondary Hospital of Tianjin Medical University, Tianjin, China
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Li T, Li Y, Gan Y, Tian R, Wu Q, Shu G, Yin G. Methylation-mediated repression of MiR-424/503 cluster promotes proliferation and migration of ovarian cancer cells through targeting the hub gene KIF23. Cell Cycle 2019; 18:1601-1618. [PMID: 31135262 PMCID: PMC6619937 DOI: 10.1080/15384101.2019.1624112] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer is one type of gynecological malignancies with extremely high lethal rate. Abnormal proliferation and metastasis are regarded to play important roles in patients' death, whereas we know little about the underlying molecular mechanisms. Under this circumstance, our current study aims to investigate the role of hub genes in ovarian cancer. Bioinformatics analysis of the data from GEO and analyses of ovarian cancer samples were performed. Then, the results showed that KIF23, a hub gene, was mainly related to cell cycle and positively associated with poor prognosis. Meanwhile, both miR-424-5p and miR-503-5p directly targeted to 3'UTR of KIF23 to suppress the expression of KIF23 and inhibit ovarian cancer cell proliferation and migration. Furthermore, we discovered that miR-424/503 was epigenetically repressed by hypermethylation in the promoter regions, which directly modulated the expression of KIF23 to improve the oncogenic performance of cancer cells in vitro. Together, our research certifies that miR-424/503 cluster is silenced by DNA hypermethylation, which promotes the expression of KIF23, thereby regulating the proliferation and migration of ovarian cancer cells. Interposing this process might be a novel approach in cancer therapy.
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Affiliation(s)
- Tong Li
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Yimin Li
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Yaqi Gan
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Ruotong Tian
- School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Qihan Wu
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Medical School, Fudan University, Shanghai, China
| | - Guang Shu
- School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Gang Yin
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
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Shaheer Malik M, Seddigi ZS, Bajee S, Azeeza S, Riyaz S, Ahmed SA, Althagafi II, Sajid Jamal QM, Kamal A. Multicomponent access to novel proline/cyclized cysteine tethered monastrol conjugates as potential anticancer agents. JOURNAL OF SAUDI CHEMICAL SOCIETY 2019. [DOI: 10.1016/j.jscs.2019.01.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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45
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Muthuraja P, Veeramani V, Prakash S, Himesh M, Venkatasubramanian U, Manisankar P. Structure-activity relationship of pyrazolo pyrimidine derivatives as inhibitors of mitotic kinesin Eg5 and anticancer agents. Bioorg Chem 2019; 84:493-504. [DOI: 10.1016/j.bioorg.2018.12.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 12/04/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023]
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Suppressor Analysis Uncovers That MAPs and Microtubule Dynamics Balance with the Cut7/Kinesin-5 Motor for Mitotic Spindle Assembly in Schizosaccharomyces pombe. G3-GENES GENOMES GENETICS 2019; 9:269-280. [PMID: 30463883 PMCID: PMC6325904 DOI: 10.1534/g3.118.200896] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The Kinesin-5 motor Cut7 in Schizosaccharomyces pombe plays essential roles in spindle pole separation, leading to the assembly of bipolar spindle. In many organisms, simultaneous inactivation of Kinesin-14s neutralizes Kinesin-5 deficiency. To uncover the molecular network that counteracts Kinesin-5, we have conducted a genetic screening for suppressors that rescue the cut7-22 temperature sensitive mutation, and identified 10 loci. Next generation sequencing analysis reveals that causative mutations are mapped in genes encoding α-, β-tubulins and the microtubule plus-end tracking protein Mal3/EB1, in addition to the components of the Pkl1/Kinesin-14 complex. Moreover, the deletion of various genes required for microtubule nucleation/polymerization also suppresses the cut7 mutant. Intriguingly, Klp2/Kinesin-14 levels on the spindles are significantly increased in cut7 mutants, whereas these increases are negated by suppressors, which may explain the suppression by these mutations/deletions. Consistent with this notion, mild overproduction of Klp2 in these double mutant cells confers temperature sensitivity. Surprisingly, treatment with a microtubule-destabilizing drug not only suppresses cut7 temperature sensitivity but also rescues the lethality resulting from the deletion of cut7, though a single klp2 deletion per se cannot compensate for the loss of Cut7. We propose that microtubule assembly and/or dynamics antagonize Cut7 functions, and that the orchestration between these two factors is crucial for bipolar spindle assembly.
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Henriques AC, Ribeiro D, Pedrosa J, Sarmento B, Silva PMA, Bousbaa H. Mitosis inhibitors in anticancer therapy: When blocking the exit becomes a solution. Cancer Lett 2018; 440-441:64-81. [PMID: 30312726 DOI: 10.1016/j.canlet.2018.10.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 09/12/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022]
Abstract
Current microtubule-targeting agents (MTAs) remain amongst the most important antimitotic drugs used against a broad range of malignancies. By perturbing spindle assembly, MTAs activate the spindle assembly checkpoint (SAC), which induces mitotic arrest and subsequent apoptosis. However, besides toxic side effects and resistance, mitotic slippage and failure in triggering apoptosis in various cancer cells are limiting factors of MTAs efficacy. Alternative strategies to target mitosis without affecting microtubules have, thus, led to the identification of small molecules, such as those that target spindle Kinesins, Aurora and Polo-like kinases. Unfortunately, these so-called second-generation of antimitotics, encompassing mitotic blockers and mitotic drivers, have failed in clinical trials. Our recent understanding regarding the mechanisms of cell death during a mitotic arrest pointed out apoptosis as the main variable, providing an opportunity to control the cell fates and influence the effectiveness of antimitotics. Here, we provide an overview on the second-generation of antimitotics, and discuss possible strategies that exploit SAC activity, mitotic slippage/exit and apoptosis induction, in order to improve the efficacy of anticancer strategies that target mitosis.
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Affiliation(s)
- Ana C Henriques
- CESPU, Instituto de Investigação e Formação Avançada Em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra PRD, Portugal; INEB, Instituto Nacional de Engenharia Biomédica, Universidade Do Porto, Porto, Portugal
| | - Diana Ribeiro
- CESPU, Instituto de Investigação e Formação Avançada Em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra PRD, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade Do Porto, Porto, Portugal
| | - Joel Pedrosa
- CESPU, Instituto de Investigação e Formação Avançada Em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra PRD, Portugal
| | - Bruno Sarmento
- CESPU, Instituto de Investigação e Formação Avançada Em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra PRD, Portugal; INEB, Instituto Nacional de Engenharia Biomédica, Universidade Do Porto, Porto, Portugal; i3S - Instituto de Investigação e Inovação Em Saúde, Universidade Do Porto, Porto, Portugal
| | - Patrícia M A Silva
- CESPU, Instituto de Investigação e Formação Avançada Em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra PRD, Portugal
| | - Hassan Bousbaa
- CESPU, Instituto de Investigação e Formação Avançada Em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra PRD, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade Do Porto, Porto, Portugal.
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48
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Kawakami M, Liu X, Dmitrovsky E. New Cell Cycle Inhibitors Target Aneuploidy in Cancer Therapy. Annu Rev Pharmacol Toxicol 2018; 59:361-377. [PMID: 30110577 DOI: 10.1146/annurev-pharmtox-010818-021649] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Aneuploidy is a hallmark of cancer. Defects in chromosome segregation result in aneuploidy. Multiple pathways are engaged in this process, including errors in kinetochore-microtubule attachments, supernumerary centrosomes, spindle assembly checkpoint (SAC) defects, and chromosome cohesion defects. Although aneuploidy provides an adaptation and proliferative advantage in affected cells, excessive aneuploidy beyond a critical level can be lethal to cancer cells. Given this, enhanced chromosome missegregation is hypothesized to limit survival of aneuploid cancer cells, especially when compared to diploid cells. Based on this concept, proteins and pathways engaged in chromosome segregation are being exploited as candidate therapeutic targets for aneuploid cancers. Agents that induce chromosome missegregation and aneuploidy now exist, including SAC inhibitors, those that alter centrosome fidelity and others that are under active study in preclinical and clinical contexts. This review explores the therapeutic potentials of such new agents, including the benefits of combining them with other antineoplastic agents.
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Affiliation(s)
- Masanori Kawakami
- Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA
| | - Xi Liu
- Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA
| | - Ethan Dmitrovsky
- Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA.,Department of Cancer Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA.,Current affiliation: Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, USA;
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Ye L, Li H, Zhang F, Lv T, Liu H, Song Y. [Expression of KIF23 and Its Prognostic Role in Non-small Cell Lung Cancer:
Analysis Based on the Data-mining of Oncomine]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2018; 20:822-826. [PMID: 29277180 PMCID: PMC5973387 DOI: 10.3779/j.issn.1009-3419.2017.12.05] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
背景与目的 非小细胞肺癌（non-small cell lung cancer, NSCLC）是全球引起死亡的最重要原因之一。大多数患者发现时处于中晚期，预后较差。本研究拟探讨驱动蛋白超家族23（kinesin family member 23, KIF23）在NSCLC中的表达及意义。 方法 收集Oncomine数据库中关于KIF23的信息，并对目前数据库中资料进行二次分析，对其在NSCLC中的作用进行荟萃分析。利用Kaplan-Meier Plotter进行患者生存周期分析。 结果 Oncomine数据库中共收集了447项不同类型的研究结果，其中关于KIF23表达有统计学差异的研究结果有67个，KIF23表达增高的研究有64项、表达降低的研究有3项。共有16项研究涉及KIF23在NSCLC癌组织和正常组织中的表达，共包括1, 189个样本，与对照组相比，KIF23在NSCLC细胞癌中高表达（P＜0.05）。不仅如此，KIF23表达量与NSCLC总体生存率存在相关性，高表达KIF23的患者总体生存率较差，低表达KIF23的患者预后较好（P＜0.05）。进一步亚组分析发现，KIF23表达水平对肺腺癌患者预后有显著影响，而在鳞癌患者中，其表达水平对预后无显著影响。 结论 我们通过对Oncomine基因芯片数据库中肿瘤相关基因信息的深入挖掘，提出KIF23在NSLCL组织中高表达，且与NSCLC预后有关，可能为肿瘤药物的开发提供重要理论依据。
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Affiliation(s)
- Liang Ye
- Department of Respiratory Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210006, China.,Department of Respiratory Medicine, Najing Hospital Affiliated to Nanjing Medical University (Nanjing First Hospital),
Nanjing 210002, China
| | - Huijuan Li
- Department of Respiratory Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210006, China
| | - Fang Zhang
- Department of Respiratory Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210006, China
| | - Tangfeng Lv
- Department of Respiratory Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210006, China
| | - Hongbing Liu
- Department of Respiratory Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210006, China
| | - Yong Song
- Department of Respiratory Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210006, China
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Yukawa M, Yamauchi T, Kurisawa N, Ahmed S, Kimura KI, Toda T. Fission yeast cells overproducing HSET/KIFC1 provides a useful tool for identification and evaluation of human kinesin-14 inhibitors. Fungal Genet Biol 2018; 116:33-41. [DOI: 10.1016/j.fgb.2018.04.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 03/29/2018] [Accepted: 04/07/2018] [Indexed: 12/14/2022]
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