|
1
|
Chen X, Xue B, Wahab S, Sultan A, Khalid M, Yang S. Structure-based molecular docking and molecular dynamics simulations study for the identification of dipeptidyl peptidase 4 inhibitors in type 2 diabetes. J Biomol Struct Dyn 2025; 43:1445-1458. [PMID: 38100564 DOI: 10.1080/07391102.2023.2291831] [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: 03/24/2023] [Accepted: 11/23/2023] [Indexed: 12/17/2023]
Abstract
Inhibition of dipeptidyl peptidase-4 (DPP4) activity has emerged as a promising therapeutic approach for the treatment of type 2 diabetes mellitus (T2DM). Bioinformatics-driven approaches have emerged as crucial tools in drug discovery. Molecular docking and molecular dynamics (MD) simulations are effective tools in drug discovery, as they reduce the time and cost associated with experimental screening. In this study, we employed structure-assisted in-silico methods, including molecular docking and MD simulations, to identify SRT2183, a small molecule that may potentially inhibit the activity of DPP4 enzyme. The interaction between the small molecule "SRT2183" and DPP4 exhibited a binding affinity of -9.9 Kcal/Mol, leading to the formation of hydrogen bonds with the amino acid residues MET348, SER376, and THR351 of DPP4. The MD simulations over a period of 100 ns indicated stable protein-ligand interactions, with no significant conformational rearrangements observed within the simulated timeframe. In conclusion, our results suggest that the small molecule SRT2183 may have the potential to inhibit the DPP4 enzyme and pave the way for the therapeutics of T2DM.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Xi Chen
- School of Management, Guangzhou College of Technology and Business, Guangzhou, China
| | - Bin Xue
- School of Engineering, Guangzhou College of Technology and Business, Guangzhou, China
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Armiya Sultan
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Mohammad Khalid
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Song Yang
- Department of Wine, Food and Molecular Biosciences, Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand
| |
Collapse
|
|
2
|
Jiang YK, Li W, Qiu YY, Yue M. Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer. World J Gastrointest Oncol 2024; 16:2318-2334. [PMID: 38994153 PMCID: PMC11236256 DOI: 10.4251/wjgo.v16.i6.2318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 04/04/2024] [Accepted: 04/18/2024] [Indexed: 06/13/2024] Open
Abstract
Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance. Human epidermal growth factor receptor 2 (HER2) is one of the most important targets in targeted therapy for gastric cancer. Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer. The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified. However, monoclonal antibodies, due to their large molecular weight, inability to penetrate the blood-brain barrier, and drug resistance, lead to decreased therapeutic efficacy, so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer. Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role.
Collapse
Affiliation(s)
- Ya-Kun Jiang
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Wei Li
- Health Management Center, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Ying-Yang Qiu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Meng Yue
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| |
Collapse
|
|
3
|
Ren X, Feng C, Wang Y, Chen P, Wang S, Wang J, Cao H, Li Y, Ji M, Hou P. SLC39A10 promotes malignant phenotypes of gastric cancer cells by activating the CK2-mediated MAPK/ERK and PI3K/AKT pathways. Exp Mol Med 2023; 55:1757-1769. [PMID: 37524874 PMCID: PMC10474099 DOI: 10.1038/s12276-023-01062-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 03/13/2023] [Accepted: 05/25/2023] [Indexed: 08/02/2023] Open
Abstract
Solute carrier family 39 member 10 (SLC39A10) belongs to a subfamily of zinc transporters and plays a key role in B-cell development. Previous studies have reported that its upregulation promotes breast cancer metastasis by enhancing the influx of zinc ions (Zn2+); however, its role in gastric cancer remains totally unclear. Here, we found that SLC39A10 expression was frequently increased in gastric adenocarcinomas and that SLC39A10 upregulation was strongly associated with poor patient outcomes; in addition, we identified SLC39A10 as a direct target of c-Myc. Functional studies showed that ectopic expression of SLC39A10 in gastric cancer cells dramatically enhanced the proliferation, colony formation, invasiveness abilities of these gastric cancer cells and tumorigenic potential in nude mice. Conversely, SLC39A10 knockdown inhibited gastric cancer cell proliferation and colony formation. Mechanistically, SLC39A10 exerted its carcinogenic effects by increasing Zn2+ availability and subsequently enhancing the enzyme activity of CK2 (casein kinase 2). As a result, the MAPK/ERK and PI3K/AKT pathways, two major downstream effectors of CK2, were activated, while c-Myc, a downstream target of these two pathways, formed a vicious feedback loop with SLC39A10 to drive the malignant progression of gastric cancer. Taken together, our data demonstrate that SLC39A10 is a functional oncogene in gastric cancer and suggest that targeting CK2 is an alternative therapeutic strategy for gastric cancer patients with high SLC39A10 expression.
Collapse
Affiliation(s)
- Xiaojuan Ren
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Chao Feng
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Yubo Wang
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Pu Chen
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Simeng Wang
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Jianling Wang
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Hongxin Cao
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Yujun Li
- Department of Endocrinology, The Second Affiliated Hospital of Xi'an Jiaotong University, 710004, Xi'an, P. R. China.
| | - Meiju Ji
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China.
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China.
| | - Peng Hou
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China.
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China.
| |
Collapse
|
|
4
|
van Ree JH, Jeganathan KB, Fierro Velasco RO, Zhang C, Can I, Hamada M, Li H, Baker DJ, van Deursen JM. Hyperphosphorylated PTEN exerts oncogenic properties. Nat Commun 2023; 14:2983. [PMID: 37225693 PMCID: PMC10209192 DOI: 10.1038/s41467-023-38740-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 05/12/2023] [Indexed: 05/26/2023] Open
Abstract
PTEN is a multifaceted tumor suppressor that is highly sensitive to alterations in expression or function. The PTEN C-tail domain, which is rich in phosphorylation sites, has been implicated in PTEN stability, localization, catalytic activity, and protein interactions, but its role in tumorigenesis remains unclear. To address this, we utilized several mouse strains with nonlethal C-tail mutations. Mice homozygous for a deletion that includes S370, S380, T382 and T383 contain low PTEN levels and hyperactive AKT but are not tumor prone. Analysis of mice containing nonphosphorylatable or phosphomimetic versions of S380, a residue hyperphosphorylated in human gastric cancers, reveal that PTEN stability and ability to inhibit PI3K-AKT depends on dynamic phosphorylation-dephosphorylation of this residue. While phosphomimetic S380 drives neoplastic growth in prostate by promoting nuclear accumulation of β-catenin, nonphosphorylatable S380 is not tumorigenic. These data suggest that C-tail hyperphosphorylation creates oncogenic PTEN and is a potential target for anti-cancer therapy.
Collapse
Affiliation(s)
- Janine H van Ree
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | - Karthik B Jeganathan
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Cheng Zhang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Ismail Can
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Masakazu Hamada
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | - Hu Li
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Darren J Baker
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Jan M van Deursen
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
5
|
Wang Q, Hu X, Shi W, Long H, Wang H. Design, synthesis and biological evaluation of chromone derivatives as novel protein kinase CK2 inhibitors. Bioorg Med Chem Lett 2022; 69:128799. [PMID: 35580724 DOI: 10.1016/j.bmcl.2022.128799] [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: 03/28/2022] [Revised: 04/30/2022] [Accepted: 05/11/2022] [Indexed: 11/02/2022]
Abstract
Protein kinase CK2 is a potential target for the discovery of anticancer drugs. Flavonoids are reported to be effective CK2 inhibitors. Herein, based on structural trimming of flavonoids, a series of chromone-2-aminothiazole derivatives (1a-d, 2a-g, 4a-j, 5a-k) were designed and synthesized by hybridizing the chromone skeleton with 2-aminothiazole scaffold. Among these compounds, compound 5i was the most effective CK2 inhibitor (IC50 = 0.08 μM) and possessed potent anti-proliferative activity against HL-60 tumor cells (IC50 = 0.25 μM). Cellular thermal shift assay (CESTA) confirmed that 5i directly bound to the CK2, and the possible binding mode of 5i toward CK2 was also simulated. Further studies showed that 5i induced the apoptosis of HL-60 cells and arrested the cell cycle. Finally, western-blot analysis showed that 5i could inhibit the downstream of CK2, including α-catenin/Akt pathway and PARP/Survivin pathway.
Collapse
Affiliation(s)
- Quan Wang
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - XiaoLong Hu
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Wei Shi
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Huan Long
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Hao Wang
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
| |
Collapse
|
|
6
|
Nipun VB, Amin KA. Recent Advances in Protein Kinase CK2, a Potential Therapeutic Target in Cancer. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2022; 48:919-931. [DOI: 10.1134/s1068162022050144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- V. B. Nipun
- Cancer Research Center, Shantou University Medical Collage, Shantou, Guangdong, 515041, PR China
- Department of Chemistry, Faculty of Science, University of Imam Abdulrahman Bin Faisal university, P.O. Box 1982, Dammam, 31441, Saudi Arabia
| | - K. A. Amin
- Department of Chemistry, Faculty of Science, University of Imam Abdulrahman Bin Faisal university, P.O. Box 1982, Dammam, 31441, Saudi Arabia
- Basic and Applied Scientific Research Center, Imam Abdulrahman Bin Faisal university, P.O. Box 1982, Dammam, 31441, Saudi Arabia
| |
Collapse
|
|
7
|
The Role of Protein Kinase CK2 in Development and Disease Progression: A Critical Review. J Dev Biol 2022; 10:jdb10030031. [PMID: 35997395 PMCID: PMC9397010 DOI: 10.3390/jdb10030031] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/22/2022] [Accepted: 07/26/2022] [Indexed: 02/01/2023] Open
Abstract
Protein kinase CK2 (CK2) is a ubiquitous holoenzyme involved in a wide array of developmental processes. The involvement of CK2 in events such as neurogenesis, cardiogenesis, skeletogenesis, and spermatogenesis is essential for the viability of almost all organisms, and its role has been conserved throughout evolution. Further into adulthood, CK2 continues to function as a key regulator of pathways affecting crucial processes such as osteogenesis, adipogenesis, chondrogenesis, neuron differentiation, and the immune response. Due to its vast role in a multitude of pathways, aberrant functioning of this kinase leads to embryonic lethality and numerous diseases and disorders, including cancer and neurological disorders. As a result, CK2 is a popular target for interventions aiming to treat the aforementioned diseases. Specifically, two CK2 inhibitors, namely CX-4945 and CIBG-300, are in the early stages of clinical testing and exhibit promise for treating cancer and other disorders. Further, other researchers around the world are focusing on CK2 to treat bone disorders. This review summarizes the current understanding of CK2 in development, the structure of CK2, the targets and signaling pathways of CK2, the implication of CK2 in disease progression, and the recent therapeutics developed to inhibit the dysregulation of CK2 function in various diseases.
Collapse
|
|
8
|
Wang S, Yadav AK, Han JY, Ahn KS, Jang BC. Anti-Growth, Anti-Angiogenic, and Pro-Apoptotic Effects by CX-4945, an Inhibitor of Casein Kinase 2, on HuCCT-1 Human Cholangiocarcinoma Cells via Control of Caspase-9/3, DR-4, STAT-3/STAT-5, Mcl-1, eIF-2α, and HIF-1α. Int J Mol Sci 2022; 23:6353. [PMID: 35683032 PMCID: PMC9181600 DOI: 10.3390/ijms23116353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/30/2022] [Accepted: 05/30/2022] [Indexed: 12/10/2022] Open
Abstract
Overexpression of casein kinase 2 (CK2) has an oncogenic and pro-survival role in many cancers. CX-4945 (Silmitasertib) is a CK2 inhibitor with anti-cancerous and anti-angiogenic effects. Up to date, the anti-cancer effect and mechanism of CX-4945 on human cholangiocarcinoma (CCA) remain unclear. This study investigated whether CX-4945 inhibits growth and induces apoptosis of HuCCT-1 cells, a human CCA cell line. Of note, treatment with CX-4945 at 20 μM markedly reduced survival and induced apoptosis of HuCCT-1 cells, as evidenced by nuclear DNA fragmentation, PARP cleavage, activation of caspase-9/3, and up-regulation of DR-4. Although CX-4945 did not affect the phosphorylation and expression of CK2, it vastly inhibited the phosphorylation of CK2 substrates, supporting the drug's efficacy in inhibiting CK2 and its downstream pathway. Importantly, knockdown of CK2 that partially suppressed the phosphorylation of CK2 substrates resulted in a significant reduction of HuCCT-1 cell survival. In addition, CX-4945 reduced the phosphorylation and expression of STAT-3 and STAT-5 in HuCCT-1 cells, and pharmacological inhibition or respective knockdown of these proteins resulted in significant growth suppression of HuCCT-1 cells. CX-4945 also had abilities to decrease Mcl-1 expression while increasing eIF-2α phosphorylation in HuCCT-1 cells. Furthermore, there was a time-differential negative regulation of HIF-1α expression by CX-4945 in HuCCT-1 cells, and knockdown of HIF-1α caused a significant reduction of the cell survival. In summary, these results demonstrated that CX-4945 has anti-growth, anti-angiogenic, and pro-apoptotic effects on HuCCT-1 cells, which are mediated through control of CK2, caspase-9/3, DR-4, STAT-3/5, Mcl-1, eIF-2α, and HIF-1α.
Collapse
Affiliation(s)
- Saini Wang
- Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea; (S.W.); (A.K.Y.)
- Department of Surgery, Keimyung University Dongsan Hospital, 1035 Dalgubeol-daero, Dalseo-gu, Daegu 41931, Korea;
| | - Anil Kumar Yadav
- Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea; (S.W.); (A.K.Y.)
- The Hormel Institute, University of Minnesota, Austin, MN 55812, USA
| | - Jin-Yi Han
- Department of Surgery, Keimyung University Dongsan Hospital, 1035 Dalgubeol-daero, Dalseo-gu, Daegu 41931, Korea;
| | - Keun Soo Ahn
- Department of Surgery, Keimyung University Dongsan Hospital, 1035 Dalgubeol-daero, Dalseo-gu, Daegu 41931, Korea;
| | - Byeong-Churl Jang
- Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea; (S.W.); (A.K.Y.)
| |
Collapse
|
|
9
|
Schwarz R, Richter A, Ito ERD, Murua Escobar H, Junghanß C, Hinz B. Validation of an LC-MS/MS Method for the Quantification of the CK2 Inhibitor Silmitasertib (CX-4945) in Human Plasma. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27082394. [PMID: 35458589 PMCID: PMC9028559 DOI: 10.3390/molecules27082394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/15/2022] [Accepted: 03/22/2022] [Indexed: 11/16/2022]
Abstract
Silmitasertib (CX-4945) is currently being investigated in clinical trials against various types of cancer. The U.S. Food and Drug Administration (FDA) has already granted orphan drug designation to the compound for the treatment of advanced cholangiocarcinoma, medulloblastoma, and biliary tract cancer. Silmitasertib inhibits the serine/threonine protein kinase CK2, which exerts a proliferation-promoting and anti-apoptotic effect on cancer cells. In view of current and future applications, the measurement of silmitasertib levels in plasma is expected to play an important role in the evaluation of therapeutic and toxic concentrations in cancer patients. In the present work, we therefore present an LC-MS/MS method for the quantification of silmitasertib in human plasma. Using a simple liquid-liquid extraction with ethyl acetate and a mixture of n-hexane and ethyl acetate, this method can be performed in any laboratory with mass spectrometry. The validation was carried out according to the FDA guideline.
Collapse
Affiliation(s)
- Rico Schwarz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, 18057 Rostock, Germany; (R.S.); (E.R.D.I.)
| | - Anna Richter
- Clinic for Hematology, Oncology and Palliative Care, Rostock University Medical Center, 18057 Rostock, Germany; (A.R.); (H.M.E.); (C.J.)
| | - Elisabeth R. D. Ito
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, 18057 Rostock, Germany; (R.S.); (E.R.D.I.)
| | - Hugo Murua Escobar
- Clinic for Hematology, Oncology and Palliative Care, Rostock University Medical Center, 18057 Rostock, Germany; (A.R.); (H.M.E.); (C.J.)
| | - Christian Junghanß
- Clinic for Hematology, Oncology and Palliative Care, Rostock University Medical Center, 18057 Rostock, Germany; (A.R.); (H.M.E.); (C.J.)
| | - Burkhard Hinz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, 18057 Rostock, Germany; (R.S.); (E.R.D.I.)
- Correspondence:
| |
Collapse
|
|
10
|
Rammohan M, Harris E, Bhansali RS, Zhao E, Li LS, Crispino JD. The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target. Oncogene 2022; 41:2003-2011. [PMID: 35220406 PMCID: PMC8977259 DOI: 10.1038/s41388-022-02245-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 11/09/2022]
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is a serine/threonine kinase that belongs to the DYRK family of proteins, a subgroup of the evolutionarily conserved CMGC protein kinase superfamily. Due to its localization on chromosome 21, the biological significance of DYRK1A was initially characterized in the pathogenesis of Down syndrome (DS) and related neurodegenerative diseases. However, increasing evidence has demonstrated a prominent role in cancer through its ability to regulate biologic processes including cell cycle progression, DNA damage repair, transcription, ubiquitination, tyrosine kinase activity, and cancer stem cell maintenance. DYRK1A has been identified as both an oncogene and tumor suppressor in different models, underscoring the importance of cellular context in its function. Here, we review mechanistic contributions of DYRK1A to cancer biology and its role as a potential therapeutic target.
Collapse
Affiliation(s)
- Malini Rammohan
- Driskill Graduate Program in Life Sciences, Northwestern University, Chicago, IL, USA
| | - Ethan Harris
- University of Illinois at Chicago College of Medicine, Chicago, IL, USA
- Division of Experimental Hematology, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Rahul S Bhansali
- Department of Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Emily Zhao
- Weinberg College of Arts and Sciences, Northwestern University, Chicago, IL, USA
| | - Loretta S Li
- Molecular and Translational Cancer Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
- Department of Pediatrics, Division of Hematology, Oncology, and Stem Cell Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - John D Crispino
- Division of Experimental Hematology, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
| |
Collapse
|
|
11
|
Zhou L, Zhang Z, Nice E, Huang C, Zhang W, Tang Y. Circadian rhythms and cancers: the intrinsic links and therapeutic potentials. J Hematol Oncol 2022; 15:21. [PMID: 35246220 PMCID: PMC8896306 DOI: 10.1186/s13045-022-01238-y] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
The circadian rhythm is an evolutionarily conserved time-keeping system that comprises a wide variety of processes including sleep-wake cycles, eating-fasting cycles, and activity-rest cycles, coordinating the behavior and physiology of all organs for whole-body homeostasis. Acute disruption of circadian rhythm may lead to transient discomfort, whereas long-term irregular circadian rhythm will result in the dysfunction of the organism, therefore increasing the risks of numerous diseases especially cancers. Indeed, both epidemiological and experimental evidence has demonstrated the intrinsic link between dysregulated circadian rhythm and cancer. Accordingly, a rapidly increasing understanding of the molecular mechanisms of circadian rhythms is opening new options for cancer therapy, possibly by modulating the circadian clock. In this review, we first describe the general regulators of circadian rhythms and their functions on cancer. In addition, we provide insights into the mechanisms underlying how several types of disruption of the circadian rhythm (including sleep-wake, eating-fasting, and activity-rest) can drive cancer progression, which may expand our understanding of cancer development from the clock perspective. Moreover, we also summarize the potential applications of modulating circadian rhythms for cancer treatment, which may provide an optional therapeutic strategy for cancer patients.
Collapse
Affiliation(s)
- Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Edouard Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Wei Zhang
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Yong Tang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Acupuncture and Chronobiology Laboratory of Sichuan Province, Chengdu, 610075, China.
| |
Collapse
|
|
12
|
Sultan A, Ali R, Sultan T, Ali S, Khan NJ, Parganiha A. Circadian clock modulating small molecules repurposing as inhibitors of SARS-CoV-2 M pro for pharmacological interventions in COVID-19 pandemic. Chronobiol Int 2021; 38:971-985. [PMID: 33820462 PMCID: PMC8022342 DOI: 10.1080/07420528.2021.1903027] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency warranting the development of targeted treatment. The main protease Mpro is considered as a key drug target in coronavirus infections because of its vital role in the proteolytic processing of two essential polyproteins required for the replication and transcription of viral RNA. Targeting and inhibiting the Mpro activity represents a valid approach to prevent the SARS-CoV-2 replication and spread. Based on the structure-assisted drug designing, here we report a circadian clock-modulating small molecule “SRT2183” as a potent inhibitor of Mpro to block the replication of SARS-CoV-2. The findings are expected to pave the way for the development of therapeutics for COVID-19.
Collapse
Affiliation(s)
- Armiya Sultan
- Functional Genomics Laboratory, Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia (A Central University), New Delhi, India.,Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi, India.,Chronobiology and Animal Behaviour Laboratory, School of Studies in Life Sciences, Pt. Ravishankar Shukla University, Raipur, India
| | - Rafat Ali
- Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Tahira Sultan
- Department of Biochemistry, University of Kashmir, Srinagar, India
| | - Sher Ali
- Department of Life Sciences, Sharda University, Greater Noida, India
| | - Nida Jamil Khan
- Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Arti Parganiha
- Chronobiology and Animal Behaviour Laboratory, School of Studies in Life Sciences, Pt. Ravishankar Shukla University, Raipur, India
| |
Collapse
|
|
13
|
Czapinska H, Winiewska-Szajewska M, Szymaniec-Rutkowska A, Piasecka A, Bochtler M, Poznański J. Halogen Atoms in the Protein-Ligand System. Structural and Thermodynamic Studies of the Binding of Bromobenzotriazoles by the Catalytic Subunit of Human Protein Kinase CK2. J Phys Chem B 2021; 125:2491-2503. [PMID: 33689348 PMCID: PMC8041304 DOI: 10.1021/acs.jpcb.0c10264] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
![]()
Binding of a family
of brominated benzotriazoles to the catalytic
subunit of human protein kinase CK2 (hCK2α) was used as a model
system to assess the contribution of halogen bonding to protein–ligand
interaction. CK2 is a constitutively active pleiotropic serine/threonine
protein kinase that belongs to the CMGC group of eukaryotic protein
kinases (EPKs). Due to the addiction of some cancer cells, CK2 is
an attractive and well-characterized drug target. Halogenated benzotriazoles
act as ATP-competitive inhibitors with unexpectedly good selectivity
for CK2 over other EPKs. We have characterized the interaction of
bromobenzotriazoles with hCK2α by X-ray crystallography, low-volume
differential scanning fluorimetry, and isothermal titration calorimetry.
Properties of free ligands in solution were additionally characterized
by volumetric and RT-HPLC measurements. Thermodynamic data indicate
that the affinity increases with bromo substitution, with greater
contributions from 5- and 6-substituents than 4- and 7-substituents.
Except for 4,7-disubstituted compounds, the bromobenzotriazoles adopt
a canonical pose with the triazole close to lysine 68, which precludes
halogen bonding. More highly substituted benzotriazoles adopt many
additional noncanonical poses, presumably driven by a large hydrophobic
contribution to binding. Some noncanonical ligand orientations allow
the formation of halogen bonds with the hinge region. Consistent with
a predominantly hydrophobic interaction, the isobaric heat capacity
decreases upon ligand binding, the more so the higher the substitution.
Collapse
Affiliation(s)
- Honorata Czapinska
- Institute of Biochemistry and Biophysics PAS, Pawińskiego 5a, 02-106 Warsaw, Poland.,International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland
| | - Maria Winiewska-Szajewska
- Institute of Biochemistry and Biophysics PAS, Pawińskiego 5a, 02-106 Warsaw, Poland.,Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Pasteura 5, 02-089 Warsaw, Poland
| | | | - Anna Piasecka
- Institute of Biochemistry and Biophysics PAS, Pawińskiego 5a, 02-106 Warsaw, Poland.,International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland
| | - Matthias Bochtler
- Institute of Biochemistry and Biophysics PAS, Pawińskiego 5a, 02-106 Warsaw, Poland.,International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland
| | - Jarosław Poznański
- Institute of Biochemistry and Biophysics PAS, Pawińskiego 5a, 02-106 Warsaw, Poland
| |
Collapse
|
|
14
|
Tang S, Yuan Y, Liu Z, He Y, Pan D. Casein kinase 2 inhibitor CX-4945 elicits an anti-Warburg effects through the downregulation of TAp73 and inhibits gastric tumorigenesis. Biochem Biophys Res Commun 2020; 530:686-691. [PMID: 32771361 DOI: 10.1016/j.bbrc.2020.07.116] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 07/24/2020] [Indexed: 11/18/2022]
Abstract
Casein kinase 2 (CK2) has become a potential therapeutic target in gastric cancer; however, the underlying mechanism remains incompletely understood. TAp73, a structural homolog of the tumor suppressor p53, acts as a critical regulator of the Warburg effect. Recent study reveals that aberrant CK2 signaling is able to inhibit TAp73 function. Here we determine that TAp73 is overexpressed in AGS-1 but not in SNU-5 gastric cancer cell line as compared with normal gastric cells. In addition, we show that TAp73 expression is required for the maintenance of glucose uptake and lactate release in AGS-1 but not in SNU-5 gastric cancer cells. Importantly, the use of CX-4945, a selective inhibitor of protein kinase CK2, inhibits cell growth and invasion, and promotes cell apoptosis in AGS-1 with decreased TAp73 expression as well as downregulated glucose uptake and lactate release. Although TAp73 knockdown resulted in significant decreases in TAp73 expressions in SNU-5 cell line, no differences in glucose uptake and lactate release were observed between SNU-5 and normal gastric cells. Moreover, TAp73 gene overexpression promotes glucose uptake and lactate release and abolishes the anti-cancer effects of CX-4945 in gastric cancer cell line AGS-1. The impacts of CX-4945 on glycolysis and tumorigenesis were strongly limited in SNU-5 gastric cancer cell line. These findings suggest that CX-4945 elicits an anti-Warburg effects in gastric cancer overexpressing Tap73 and inhibits gastric tumorigenesis.
Collapse
Affiliation(s)
- Shengli Tang
- Department of General Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei, 430071, China.
| | - Yufeng Yuan
- Department of General Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei, 430071, China
| | - Zhisu Liu
- Department of General Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei, 430071, China
| | - Yueming He
- Department of General Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei, 430071, China
| | - Dingyu Pan
- Department of General Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei, 430071, China
| |
Collapse
|
|
15
|
ShiYang X, Miao Y, Cui Z, Lu Y, Zhou C, Zhang Y, Xiong B. Casein kinase 2 modulates the spindle assembly checkpoint to orchestrate porcine oocyte meiotic progression. J Anim Sci Biotechnol 2020; 11:31. [PMID: 32292585 PMCID: PMC7140493 DOI: 10.1186/s40104-020-00438-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 02/17/2020] [Indexed: 11/10/2022] Open
Abstract
Background CK2 (casein kinase 2) is a serine/threonine-selective protein kinase that has been involved in a variety of cellular processes such as DNA repair, cell cycle control and circadian rhythm regulation. However, its functional roles in oocyte meiosis have not been fully determined. Results We report that CK2 is essential for porcine oocyte meiotic maturation by regulating spindle assembly checkpoint (SAC). Immunostaining and immunoblotting analysis showed that CK2 was constantly expressed and located on the chromosomes during the entire oocyte meiotic maturation. Inhibition of CK2 activity by its selective inhibitor CX-4945 impaired the first polar body extrusion and arrested oocytes at M I stage, accompanied by the presence of BubR1 at kinetochores, indicative of activated SAC. In addition, we found that spindle/chromosome structure was disrupted in CK2-inhibited oocytes due to the weakened microtubule stability, which is a major cause resulting in the activation of SAC. Last, we found that the level DNA damage as assessed by γH2A.X staining was considerably elevated when CK2 was inhibited, suggesting that DNA damage might be another critical factor leading to the SAC activation and meiotic failure of oocytes. Conclusions Our findings demonstrate that CK2 promotes the porcine oocyte maturation by ensuring normal spindle assembly and DNA damage repair.
Collapse
Affiliation(s)
- Xiayan ShiYang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Yilong Miao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Zhaokang Cui
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Yajuan Lu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Changyin Zhou
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Yu Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Bo Xiong
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| |
Collapse
|