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Htun TS, Tanaka H, Singh SK, Diez D, Akira S. Regnase-1 D141N mutation induces CD4+ T cell-mediated lung granuloma formation via upregulation of Pim2. Int Immunol 2024; 36:497-516. [PMID: 38700370 DOI: 10.1093/intimm/dxae026] [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: 12/06/2023] [Accepted: 05/02/2024] [Indexed: 05/05/2024] Open
Abstract
Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory messenger RNAs (mRNAs). Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of the RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of the Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs, and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated the mTORC1 pathway and facilitated the autoimmune trait in the D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration, and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune functions and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses.
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Affiliation(s)
- Thin Sandi Htun
- Laboratory of Host Defense, World Premier Institute-Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroki Tanaka
- Laboratory of Host Defense, World Premier Institute-Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka 565-0871, Japan
| | - Shailendra Kumar Singh
- Laboratory of Host Defense, World Premier Institute-Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka 565-0871, Japan
| | - Diego Diez
- Quantitative Immunology Research Unit, World Premier Institute-Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka 565-0871, Japan
| | - Shizuo Akira
- Laboratory of Host Defense, World Premier Institute-Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka 565-0871, Japan
- Department of Host Defense, Research Institute for Microbial Research, Osaka University, Suita, Osaka 565-0871, Japan
- Center for Advanced Modalities and Drug Delivery System, Osaka University, Suita, Osaka 565-0871, Japan
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2
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Noura M, Tomita S, Yasuda T, Tsuzuki S, Kiyoi H, Hayakawa F. NUP98-BPTF promotes oncogenic transformation through PIM1 upregulation. Cancer Med 2024; 13:e7445. [PMID: 38940430 PMCID: PMC11212001 DOI: 10.1002/cam4.7445] [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: 01/19/2024] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 06/29/2024] Open
Abstract
INTRODUCTION Nucleoporin 98 (NUP98) fusion proteins are recurrently found in leukemia and are associated with unfavorable clinical outcomes. They are distributed to the nucleus and contribute to leukemogenesis via aberrant transcriptional regulation. We previously identified NUP98-BPTF (NB) fusion in patients with T-cell acute lymphoblastic leukemia (T-ALL) using next-generation sequencing. The FG-repeat of NUP98 and the PHD finger and bromodomain of bromodomain PHD finger transcription factor (BPTF) are retained in the fusion. Like other NUP98 fusion proteins, NB is considered to regulate genes that are essential for leukemogenesis. However, its target genes or pathways remain unknown. MATERIALS AND METHODS To investigate the potential oncogenic properties of the NB fusion protein, we lentivirally transduced a doxycycline-inducible NB expression vector into mouse NIH3T3 fibroblasts and human Jurkat T-ALL cells. RESULTS NB promoted the transformation of mouse NIH3T3 fibroblasts by upregulating the proto-oncogene Pim1, which encodes a serine/threonine kinase. NB transcriptionally regulated Pim1 expression by binding to its promoter and activated MYC and mTORC1 signaling. PIM1 knockdown or pharmacological inhibition of mTORC1 signaling suppressed NB-induced NIH3T3 cell transformation. Furthermore, NB enhanced the survival of human Jurkat T-ALL cells by inactivating the pro-apoptotic protein BCL2-associated agonist of cell death (BAD). CONCLUSION We demonstrated the pivotal role of NB in cell transformation and survival and identified PIM1as a key downstream target of NB. These findings propose a promising therapeutic strategy for patients with NB fusion-positive leukemia.
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Affiliation(s)
- Mina Noura
- Division of Cellular and Genetic Sciences, Department of Integrated Health SciencesNagoya University Graduate School of MedicineNagoyaJapan
| | - Sakura Tomita
- Division of Cellular and Genetic Sciences, Department of Integrated Health SciencesNagoya University Graduate School of MedicineNagoyaJapan
| | - Takahiko Yasuda
- Clinical Research Center, National Hospital Organization Nagoya Medical CenterNagoyaJapan
| | - Shinobu Tsuzuki
- Department of BiochemistryAichi Medical University School of MedicineNagakuteJapan
| | - Hitoshi Kiyoi
- Department of Hematology and OncologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Fumihiko Hayakawa
- Division of Cellular and Genetic Sciences, Department of Integrated Health SciencesNagoya University Graduate School of MedicineNagoyaJapan
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Rout AK, Dehury B, Parida SN, Rout SS, Jena R, Kaushik N, Kaushik NK, Pradhan SK, Sahoo CR, Singh AK, Arya M, Behera BK. A review on structure-function mechanism and signaling pathway of serine/threonine protein PIM kinases as a therapeutic target. Int J Biol Macromol 2024; 270:132030. [PMID: 38704069 DOI: 10.1016/j.ijbiomac.2024.132030] [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: 11/24/2023] [Revised: 04/05/2024] [Accepted: 04/30/2024] [Indexed: 05/06/2024]
Abstract
The proviral integration for the Moloney murine leukemia virus (PIM) kinases, belonging to serine/threonine kinase family, have been found to be overexpressed in various types of cancers, such as prostate, breast, colon, endometrial, gastric, and pancreatic cancer. The three isoforms PIM kinases i.e., PIM1, PIM2, and PIM3 share a high degree of sequence and structural similarity and phosphorylate substrates controlling tumorigenic phenotypes like proliferation and cell survival. Targeting short-lived PIM kinases presents an intriguing strategy as in vivo knock-down studies result in non-lethal phenotypes, indicating that clinical inhibition of PIM might have fewer adverse effects. The ATP binding site (hinge region) possesses distinctive attributes, which led to the development of novel small molecule scaffolds that target either one or all three PIM isoforms. Machine learning and structure-based approaches have been at the forefront of developing novel and effective chemical therapeutics against PIM in preclinical and clinical settings, and none have yet received approval for cancer treatment. The stability of PIM isoforms is maintained by PIM kinase activity, which leads to resistance against PIM inhibitors and chemotherapy; thus, to overcome such effects, PIM proteolysis targeting chimeras (PROTACs) are now being developed that specifically degrade PIM proteins. In this review, we recapitulate an overview of the oncogenic functions of PIM kinases, their structure, function, and crucial signaling network in different types of cancer, and the potential of pharmacological small-molecule inhibitors. Further, our comprehensive review also provides valuable insights for developing novel antitumor drugs that specifically target PIM kinases in the future. In conclusion, we provide insights into the benefits of degrading PIM kinases as opposed to blocking their catalytic activity to address the oncogenic potential of PIM kinases.
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Affiliation(s)
- Ajaya Kumar Rout
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India
| | - Budheswar Dehury
- Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal-576104, India
| | - Satya Narayan Parida
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India
| | - Sushree Swati Rout
- Department of Zoology, Fakir Mohan University, Balasore-756089, Odisha, India
| | - Rajkumar Jena
- Department of Zoology, Fakir Mohan University, Balasore-756089, Odisha, India
| | - Neha Kaushik
- Department of Biotechnology, The University of Suwon, Hwaseong si, South Korea
| | | | - Sukanta Kumar Pradhan
- Department of Bioinformatics, Odisha University of Agriculture and Technology, Bhubaneswar-751003, Odisha, India
| | - Chita Ranjan Sahoo
- ICMR-Regional Medical Research Centre, Department of Health Research, Ministry of Health and Family Welfare, Government of India, Bhubaneswar-751023, India
| | - Ashok Kumar Singh
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India
| | - Meenakshi Arya
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India.
| | - Bijay Kumar Behera
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India.
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Wen S, Zhao P, Chen S, Deng B, Fang Q, Wang J. The impact of MCCK1, an inhibitor of IKBKE kinase, on acute B lymphocyte leukemia cells. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2024; 21:5164-5180. [PMID: 38872531 DOI: 10.3934/mbe.2024228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
B-cell acute lymphoblastic leukemia (B-ALL) is a malignant blood disorder, particularly detrimental to children and adolescents, with recurrent or unresponsive cases contributing significantly to cancer-associated fatalities. IKBKE, associated with innate immunity, tumor promotion, and drug resistance, remains poorly understood in the context of B-ALL. Thus, this research aimed to explore the impact of the IKBKE inhibitor MCCK1 on B-ALL cells. The study encompassed diverse experiments, including clinical samples, in vitro and in vivo investigations. Quantitative real-time fluorescence PCR and protein blotting revealed heightened IKBKE mRNA and protein expression in B-ALL patients. Subsequent in vitro experiments with B-ALL cell lines demonstrated that MCCK1 treatment resulted in reduced cell viability and survival rates, with flow cytometry indicating cell cycle arrest. In vivo experiments using B-ALL mouse tumor models substantiated MCCK1's efficacy in impeding tumor proliferation. These findings collectively suggest that IKBKE, found to be elevated in B-ALL patients, may serve as a promising drug target, with MCCK1 demonstrating potential for inducing apoptosis in B-ALL cells both in vitro and in vivo.
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Affiliation(s)
| | - Peng Zhao
- Hematology Department, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Siyu Chen
- The Second Affiliated Hospital, The Third Military Medical University, Chongqing 400000, China
| | - Bo Deng
- Guizhou Medical University, Guiyang 550004, China
| | - Qin Fang
- Pharmacy Department, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Jishi Wang
- Hematology Department, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
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Guo Y, Li X, Yuan R, Ren J, Huang Y, Yu Y, Tian H. KZ02 enhances the radiosensitivity of BRAF-mutated CRC in vitro and in vivo. Eur J Pharmacol 2023; 959:176060. [PMID: 37775019 DOI: 10.1016/j.ejphar.2023.176060] [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: 03/28/2023] [Revised: 09/16/2023] [Accepted: 09/18/2023] [Indexed: 10/01/2023]
Abstract
Colorectal cancer (CRC) is a common malignant tumor with a high incidence and mortality worldwide. Preoperative chemoradiotherapy is a common treatment for patients with metastatic colorectal cancer (mCRC) as it reduces colostomy and local recurrence. The RAS (rat sarcoma)-RAF (extracellular signal-regulated kinase)-MEK (mitogen-activated protein kinase)-ERK (extracellular signal-regulated kinase) pathway regulates important cellular processes in the CRC. Abnormal ERK activation stimulates cell growth and provides a survival advantage. Our group has previously reported that the compound KZ02 has a stronger ability to inhibit tumor growth than AZD6244 (a MEK inhibitor). In this study, we evaluated the antitumor activity of KZ02 in combination with ionizing radiation (IR) and investigated its mechanism of action in BRAF-mutated colorectal cancer. Our results showed that this combination kills tumor cells better than either radiation or drugs alone, both in vivo and in vitro. Furthermore, studies have shown that KZ02 inhibits ERK overactivation. The combination resulted in a G1 phase arrest, a reduction in the radioresistant S phase, and aggravating DNA damage. It can also inhibit Pim-1 (Moloney murine leukemia virus-1), p-BAD (Bcl-2 associated agonist of cell death), Bcl-2 (B-cell lymphoma 2) and Bcl-XL (B-cell lymphoma-extra large) levels and promote apoptosis when combined with radiation. Our results suggest that KZ02 significantly increases the radiosensitivity of BRAF-mutated CRC cells by perturbing the cell cycle, increasing DNA damage, and promoting tumor apoptosis.
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Affiliation(s)
- Yuying Guo
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China
| | - Xuejiao Li
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China
| | - Renbin Yuan
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China
| | - Jingming Ren
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China
| | - Yichi Huang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China
| | - Yanxiang Yu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China
| | - Hongqi Tian
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China.
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Angot L, Schneider P, Vannier JP, Abdoul-Azize S. Beyond Corticoresistance, A Paradoxical Corticosensitivity Induced by Corticosteroid Therapy in Pediatric Acute Lymphoblastic Leukemias. Cancers (Basel) 2023; 15:2812. [PMID: 37345151 DOI: 10.3390/cancers15102812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/10/2023] [Accepted: 05/16/2023] [Indexed: 06/23/2023] Open
Abstract
Known as a key effector in relapse of acute lymphoblastic leukemia (ALL), resistance to drug-induced apoptosis, is tightly considered one of the main prognostic factors for the disease. ALL cells are constantly developing cellular strategies to survive and resist therapeutic drugs. Glucocorticoids (GCs) are one of the most important agents used in the treatment of ALL due to their ability to induce cell death. The mechanisms of GC resistance of ALL cells are largely unknown and intense research is currently focused on this topic. Such resistance can involve different cellular and molecular mechanisms, including the modulation of signaling pathways involved in the regulation of proliferation, apoptosis, autophagy, metabolism, epigenetic modifications and tumor suppressors. Recently, several studies point to the paradoxical role of GCs in many survival processes that may lead to therapy-induced resistance in ALL cells, which we called "paradoxical corticosensitivity". In this review, we aim to summarize all findings on cell survival pathways paradoxically activated by GCs with an emphasis on previous and current knowledge on gene expression and signaling pathways.
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Affiliation(s)
- Laure Angot
- Normandie University, UNIROUEN, IRIB, Inserm, U1234, 76183 Rouen, France
| | - Pascale Schneider
- Normandie University, UNIROUEN, IRIB, Inserm, U1234, 76183 Rouen, France
- Department of Pediatric Immuno-Hemato-Oncology, Rouen University Hospital, 76038 Rouen, France
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Bangaru M, Kumar Nukala S, Kannekanti PK, Sirassu N, Manchal R, Swamy Thirukovela N. Synthesis of Quinoline‐Thiazolidine‐2,4‐dione Coupled Pyrazoles as in vitro EGFR Targeting Anti‐Breast Cancer Agents and Their in silico Studies. ChemistrySelect 2023. [DOI: 10.1002/slct.202204414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
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Targeting Pim kinases in hematological cancers: molecular and clinical review. Mol Cancer 2023; 22:18. [PMID: 36694243 PMCID: PMC9875428 DOI: 10.1186/s12943-023-01721-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 01/13/2023] [Indexed: 01/26/2023] Open
Abstract
Decades of research has recognized a solid role for Pim kinases in lymphoproliferative disorders. Often up-regulated following JAK/STAT and tyrosine kinase receptor signaling, Pim kinases regulate cell proliferation, survival, metabolism, cellular trafficking and signaling. Targeting Pim kinases represents an interesting approach since knock-down of Pim kinases leads to non-fatal phenotypes in vivo suggesting clinical inhibition of Pim may have less side effects. In addition, the ATP binding site offers unique characteristics that can be used for the development of small inhibitors targeting one or all Pim isoforms. This review takes a closer look at Pim kinase expression and involvement in hematopoietic cancers. Current and past clinical trials and in vitro characterization of Pim kinase inhibitors are examined and future directions are discussed. Current studies suggest that Pim kinase inhibition may be most valuable when accompanied by multi-drug targeting therapy.
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9
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Clements AN, Warfel NA. Targeting PIM Kinases to Improve the Efficacy of Immunotherapy. Cells 2022; 11:3700. [PMID: 36429128 PMCID: PMC9688203 DOI: 10.3390/cells11223700] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/13/2022] [Accepted: 11/16/2022] [Indexed: 11/23/2022] Open
Abstract
The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases is a family of serine/threonine kinases that regulates numerous signaling networks that promote cell growth, proliferation, and survival. PIM kinases are commonly upregulated in both solid tumors and hematological malignancies. Recent studies have demonstrated that PIM facilitates immune evasion in cancer by promoting an immunosuppressive tumor microenvironment that suppresses the innate anti-tumor response. The role of PIM in immune evasion has sparked interest in examining the effect of PIM inhibition in combination with immunotherapy. This review focuses on the role of PIM kinases in regulating immune cell populations, how PIM modulates the immune tumor microenvironment to promote immune evasion, and how PIM inhibitors may be used to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Amber N. Clements
- Cancer Biology Graduate Program, University of Arizona, Tucson, AZ 85724, USA
| | - Noel A. Warfel
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
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10
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Koike A, Becker F, Sennhenn P, Kim J, Zhang J, Hannus S, Brehm K. Targeting Echinococcus multilocularis PIM kinase for improving anti-parasitic chemotherapy. PLoS Negl Trop Dis 2022; 16:e0010483. [PMID: 36190997 PMCID: PMC9560627 DOI: 10.1371/journal.pntd.0010483] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 10/13/2022] [Accepted: 09/20/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The potentially lethal zoonosis alveolar echinococcosis (AE) is caused by the metacestode larval stage of the tapeworm Echinococcus multilocularis. Current AE treatment options are limited and rely on surgery as well as on chemotherapy involving benzimidazoles (BZ). BZ treatment, however, is mostly parasitostatic only, must be given for prolonged time periods, and is associated with adverse side effects. Novel treatment options are thus urgently needed. METHODOLOGY/PRINCIPAL FINDINGS By applying a broad range of kinase inhibitors to E. multilocularis stem cell cultures we identified the proto-oncogene PIM kinase as a promising target for anti-AE chemotherapy. The gene encoding the respective E. multilocularis ortholog, EmPim, was characterized and in situ hybridization assays indicated its expression in parasite stem cells. By yeast two-hybrid assays we demonstrate interaction of EmPim with E. multilocularis CDC25, indicating an involvement of EmPim in parasite cell cycle regulation. Small molecule compounds SGI-1776 and CX-6258, originally found to effectively inhibit human PIM kinases, exhibited detrimental effects on in vitro cultured parasite metacestode vesicles and prevented the formation of mature vesicles from parasite stem cell cultures. To improve compound specificity for EmPim, we applied a high throughput in silico modelling approach, leading to the identification of compound Z196138710. When applied to in vitro cultured metacestode vesicles and parasite cell cultures, Z196138710 proved equally detrimental as SGI-1776 and CX-6258 but displayed significantly reduced toxicity towards human HEK293T and HepG2 cells. CONCLUSIONS/SIGNIFICANCE Repurposing of kinase inhibitors initially designed to affect mammalian kinases for helminth disease treatment is often hampered by adverse side effects of respective compounds on human cells. Here we demonstrate the utility of high throughput in silico approaches to design small molecule compounds of higher specificity for parasite cells. We propose EmPim as a promising target for respective approaches towards AE treatment.
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Affiliation(s)
- Akito Koike
- University of Würzburg, Institute of Hygiene and Microbiology, Consultant Laboratory for Echinococcosis, Würzburg, Germany
| | | | | | - Jason Kim
- Immuneering Corporation, Cambridge, Massachusetts, United States of America
| | - Jenny Zhang
- Immuneering Corporation, Cambridge, Massachusetts, United States of America
| | | | - Klaus Brehm
- University of Würzburg, Institute of Hygiene and Microbiology, Consultant Laboratory for Echinococcosis, Würzburg, Germany
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PIM3-AMPK-HDAC4/5 axis restricts MuERVL-marked 2-cell-like state in embryonic stem cells. Stem Cell Reports 2022; 17:2256-2271. [PMID: 36150380 PMCID: PMC9561635 DOI: 10.1016/j.stemcr.2022.08.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/24/2022] Open
Abstract
A minority of embryonic stem cells (ESCs) marked by endogenous retrovirus MuERVL are totipotent 2-cell-like cells. However, the majority of ESCs repress MuERVL. Currently, it is still unclear regarding the signaling pathway(s) repressing the MuERVL-associated 2-cell-like state of ESCs. Here, we identify the PIM3-downstream signaling axis as a key route to repress MuERVL and 2-cell-like state. Downregulation, deletion, or inhibition of PIM3 activated MuERVL, 2-cell genes, and trophectodermal genes in ESCs. By screening PIM3-regulated pathways, we discovered AMPK as its key target. The loss of Pim3 caused an increase in AMPK phosphorylation, which phosphorylated HDAC4/5 and triggered their transfer out of the nucleus in Pim3−/− ESCs. The reduction of nuclear HDAC4/5 caused increased H3K9ac and reduced H3K9me1/2 enrichment on MuERVL, thus activating MuERVL and 2-cell-like state. In summary, our study uncovers a novel axis by which PIM3 suppresses 2-cell marker MuERVL and totipotent state in ESCs.
PIM3 signaling pathway represses MuERVL and 2-cell-like state Pim3 loss promotes AMPK phosphorylation, which activates MuERVL Phosphorylated AMPK mediates HDAC4/5 export from the nucleus HDAC4/5 repress MuERVL through modulating H3K9ac and H3K9me1/2
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New molecular hybrids containing benzimidazole, thiazolidine-2,4-dione and 1,2,4-oxadiazole as EGFR directing cytotoxic agents. Tetrahedron 2022. [DOI: 10.1016/j.tet.2022.132991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Gnawali GR, Okumura K, Perez K, Gallagher R, Wulfkuhle J, Petricoin EF, Padi SKR, Bearss J, He Z, Wang W, Kraft AS. Synthesis of 2-oxoquinoline derivatives as dual pim and mTORC protein kinase inhibitors. Med Chem Res 2022; 31:1154-1175. [DOI: 10.1007/s00044-022-02904-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Gangadhar KH, Benarjee V, Ratnamala A. Synthesis of Coumarin‐Thiazolidine‐2,4‐dione‐Pyrazole Hybrids as Epidermal Growth Factor Receptor (EGFR)‐Targeted Agents. ChemistrySelect 2022. [DOI: 10.1002/slct.202200270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
| | - Velaga Benarjee
- Department of Inorganic and Analytical Chemistry Andhra University Visakhapatnam Andhra Pradesh India
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Effective therapy for AML with RUNX1 mutation by cotreatment with inhibitors of protein translation and BCL2. Blood 2022; 139:907-921. [PMID: 34601571 PMCID: PMC8832475 DOI: 10.1182/blood.2021013156] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/19/2021] [Indexed: 11/20/2022] Open
Abstract
The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed enhancers and their BRD4 occupancy and was associated with reduced levels of c-Myc, c-Myb, MCL1, and Bcl-xL. Consistent with this, cotreatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared with each agent alone, cotreatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune-depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.
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Engineered Fully Human Single-Chain Monoclonal Antibodies to PIM2 Kinase. Molecules 2021; 26:molecules26216436. [PMID: 34770845 PMCID: PMC8588357 DOI: 10.3390/molecules26216436] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 10/24/2021] [Indexed: 11/17/2022] Open
Abstract
Proviral integration site of Moloney virus-2 (PIM2) is overexpressed in multiple human cancer cells and high level is related to poor prognosis; thus, PIM2 kinase is a rational target of anti-cancer therapeutics. Several chemical inhibitors targeting PIMs/PIM2 or their downstream signaling molecules have been developed for treatment of different cancers. However, their off-target toxicity is common in clinical trials, so they could not be advanced to official approval for clinical application. Here, we produced human single-chain antibody fragments (HuscFvs) to PIM2 by using phage display library, which was constructed in a way that a portion of phages in the library carried HuscFvs against human own proteins on their surface with the respective antibody genes in the phage genome. Bacterial derived-recombinant PIM2 (rPIM2) was used as an antigenic bait to fish out the rPIM2-bound phages from the library. Three E. coli clones transfected with the HuscFv genes derived from the rPIM2-bound phages expressed HuscFvs that bound also to native PIM2 from cancer cells. The HuscFvs presumptively interact with the PIM2 at the ATP binding pocket and kinase active loop. They were as effective as small chemical drug inhibitor (AZD1208, which is an ATP competitive inhibitor of all PIM isoforms for ex vivo use) in inhibiting PIM kinase activity. The HuscFvs should be engineered into a cell-penetrating format and tested further towards clinical application as a novel and safe pan-anti-cancer therapeutics.
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17
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Rathi A, Kumar D, Hasan GM, Haque MM, Hassan MI. Therapeutic targeting of PIM KINASE signaling in cancer therapy: Structural and clinical prospects. Biochim Biophys Acta Gen Subj 2021; 1865:129995. [PMID: 34455019 DOI: 10.1016/j.bbagen.2021.129995] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/28/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND PIM kinases are well-studied drug targets for cancer, belonging to Serine/Threonine kinases family. They are the downstream target of various signaling pathways, and their up/down-regulation affects various physiological processes. PIM family comprises three isoforms, namely, PIM-1, PIM-2, and PIM-3, on alternative initiation of translation and they have different levels of expression in different types of cancers. Its structure shows a unique ATP-binding site in the hinge region which makes it unique among other kinases. SCOPE OF REVIEW PIM kinases are widely reported in hematological malignancies along with prostate and breast cancers. Currently, many drugs are used as inhibitors of PIM kinases. In this review, we highlighted the physiological significance of PIM kinases in the context of disease progression and therapeutic targeting. We comprehensively reviewed the PIM kinases in terms of their expression and regulation of different physiological roles. We further predicted functional partners of PIM kinases to elucidate their role in the cellular physiology of different cancer and mapped their interaction network. MAJOR CONCLUSIONS A deeper mechanistic insight into the PIM signaling involved in regulating different cellular processes, including transcription, apoptosis, cell cycle regulation, cell proliferation, cell migration and senescence, is provided. Furthermore, structural features of PIM have been dissected to understand the mechanism of inhibition and subsequent implication of designed inhibitors towards therapeutic management of prostate, breast and other cancers. GENERAL SIGNIFICANCE Being a potential drug target for cancer therapy, available drugs and PIM inhibitors at different stages of clinical trials are discussed in detail.
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Affiliation(s)
- Aanchal Rathi
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Dhiraj Kumar
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | | | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
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18
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PIM Kinases in Multiple Myeloma. Cancers (Basel) 2021; 13:cancers13174304. [PMID: 34503111 PMCID: PMC8428354 DOI: 10.3390/cancers13174304] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 08/20/2021] [Accepted: 08/23/2021] [Indexed: 11/16/2022] Open
Abstract
Multiple myeloma (MM) remains an incurable disease and novel therapeutic agents/approaches are urgently needed. The PIM (Proviral insertion in murine malignancies) serine/threonine kinases have 3 isoforms: PIM1, PIM2, and PIM3. PIM kinases are engaged with an expansive scope of biological activities including cell growth, apoptosis, drug resistance, and immune response. An assortment of molecules and pathways that are critical to myeloma tumorigenesis has been recognized as the downstream targets of PIM kinases. The inhibition of PIM kinases has become an emerging scientific interest for the treatment of multiple myeloma and several PIM kinase inhibitors, such as SGI-1776, AZD1208, and PIM447 (formerly LGH447), have been developed and are under different phases of clinical trials. Current research has been focused on the development of a new generation of potent PIM kinase inhibitors with appropriate pharmacological profiles reasonable for human malignancy treatment. Combination therapy of PIM kinase inhibitors with chemotherapeutic appears to create an additive cytotoxic impact in cancer cells. Notwithstanding, the mechanisms by which PIM kinases modulate the immune microenvironment and synergize with the immunomodulatory agents such as lenalidomide have not been deliberately depicted. This review provides a comprehensive overview of the PIM kinase pathways and the current research status of the development of PIM kinase inhibitors for the treatment of MM. Additionally, the combinatorial effects of the PIM kinase inhibitors with other targeted agents and the promising strategies to exploit PIM as a therapeutic target in malignancy are highlighted.
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19
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Unsworth AJ, Bye AP, Sage T, Gaspar RS, Eaton N, Drew C, Stainer A, Kriek N, Volberding PJ, Hutchinson JL, Riley R, Jones S, Mundell SJ, Cui W, Falet H, Gibbins JM. Antiplatelet properties of Pim kinase inhibition are mediated through disruption of thromboxane A2 receptor signaling. Haematologica 2021; 106:1968-1978. [PMID: 32467143 PMCID: PMC8252961 DOI: 10.3324/haematol.2019.223529] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Indexed: 12/17/2022] Open
Abstract
Pim kinases are upregulated in several forms of cancer, contributing to cell survival and tumor development, but their role in platelet function and thrombotic disease has not been explored. We report for the first time that Pim-1 kinase is expressed in human and mouse platelets. Genetic deletion or pharmacological inhibition of Pim kinase results in reduced thrombus formation but is not associated with impaired hemostasis. Attenuation of thrombus formation was found to be due to inhibition of the thromboxane A2 receptor as effects on platelet function were non-additive to inhibition caused by the cyclo-oxygenase inhibitor indomethacin or the thromboxane A2 receptor antagonist GR32191. Treatment with Pim kinase inhibitors caused reduced surface expression of the thromboxane A2 receptor and resulted in reduced responses to thromboxane A2 receptor agonists, indicating a role for Pim kinase in the regulation of thromboxane A2 receptor function. Our research identifies a novel, Pim kinase-dependent regulatory mechanism for the thromboxane A2 receptor and represents a new targeting strategy that is independent of cyclo-oxygenase-1 inhibition or direct antagonism of the thromboxane A2 receptor that, while attenuating thrombosis, does not increase bleeding.
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Affiliation(s)
- Amanda J Unsworth
- University of Reading and Dept. of Life Sciences, Manchester Metropolitan University Manchester, UK
| | - Alexander P Bye
- Institute for Cardiovascular, Metabolic Research, University of Reading, Reading, UK
| | - Tanya Sage
- Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK
| | - Renato S Gaspar
- Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK
| | - Nathan Eaton
- Blood Research Institute and Medical College of Wisconsin, Versiti, Milwaukee, WI, USA
| | - Caleb Drew
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Alexander Stainer
- Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK
| | - Neline Kriek
- Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK
| | - Peter J Volberding
- Blood Research Institute and Medical College of Wisconsin, Versiti, Milwaukee, WI, USA
| | - James L Hutchinson
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Ryan Riley
- Department of Life Sciences, Manchester Metropolitan University, Manchester, UK
| | - Sarah Jones
- Department of Life Sciences, Manchester Metropolitan University, Manchester, UK
| | - Stuart J Mundell
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Weiguo Cui
- Blood Research Institute, Versiti and Medical College of Wisconsin, Milwaukee, WI, USA
| | - Hervé Falet
- Blood Research Institute, Versiti and Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jonathan M Gibbins
- Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK
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20
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Wang Y, Xiu J, Ren C, Yu Z. Protein kinase PIM2: A simple PIM family kinase with complex functions in cancer metabolism and therapeutics. J Cancer 2021; 12:2570-2581. [PMID: 33854618 PMCID: PMC8040705 DOI: 10.7150/jca.53134] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 02/12/2021] [Indexed: 12/13/2022] Open
Abstract
PIM2 (proviral integration site for Moloney murine leukemia virus 2) kinase plays an important role as an oncogene in multiple cancers, such as leukemia, liver, lung, myeloma, prostate and breast cancers. PIM2 is largely expressed in both leukemia and solid tumors, and it promotes the transcriptional activation of genes involved in cell survival, cell proliferation, and cell-cycle progression. Many tumorigenic signaling molecules have been identified as substrates for PIM2 kinase, and a variety of inhibitors have been developed for its kinase activity, including SMI-4a, SMI-16a, SGI-1776, JP11646 and DHPCC-9. Here, we summarize the signaling pathways involved in PIM2 kinase regulation and PIM2 mechanisms in various neoplastic diseases. We also discuss the current status and future perspectives for the development of PIM2 kinase inhibitors to combat human cancer, and PIM2 will become a therapeutic target in cancers in the future.
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Affiliation(s)
- Yixin Wang
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, P.R. China
| | - Jing Xiu
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, P.R. China
| | - Chune Ren
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, P.R. China
| | - Zhenhai Yu
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, P.R. China
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21
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Cordo' V, van der Zwet JC, Canté-Barrett K, Pieters R, Meijerink JP. T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies. Blood Cancer Discov 2021; 2:19-31. [PMID: 34661151 PMCID: PMC8447273 DOI: 10.1158/2643-3230.bcd-20-0093] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 10/08/2020] [Accepted: 10/28/2020] [Indexed: 11/16/2022] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with T-ALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent T-ALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of T-ALL and gives a comprehensive overview of the novel treatments for patients with T-ALL that are currently under clinical investigation or that are emerging from preclinical research. SIGNIFICANCE T-ALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.
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22
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Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma. Blood 2020; 135:1685-1695. [PMID: 32315407 DOI: 10.1182/blood.2019003880] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/24/2020] [Indexed: 12/21/2022] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) and T-cell acute lymphoblastic lymphoma (T-LBL) are aggressive hematological malignancies that are currently treated with high-dose chemotherapy. Over the last several years, the search toward novel and less-toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell-intrinsic properties of the tumor cell. However, non-cell-autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous interleukin 7 (IL7) can increase the expression of the oncogenic kinase proviral integration site for Moloney-murine leukemia 1 (PIM1) in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared with bulk nontreated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL patient-derived xenograft (PDX) cells, ultimately resulting in non-cell-autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.
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23
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Hong VS, Jeong S, Yun Y, Choo H, Won J, Lee J. 1,3,
4‐Oxadiazole
‐2(
3
H
)‐thione Analogs as
PIM
Kinase Inhibitors. B KOREAN CHEM SOC 2020. [DOI: 10.1002/bkcs.12101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Victor Sukbong Hong
- Department of Chemistry, College of Natural Sciences Keimyung University Daegu Republic of Korea
| | - Seungik Jeong
- Department of Chemistry, College of Natural Sciences Keimyung University Daegu Republic of Korea
| | - Yanghwan Yun
- Department of Chemistry, College of Natural Sciences Keimyung University Daegu Republic of Korea
| | - Hyeonseong Choo
- Department of Chemistry, College of Natural Sciences Keimyung University Daegu Republic of Korea
| | - Jongin Won
- Department of Chemistry, College of Natural Sciences Keimyung University Daegu Republic of Korea
| | - Jinho Lee
- Department of Chemistry, College of Natural Sciences Keimyung University Daegu Republic of Korea
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24
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Alnabulsi S, Al-Hurani EA. Pim kinase inhibitors in cancer: medicinal chemistry insights into their activity and selectivity. Drug Discov Today 2020; 25:S1359-6446(20)30374-3. [PMID: 32971234 DOI: 10.1016/j.drudis.2020.09.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 08/09/2020] [Accepted: 09/14/2020] [Indexed: 01/09/2023]
Abstract
The oncogenic Pim kinase proteins (Pim-1/2/3) regulate tumorigenesis through phosphorylating essential proteins that control cell cycle and proliferation. Pim kinase is a potential chemotherapeutic target in cancer and its inhibition is currently the focus of intensive drug design and development efforts. The distinctive presence of proline amino acids in the hinge region provides an opportunity to inhibit Pim kinase while conserving the physiological functions of other kinases and reducing the toxicity profiles of the inhibitors. Various Pim kinase inhibitors have been clinically evaluated for the treatment of hematological cancers, yet none has reached the clinic. In this review, we discuss the design and development of selective and potent Pim inhibitors with novel chemotypes focusing on structural features essential for high potency and selectivity.
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Affiliation(s)
- Soraya Alnabulsi
- Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan.
| | - Enas A Al-Hurani
- Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan
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25
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Lim JT, Singh N, Leuvano LA, Calvert VS, Petricoin EF, Teachey DT, Lock RB, Padi M, Kraft AS, Padi SKR. PIM Kinase Inhibitors Block the Growth of Primary T-cell Acute Lymphoblastic Leukemia: Resistance Pathways Identified by Network Modeling Analysis. Mol Cancer Ther 2020; 19:1809-1821. [PMID: 32753387 DOI: 10.1158/1535-7163.mct-20-0160] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/27/2020] [Accepted: 07/10/2020] [Indexed: 11/16/2022]
Abstract
Despite significant progress in understanding the genetic landscape of T-cell acute lymphoblastic leukemia (T-ALL), the discovery of novel therapeutic targets has been difficult. Our results demonstrate that the levels of PIM1 protein kinase is elevated in early T-cell precursor ALL (ETP-ALL) but not in mature T-ALL primary samples. Small-molecule PIM inhibitor (PIMi) treatment decreases leukemia burden in ETP-ALL. However, treatment of animals carrying ETP-ALL with PIMi was not curative. To model other pathways that could be targeted to complement PIMi activity, HSB-2 cells, previously characterized as a PIMi-sensitive T-ALL cell line, were grown in increasing doses of PIMi. Gene set enrichment analysis of RNA sequencing data and functional enrichment of network modules demonstrated that the HOXA9, mTOR, MYC, NFκB, and PI3K-AKT pathways were activated in HSB-2 cells after long-term PIM inhibition. Reverse phase protein array-based pathway activation mapping demonstrated alterations in the mTOR, PI3K-AKT, and NFκB pathways, as well. PIMi-tolerant HSB-2 cells contained phosphorylated RelA-S536 consistent with activation of the NFκB pathway. The combination of NFκB and PIMis markedly reduced the proliferation in PIMi-resistant leukemic cells showing that this pathway plays an important role in driving the growth of T-ALL. Together these results demonstrate key pathways that are activated when HSB-2 cell line develop resistance to PIMi and suggest pathways that can be rationally targeted in combination with PIM kinases to inhibit T-ALL growth.
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Affiliation(s)
- James T Lim
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona
| | - Neha Singh
- University of Arizona Cancer Center, University of Arizona, Tucson, Arizona
| | - Libia A Leuvano
- University of Arizona Cancer Center, University of Arizona, Tucson, Arizona
| | - Valerie S Calvert
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - Emanuel F Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - David T Teachey
- Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Richard B Lock
- Children's Cancer Institute, School of Women's and Children's Health, UNSW Sydney, Sydney, Australia
| | - Megha Padi
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona
- Bioinformatics Shared Resource, University of Arizona Cancer Center, Tucson, Arizona
| | - Andrew S Kraft
- University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.
| | - Sathish K R Padi
- University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.
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26
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Li Y, Cheng Y, Zhang M, He X, Kong L, Zhou K, Zhou Y, Li L, Tian H, Song X, Cui Y. A New Compound with Increased Antitumor Activity by Cotargeting MEK and Pim-1. iScience 2020; 23:101254. [PMID: 32585592 PMCID: PMC7322072 DOI: 10.1016/j.isci.2020.101254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/26/2020] [Accepted: 06/05/2020] [Indexed: 02/05/2023] Open
Abstract
Feedback circuits are one of the major causes underlying tumor resistance. Thus, compounds that target one oncogenic pathway with simultaneously blocking its compensatory pathway will be of great value for cancer treatment. Here, we develop a new MEK inhibitor designated as KZ-02 that exhibits unexpectedly higher cytotoxicity than its starting compound AZD6244, a well-known MEK inhibitor, in colorectal cancer (CRC). Subsequent kinase selectivity study identified Pim-1 as an additional cellular target for KZ-02. Further studies showed that AZD6244 and Pim-1 1 (a Pim-1 inhibitor) have a synergistic effect on CRC suppression. Mechanistic study revealed that MEK inhibition by AZD6244 leads to increased Pim-1 expression, which could be a general mechanism behind the compromised cell-killing activity of MEK inhibitors. KZ-02, despite increasing Pim-1 mRNA expression, simultaneously promotes Pim-1 proteasomal degradation. Therefore, we uncover a new MEK inhibitor KZ-02 with significantly enhanced antitumor activity by co-targeting MEK and Pim-1.
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Affiliation(s)
- Yanan Li
- College of Medical Imaging, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China
| | - Ying Cheng
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 238 Baidi Road, Tianjin 300192, China
| | - Maoqi Zhang
- Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China
| | - Xiaoli He
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Li Kong
- Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China
| | - Kexiang Zhou
- Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China
| | - Yunfu Zhou
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Lin Li
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Hongqi Tian
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 238 Baidi Road, Tianjin 300192, China.
| | - Xiaomin Song
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
| | - Yukun Cui
- Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China.
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27
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Razmazma H, Ebrahimi A, Hashemi M. Structural insights for rational design of new PIM-1 kinase inhibitors based on 3,5-disubstituted indole derivatives: An integrative computational approach. Comput Biol Med 2020; 118:103641. [PMID: 32174320 DOI: 10.1016/j.compbiomed.2020.103641] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/13/2022]
Abstract
Proviral integration Moloney virus (PIM) 1, 2, and 3 kinases are a family of constitutively active serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. Their overexpression in a variety of human hematopoietic malignancies and solid tumors suggest that inhibition of PIM signaling could provide patients with therapeutic benefit. In this study, a series of 3,5-disubstituted indole derivatives have been systematically studied using three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, molecular docking simulation, and partial least-squares (PLS) analysis methods to explore the influence of the structural characteristics on the inhibitory activity and use them to propose novel bioactive molecules. The comparative molecular field and comparative molecular similarity indices analyses (CoMFA and CoMSIA) models exhibited a good correlation between the predicted and experimental activities with excellent predictive capability and yielded statistically reliable value (CoMFA: Q2 = 0.535, R2 = 0.987, r2pred = 0.909; CoMSIA: Q2 = 0.785, R2 = 0.989, r2pred = 0.969). Based on the CoMFA and CoMSIA models and docking results, ten novel potent PIM-1 inhibitors (N1-N10) have been designed and the molecular models have validated their inhibitory activities. These results provided strong theoretical guidance for the development of novel PIM-1 inhibitors.
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Affiliation(s)
- Hafez Razmazma
- Laboratory of Computational Quantum Chemistry and Drug Design, Department of Chemistry, University of Sistan and Baluchestan, Zahedan, Iran
| | - Ali Ebrahimi
- Laboratory of Computational Quantum Chemistry and Drug Design, Department of Chemistry, University of Sistan and Baluchestan, Zahedan, Iran.
| | - Mohammad Hashemi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
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28
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Malone T, Schäfer L, Simon N, Heavey S, Cuffe S, Finn S, Moore G, Gately K. Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer. Pharmacol Ther 2019; 207:107454. [PMID: 31836451 DOI: 10.1016/j.pharmthera.2019.107454] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 12/03/2019] [Indexed: 12/22/2022]
Abstract
PIM kinases are a class of serine/threonine kinases that play a role in several of the hallmarks of cancer including cell cycle progression, metabolism, inflammation and immune evasion. Their constitutively active nature and unique catalytic structure has led them to be an attractive anticancer target through the use of small molecule inhibitors. This review highlights the enhanced activity of PIM kinases in cancer that can be driven by hypoxia in the tumour microenvironment and the important role that aberrant PIM kinase activity plays in resistance mechanisms to chemotherapy, radiotherapy, anti-angiogenic therapies and targeted therapies. We highlight an interaction of PIM kinases with numerous major oncogenic players, including but not limited to, stabilisation of p53, synergism with c-Myc, and notable parallel signalling with PI3K/Akt. We provide a comprehensive overview of PIM kinase's role as an escape mechanism to targeted therapies including PI3K/mTOR inhibitors, MET inhibitors, anti-HER2/EGFR treatments and the immunosuppressant rapamycin, providing a rationale for co-targeting treatment strategies for a more durable patient response. The current status of PIM kinase inhibitors and their use as a combination therapy with other targeted agents, in addition to the development of novel multi-molecularly targeted single therapeutic agents containing a PIM kinase targeting moiety are discussed.
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Affiliation(s)
- Tom Malone
- Dept. of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland
| | - Lea Schäfer
- Dept. of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland
| | - Nathalie Simon
- Dept. of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland
| | - Susan Heavey
- Molecular Diagnostics and Therapeutics Group, University College London, London, UK
| | - Sinead Cuffe
- Dept. of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland
| | - Stephen Finn
- Dept. of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland
| | - Gillian Moore
- School of Pharmacy and Biomolecular Sciences, RCSI, Dublin, Ireland
| | - Kathy Gately
- Dept. of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland.
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Comparative acetylome analysis reveals the potential roles of lysine acetylation for DON biosynthesis in Fusarium graminearum. BMC Genomics 2019; 20:841. [PMID: 31718553 PMCID: PMC6852988 DOI: 10.1186/s12864-019-6227-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 10/25/2019] [Indexed: 01/07/2023] Open
Abstract
Background Fusarium graminearum is a destructive fungal pathogen of wheat, barley and other small grain cereals. During plant infection, the pathogen produces trichothecene mycotoxin deoxynivalenol (DON), which is harmful to human and livestock. FgGCN5 encodes a GCN5 acetyltransferase. The gene deletion mutant Fggcn5 failed to produce DON. We assumed that lysine acetylation might play a key regulatory role in DON biosynthesis in the fungus. Results In this study, the acetylome comparison between Fggcn5 mutant and wild-type strain PH-1 was performed by using affinity enrichment and high resolution LC-MS/MS analysis. Totally, 1875 acetylated proteins were identified in Fggcn5 mutant and PH-1. Among them, 224 and 267 acetylated proteins were identified exclusively in Fggcn5 mutant and PH-1, respectively. Moreover, 95 differentially acetylated proteins were detected at a significantly different level in the gene deletion mutant:43 were up-regulated and 52 were down-regulated. GO enrichment and KEGG-pathways enrichment analyses revealed that acetylation plays a key role in metabolism process in F. graminearum. Conclusions Seeing that the gens playing critical roles in DON biosynthesis either in Fggcn5 mutant or PH-1. Therefore, we can draw the conclusion that the regulatory roles of lysine acetylation in DON biosynthesis in F. graminearum results from the positive and negative regulation of the related genes. The study would be a foundation to insight into the regulatory mechanism of lysine acetylation on DON biosynthesis.
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STAT5 is essential for IL-7-mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells. Blood Adv 2019; 2:2199-2213. [PMID: 30185437 DOI: 10.1182/bloodadvances.2018021063] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/04/2018] [Indexed: 12/22/2022] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) constitutes an aggressive subset of ALL, the most frequent childhood malignancy. Whereas interleukin-7 (IL-7) is essential for normal T-cell development, it can also accelerate T-ALL development in vivo and leukemia cell survival and proliferation by activating phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling. Here, we investigated whether STAT5 could also mediate IL-7 T-ALL-promoting effects. We show that IL-7 induces STAT pathway activation in T-ALL cells and that STAT5 inactivation prevents IL-7-mediated T-ALL cell viability, growth, and proliferation. At the molecular level, STAT5 is required for IL-7-induced downregulation of p27kip1 and upregulation of the transferrin receptor, CD71. Surprisingly, STAT5 inhibition does not significantly affect IL-7-mediated Bcl-2 upregulation, suggesting that, contrary to normal T-cells, STAT5 promotes leukemia cell survival through a Bcl-2-independent mechanism. STAT5 chromatin immunoprecipitation sequencing and RNA sequencing reveal a diverse IL-7-driven STAT5-dependent transcriptional program in T-ALL cells, which includes BCL6 inactivation by alternative transcription and upregulation of the oncogenic serine/threonine kinase PIM1 Pharmacological inhibition of PIM1 abrogates IL-7-mediated proliferation on T-ALL cells, indicating that strategies involving the use of PIM kinase small-molecule inhibitors may have therapeutic potential against a majority of leukemias that rely on IL-7 receptor (IL-7R) signaling. Overall, our results demonstrate that STAT5, in part by upregulating PIM1 activity, plays a major role in mediating the leukemia-promoting effects of IL-7/IL-7R.
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De Smedt R, Morscio J, Goossens S, Van Vlierberghe P. Targeting steroid resistance in T-cell acute lymphoblastic leukemia. Blood Rev 2019; 38:100591. [PMID: 31353059 DOI: 10.1016/j.blre.2019.100591] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/15/2019] [Accepted: 07/18/2019] [Indexed: 12/16/2022]
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is characterized by a variable response to steroids during induction and/or consolidation therapy. Notably, recent work suggested that these differences in glucocorticoid sensitivity might, at least in part, be mediated by hyperactivation of specific oncogenic pathways such as RAS/MEK/ERK, PI3K/AKT and IL7R/JAK/STAT. In this review, we elaborate on putative associations between aberrant signaling, therapy resistance, incidence of relapse and clinical outcome in human T-ALL. Furthermore, we emphasize that this potential association with clinical parameters might also be mediated by the tumor microenvironment as a result of increased sensitivity of leukemic T-cells towards cytokine induced signaling pathway activation. With this in mind, we provide an overview of small molecule inhibitors that might have clinical potential for the treatment of human T-ALL in the near future as a result of their ability to overcome steroid resistance thereby potentially increasing survival rates in this aggressive hematological neoplasm.
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Affiliation(s)
- Renate De Smedt
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Julie Morscio
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Steven Goossens
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Pieter Van Vlierberghe
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
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Fu R, Xia Y, Li M, Mao R, Guo C, Zhou M, Tan H, Liu M, Wang S, Yang N, Zhao J. Pim-1 as a Therapeutic Target in Lupus Nephritis. Arthritis Rheumatol 2019; 71:1308-1318. [PMID: 30791224 DOI: 10.1002/art.40863] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 02/14/2019] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Lupus nephritis (LN) is a major determinant of morbidity and mortality in systemic lupus erythematosus (SLE). Pim-1 regulates lymphocyte proliferation and activation. The role of Pim-1 in autoimmune disease remains unclear. This study was undertaken to test the hypothesis that inhibition of Pim-1 would have therapeutic potential in patients with LN. METHODS Pim-1 expression was analyzed in lupus-prone (NZB × NZW)F1 mice (n = 6), human peripheral blood mononuclear cells (PBMCs) from SLE patients (n = 10), and glomeruli from patients with LN (n = 8). The therapeutic effect of the Pim-1 inhibitor AZD1208 was assessed in the same murine lupus model (n = 10 mice per group). In vitro analysis was conducted to explore the mechanisms of action of Pim-1 in mouse and human podocytes after Pim-1 expression had been induced by anti-double-stranded DNA (anti-dsDNA) antibody-positive serum. Finally, MRL/lpr mice were used to confirm the therapeutic effects of Pim-1 inhibition in vivo (n = 10 mice per group). RESULTS Up-regulation of Pim-1 was seen in renal lysates from diseased (NZB × NZW)F1 mice and in PBMCs from patients with SLE and renal biopsy tissue from patients with LN, relative to their control counterparts (each P < 0.05). The Pim-1 inhibitor AZD1208 reduced the severity of proteinuria, glomerulonephritis, renal immune complex deposits, and serum anti-dsDNA antibody levels, concomitant with the suppression of NFATc1 expression and NLRP3 inflammasome activation, in diseased (NZB × NZW)F1 mice (each P < 0.05 versus controls). Moreover, in mouse and human podocytes, Pim-1 knockdown with targeted small interfering RNA (siRNA) suppressed NFATc1 and NLRP3 inflammasome signaling in the presence of anti-dsDNA-positive serum (each P < 0.05 versus control siRNA). Mechanistically, Pim-1 modulated NLRP3 inflammasome activation through intracellular Ca2+ (P < 0.05 versus normal controls). The therapeutic effect of Pim-1 blockade was replicated in MRL/lpr mice. CONCLUSION These data identify Pim-1 as a critical regulator of LN pathogenesis in patients with SLE. Targeting of the Pim-1/NFATc1/NLRP3 pathway might therefore have therapeutic potential in human LN.
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Affiliation(s)
- Rong Fu
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yong Xia
- Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Meirong Li
- Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Renxiang Mao
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chaohuan Guo
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mianjing Zhou
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hechang Tan
- Fourth Affiliated Hospital of Guangxi Medical University, Guangxi, China
| | - Meiling Liu
- Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shuang Wang
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Niansheng Yang
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jijun Zhao
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Cervantes-Gomez F, Stellrecht CM, Ayres ML, Keating MJ, Wierda WG, Gandhi V. PIM kinase inhibitor, AZD1208, inhibits protein translation and induces autophagy in primary chronic lymphocytic leukemia cells. Oncotarget 2019; 10:2793-2809. [PMID: 31073371 PMCID: PMC6497463 DOI: 10.18632/oncotarget.26876] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 03/23/2019] [Indexed: 11/25/2022] Open
Abstract
The PIM1, PIM2, and PIM3 serine/threonine kinases play a role in the proliferation and survival of cancer cells. Mice lacking these three kinases were viable. Further, in human hematological malignancies, these proteins are overexpressed making them suitable targets. Several small molecule inhibitors against this enzyme were synthesized and tested. AZD1208, an orally available small-molecule drug, inhibits all three PIM kinases at a low nanomolar range. AZD1208 has been tested in clinical trials for patients with solid tumors and hematological malignancies, especially acute myelogenous leukemia. The present study evaluated the efficacy and biological actions of AZD1208 in chronic lymphocytic leukemia (CLL) cells. CLL cells had higher levels of PIM2 protein and mRNAs than did normal lymphocytes from healthy donors. Treatment of CLL lymphocytes with AZD1208 resulted in modest cell death, whereas practically no cytotoxicity was observed in healthy lymphocytes. To determine the mechanism by which AZD1208 inhibits PIM kinase function, we evaluated PIM kinase pathway and downstream substrates. Because peripheral blood CLL cells are replicationally quiescent, we analyzed substrates involved in apoptosis, transcription, and translation but not cell cycle targets. AZD1208 inhibited protein translation by decreasing phosphorylation levels of 4E-binding protein 1 (4E-BP1). AZD1208 induced autophagy in replicationally-quiescent CLL cells, which is consistent with protein translation inhibition. These data suggest that AZD1208 may elicit cytotoxicity in CLL cells through inhibiting translation and autophagy induction.
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Affiliation(s)
- Fabiola Cervantes-Gomez
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christine M Stellrecht
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX, USA
| | - Mary L Ayres
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael J Keating
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - William G Wierda
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Varsha Gandhi
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX, USA
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34
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Kuang X, Xiong J, Wang W, Li X, Lu T, Fang Q, Wang J. PIM inhibitor SMI-4a induces cell apoptosis in B-cell acute lymphocytic leukemia cells via the HO-1-mediated JAK2/STAT3 pathway. Life Sci 2019; 219:248-256. [PMID: 30658101 DOI: 10.1016/j.lfs.2019.01.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 01/03/2019] [Accepted: 01/14/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The serine/threonine PIM protein kinases are critical regulators of tumorigenesis in multiple cancers. However, whether PIMs are potential therapeutic targets for treating B-cell acute lymphocytic leukemia (B-ALL) remains unclear. Therefore, here, PIM expression was detected in B-ALL patients and the effects of SMI-4a, a pan-PIM small molecule inhibitor, were investigated in B-ALL cells. METHODS PIM1 and PIM2 expression in 26 newly diagnosed B-ALL cases was detected by real-time PCR and Western blot. B-ALL cells were treated with varied SMI-4a doses and the viability of treated cells was investigated using a cell-counting kit-8 (CCK-8) assay. Apoptosis and cell cycles were analyzed by flow cytometry. Western blot analysis was then used to explore the expression of apoptosis-related proteins and the JAK2/STAT3 pathway. RESULTS PIM1 and 2 were overexpressed in B-ALL patients with high HO-1 level. SMI-4a induced decreases in PIMs and HO-1 expressions and inhibited B-ALL cell viability. Treatment with SMI-4a induced apoptosis by downregulating Bcl-2, upregulating Bax and other antiapoptotic proteins, and decreasing protein levels of p-JAK2 and p-STAT3. In addition, upregulation of HO-1 alleviated decrease in p-JAK2 and p-STAT3 expression, reduced SMI-4a-induced apoptosis of B-ALL cells, and influenced B-ALL cell survival. CONCLUSIONS PIMs were highly expressed in B-ALL patients. SMI-4a inhibited B-ALL proliferation and induced apoptosis via the HO-1-mediated JAK2/STAT3 pathway. SMI-4a might be applicable for treatment of B-ALL cells.
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Affiliation(s)
- Xingyi Kuang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Guizhou Province Hematopoietic Stem Cell Transplantation Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Key Laboratory of Hematological Disease Diagnostic Treat Centre of Guizhou Province, Guiyang, PR China
| | - Jie Xiong
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Guizhou Province Hematopoietic Stem Cell Transplantation Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Key Laboratory of Hematological Disease Diagnostic Treat Centre of Guizhou Province, Guiyang, PR China
| | - Weili Wang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Guizhou Province Hematopoietic Stem Cell Transplantation Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Key Laboratory of Hematological Disease Diagnostic Treat Centre of Guizhou Province, Guiyang, PR China
| | - Xinyao Li
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Guizhou Province Hematopoietic Stem Cell Transplantation Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Key Laboratory of Hematological Disease Diagnostic Treat Centre of Guizhou Province, Guiyang, PR China
| | - Tingting Lu
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Guizhou Province Hematopoietic Stem Cell Transplantation Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Key Laboratory of Hematological Disease Diagnostic Treat Centre of Guizhou Province, Guiyang, PR China
| | - Qin Fang
- Department of Pharmacy, The Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang, Guizhou, PR China
| | - Jishi Wang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Guizhou Province Hematopoietic Stem Cell Transplantation Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China; Key Laboratory of Hematological Disease Diagnostic Treat Centre of Guizhou Province, Guiyang, PR China.
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35
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Zheng J, Sha Y, Roof L, Foreman O, Lazarchick J, Venkta JK, Kozlowski C, Gasparetto C, Chao N, Ebens A, Hu J, Kang Y. Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade. Cancer Lett 2018; 440-441:1-10. [PMID: 30312729 DOI: 10.1016/j.canlet.2018.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 09/19/2018] [Accepted: 10/02/2018] [Indexed: 12/22/2022]
Abstract
Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities. Further investigations indicated that treatment with a pan-PIM kinase inhibitor promoted increased ubiquitination and subsequent degradation of IKZF1 and IKZF3, two transcription factors crucial for survival of myeloma cells. Combining a pan-PIM kinase inhibitor with lenalidomide led to more effective degradation of IKZF1 and IKZF3 in multiple myeloma cell lines as well as xenografts of myeloma tumors. We also demonstrated that treatment with a pan-PIM kinase inhibitor resulted in increased expression of cereblon, and that knockdown of cereblon via a shRNA lentivirus abolished the effects of PIM kinase inhibition on the degradation of IKZF1 and IKZF3 and myeloma cell apoptosis, demonstrating a central role of cereblon in pan-PIM kinase inhibitor-mediated down-regulation of IKZF1 and IKZF3 and myeloma cell killing. These data elucidate the mechanism of pan-PIM kinase inhibitor mediated anti-myeloma effect and the rationale for the synergy observed with lenalidomide co-treatment, and provide justification for a clinical trial of the combination of pan-PIM kinase inhibitors and lenalidomide for the treatment of multiple myeloma.
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Affiliation(s)
- Jing Zheng
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, USA; Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, China
| | - Yonggang Sha
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Logan Roof
- Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA
| | - Oded Foreman
- Genentech Research Oncology, Genentech Inc., San Francisco, CA, USA
| | - John Lazarchick
- Department of Pathology, Medical University of South Carolina, Charleston, SC, USA
| | - Jagadish Kummetha Venkta
- Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Cleopatra Kozlowski
- Genentech Safety Assessment Pathology, Genentech Inc, San Francisco, CA, USA
| | - Cristina Gasparetto
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Nelson Chao
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Allen Ebens
- Genentech Research Oncology, Genentech Inc., San Francisco, CA, USA
| | - Jianda Hu
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, China.
| | - Yubin Kang
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
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De Smedt R, Peirs S, Morscio J, Matthijssens F, Roels J, Reunes L, Lintermans B, Goossens S, Lammens T, Van Roy N, Touzart A, Jenni S, Tsai YC, Lovisa F, Mussolin L, Serafin V, Van Nieuwerburgh F, Deforce D, Uyttebroeck A, Tousseyn T, Burkhardt B, Klapper W, De Moerloose B, Benoit Y, Macintyre E, Bourquin JP, Basso G, Accordi B, Bornhauser B, Meijerink J, Vandenberghe P, Van Vlierberghe P. Pre-clinical evaluation of second generation PIM inhibitors for the treatment of T-cell acute lymphoblastic leukemia and lymphoma. Haematologica 2018; 104:e17-e20. [PMID: 30076176 DOI: 10.3324/haematol.2018.199257] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Renate De Smedt
- Department of Biomolecular Medicine, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium
| | - Sofie Peirs
- Department of Biomolecular Medicine, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium
| | - Julie Morscio
- Department of Biomolecular Medicine, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium
| | - Filip Matthijssens
- Department of Biomolecular Medicine, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium
| | - Juliette Roels
- Department of Biomolecular Medicine, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium.,Diagnostic Sciences, Ghent University, Belgium
| | - Lindy Reunes
- Department of Biomolecular Medicine, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium
| | - Beatrice Lintermans
- Department of Biomolecular Medicine, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium
| | - Steven Goossens
- Department of Biomolecular Medicine, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium.,Molecular and Cellular Oncology Lab, Department for Biomedical Molecular Biology, Ghent University, Belgium
| | - Tim Lammens
- Cancer Research Institute Ghent (CRIG), Belgium.,Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium
| | - Nadine Van Roy
- Department of Biomolecular Medicine, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium
| | - Aurore Touzart
- Department of Hematology, APHP-Hôpital Necker, Paris, France
| | - Silvia Jenni
- Department of Oncology, and Children's Research Center, University Children's Hospital Zurich, Switzerland
| | - Yi-Chien Tsai
- Department of Oncology, and Children's Research Center, University Children's Hospital Zurich, Switzerland
| | - Federica Lovisa
- Department of Woman's and Child's Health, Hematology-Oncology Laboratory, Istituto di Ricerca Pediatrica (IRP) and University of Padova, Italy
| | - Lara Mussolin
- Department of Woman's and Child's Health, Hematology-Oncology Laboratory, Istituto di Ricerca Pediatrica (IRP) and University of Padova, Italy
| | - Valentina Serafin
- Department of Woman's and Child's Health, Hematology-Oncology Laboratory, Istituto di Ricerca Pediatrica (IRP) and University of Padova, Italy
| | | | - Dieter Deforce
- Laboratory of Pharmaceutical Biotechnology, Ghent University, Belgium
| | - Anne Uyttebroeck
- Department of Pediatric Hematology-Oncology, University Hospitals Leuven, Belgium.,Department of Oncology, KU Leuven, Belgium
| | - Thomas Tousseyn
- Translational Cell and Tissue Research laboratory, KU Leuven, Belgium
| | - Birgit Burkhardt
- Department of Pediatric Hematology and Oncology, University of Münster, Germany
| | - Wolfram Klapper
- Department of Pathology, Hematopathology Section, UKSH Campus Kiel, Germany
| | - Barbara De Moerloose
- Cancer Research Institute Ghent (CRIG), Belgium.,Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium
| | - Yves Benoit
- Cancer Research Institute Ghent (CRIG), Belgium.,Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium
| | | | - Jean-Pierre Bourquin
- Department of Oncology, and Children's Research Center, University Children's Hospital Zurich, Switzerland
| | - Giuseppe Basso
- Department of Woman's and Child's Health, Hematology-Oncology Laboratory, Istituto di Ricerca Pediatrica (IRP) and University of Padova, Italy
| | - Benedetta Accordi
- Department of Woman's and Child's Health, Hematology-Oncology Laboratory, Istituto di Ricerca Pediatrica (IRP) and University of Padova, Italy
| | - Beat Bornhauser
- Department of Oncology, and Children's Research Center, University Children's Hospital Zurich, Switzerland
| | - Jules Meijerink
- The Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Peter Vandenberghe
- Department of Hematology, University Hospitals Leuven, Belgium.,Center for Human Genetics, KU Leuven, Belgium
| | - Pieter Van Vlierberghe
- Department of Biomolecular Medicine, Ghent University, Belgium .,Cancer Research Institute Ghent (CRIG), Belgium
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Kong D, Zhao L, Sun L, Fan S, Li H, Zhao Y, Guo Z, Lin L, Cui L, Wang K, Chen W, Zhang Y, Zhou J, Li Y. MYCN is a novel oncogenic target in adult B-ALL that activates the Wnt/β-catenin pathway by suppressing DKK3. J Cell Mol Med 2018; 22:3627-3637. [PMID: 29673070 PMCID: PMC6010754 DOI: 10.1111/jcmm.13644] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 03/08/2018] [Indexed: 12/11/2022] Open
Abstract
Dickkopf‐3 (DKK3) is frequently down‐regulated by promoter hypermethylation and is closely associated with a poor prognosis in many cancers. Our previous studies have shown that miR‐708 down‐regulates DKK3 at the post‐transcriptional level in B‐ALL. However, whether transcriptional mechanisms lead to DKK3 silencing remains unclear. Here, we analysed the promoter regions of DKK3 by bioinformatics and found binding sites for MYCN. A dual‐luciferase reporter gene assay and ChIP experiments revealed that MYCN negatively regulates DKK3 at the transcriptional level in B‐ALL cell lines, and using bisulphite sequencing PCR, we affirmed that MYCN has no effect on the methylation of the DKK3 promoter. MYCN silencing in B‐ALL cells resulted in reduced cell proliferation, increased apoptosis and G1 phase arrest. Treatment with MYCN siRNA or 5‐aza‐2′‐deoxycytidine (5‐AdC), a demethylating agent, significantly increased the levels of DKK3 mRNA and protein and decreased the protein levels of p‐GSK3β and nuclear β‐catenin, which indicates inhibition of the Wnt/β‐catenin pathway in vitro. MYCN knockdown significantly decreased the tumorigenic capacity of Nalm6 cells, which restored DKK3 levels and inhibited the Wnt/β‐catenin pathway in vivo. Our study provides an increased understanding of adult B‐ALL pathogenesis, which may be beneficial to the development of effective prognostic markers or therapeutic targets.
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Affiliation(s)
- Desheng Kong
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China.,Department of Hematology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Linlin Zhao
- Department of Blood Transfusion, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Lili Sun
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Shengjin Fan
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Huibo Li
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yanqiu Zhao
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Zhibo Guo
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Leilei Lin
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Lin Cui
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Ke Wang
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Wenjia Chen
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yihui Zhang
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Jin Zhou
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yinghua Li
- Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
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Lim R, Barker G, Lappas M. Inhibition of PIM1 kinase attenuates inflammation-induced pro-labour mediators in human foetal membranes in vitro. Mol Hum Reprod 2018; 23:428-440. [PMID: 28333279 DOI: 10.1093/molehr/gax013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 03/06/2017] [Indexed: 01/29/2023] Open
Abstract
STUDY QUESTION Does proviral integration site for Moloney murine leukaemic virus (PIM)1 kinase play a role in regulating the inflammatory processes of human labour and delivery? SUMMARY ANSWER PIM1 kinase plays a critical role in foetal membranes in regulating pro-inflammatory and pro-labour mediators. WHAT IS KNOWN ALREADY Infection and inflammation have strong causal links to preterm delivery by stimulating pro-inflammatory cytokines and collagen degrading enzymes, which can lead to rupture of membranes. PIM1 has been shown to have a role in immune regulation and inflammation in non-gestational tissues; however, its role has not been explored in the field of human labour. STUDY DESIGN, SIZE, DURATION PIM1 expression was analysed in myometrium and/or foetal membranes obtained at term and preterm (n = 8-9 patients per group). Foetal membranes, freshly isolated amnion cells and primary myometrial cells were used to investigate the effect of PIM1 inhibition on pro-labour mediators (n = 5 patients per treatment group). PARTICIPANTS/MATERIALS, SETTING AND METHODS Foetal membranes, from term and preterm, were obtained from non-labouring and labouring women, and from preterm pre-labour rupture of membranes (PPROM) (n = 9 per group). Amnion was collected from women with and without preterm chorioamnionitis (n = 8 per group). Expression of PIM1 kinase was determined by qRT-PCR and western blotting. To determine the effect of PIM1 kinase inhibition on the expression of pro-inflammatory and pro-labour mediators induced by bacterial products lipopolysaccharide (LPS) (10 μg/ml) and flagellin (1 μg/ml) and pro-inflammatory cytokine tumour necrosis factor (TNF) (10 ng/ml), chemical inhibitors SMI-4a (20 μM) and AZD1208 (50 μM) were used in foetal membrane explants and siRNA against PIM1 was used in primary amnion cells. Statistical significance was set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE PIM1 expression was significantly increased in foetal membranes after spontaneous term labour compared to no labour at term and in amnion with preterm chorioamnionitis compared to preterm with no chorioamnionitis. There was no change in PIM1 expression with preterm labour or PPROM compared to preterm with no labour or PPROM. In human foetal membranes, PIM1 inhibitors SMI-4a and AZD1208 significantly decreased the expression of pro-inflammatory cytokine interleukin-6 (IL6) and chemokines CXCL8 and CCL2 mRNA and release, prostaglandin prostaglandin F2α (PGF2α) release, adhesion molecule intercellular adhesion molecule 1 mRNA expression and release, and oxidative stress marker 8-isoprostane release after stimulation with either LPS or flagellin. Primary amnion cells transfected with PIM1 siRNA also showed decreased expression of IL6, CXCL8 and CCL2, PTGS2 mRNA and PGF2α release, and matrix metalloproteinase-9 (MMP9) expression, when stimulated with TNF. LARGE SCALE DATA None. LIMITATIONS, REASONS FOR CAUTION The conclusions were drawn from in vitro experiments using foetal membrane explants and primary cells isolated from amnion. Animal models are necessary to determine whether PIM1 kinase inhibitors can prevent spontaneous preterm birth in vivo. WIDER IMPLICATIONS OF THE FINDINGS PIM1 kinase inhibitors may provide a novel therapeutic approach for preventing spontaneous preterm birth. STUDY FUNDING/COMPETING INTEREST(S) Associate Professor Martha Lappas is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; grant no. 1047025). Funding for this study was provided by the NHMRC (grant no. 1058786), Norman Beischer Medical Research Foundation and the Mercy Research Foundation. The authors have no conflict of interest.
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Affiliation(s)
- Ratana Lim
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia.,Mercy Perinatal Research Centre, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia
| | - Gillian Barker
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia.,Mercy Perinatal Research Centre, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia
| | - Martha Lappas
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia.,Mercy Perinatal Research Centre, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia
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Padi SKR, Luevano LA, An N, Pandey R, Singh N, Song JH, Aster JC, Yu XZ, Mehrotra S, Kraft AS. Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset. Oncotarget 2018; 8:30199-30216. [PMID: 28415816 PMCID: PMC5444737 DOI: 10.18632/oncotarget.16320] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 03/08/2017] [Indexed: 12/13/2022] Open
Abstract
New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors. Gene profiling using a publically available T-ALL dataset demonstrated overexpression of PIM1 in the majority of early T-cell precursor (ETP)-ALLs and a small subset of non-ETP ALL. While the PIM inhibitors blocked growth, they also stimulated ERK and STAT5 phosphorylation, demonstrating that activation of additional signaling pathways occurs with PIM inhibitor treatment. To block these pathways, Ponatinib, a broadly active tyrosine kinase inhibitor (TKI) used to treat chronic myelogenous leukemia, was added to this PIM-inhibitor regimen. The combination of Ponatinib with a PIM inhibitor resulted in synergistic T-ALL growth inhibition and marked apoptotic cell death. Treatment of mice engrafted with human T-ALL with these two agents significantly decreased the tumor burden and improved the survival of treated mice. This dual therapy has the potential to be developed as a novel approach to treat T-ALL with high PIM expression.
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Affiliation(s)
- Sathish K R Padi
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Libia A Luevano
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Ningfei An
- Department of Pathology, Pediatric Hematology/Oncology Division, University of Chicago, Chicago, IL, USA
| | - Ritu Pandey
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.,Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Neha Singh
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Jin H Song
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.,Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Jon C Aster
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Shikhar Mehrotra
- Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Andrew S Kraft
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
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Lv DL, Chen L, Ding W, Zhang W, Wang HL, Wang S, Liu WB. Ginsenoside G-Rh2 synergizes with SMI-4a in anti-melanoma activity through autophagic cell death. Chin Med 2018; 13:11. [PMID: 29483938 PMCID: PMC5820787 DOI: 10.1186/s13020-018-0168-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 02/12/2018] [Indexed: 12/15/2022] Open
Abstract
Background Melanoma is a leading cause of cancer death worldwide, and SMI-4a and G-Rh2 exert anti-tumor activity in multiple cancer. However, SMI-4a as well as a synergistic relationship between SMI-4a and G-Rh2 in anti-melanoma capacity are still unknown. Therefore, we investigated the effects of SMI-4a and combined SMI-4a with G-Rh2 on the viability, apoptosis and autophagy of melanoma, and to preliminarily explore the underlying mechanism of SMI-4a and combined SMI-4a with G-Rh2 in inhibiting tumor growth. Methods Cell viability was examined with cell counting Kit 8 assay and colony formation assay; Apoptosis was evaluated by flow cytometry and Caspase 3/7 activity assay; Western blotting was used to test proteins related to autophagy and the AKT/mammalian target of rapamycin (mTOR) signaling pathway; Tumor xenograft model in BALB/c nude mice was performed to evaluate the effects of SMI-4a and combined SMI-4a with G-Rh2 in anti-melanoma in vivo. Results SMI-4a, a pharmacological inhibitor of PIM-1, could decrease cell viability, induce apoptosis, and promote Caspase 3/7 activity in both A375 and G361 melanoma cells, and SMI-4a inhibited tumor growth by inducing autophagy via down-regulating AKT/mTOR axis in melanoma cells. Furthermore, G-Rh2 amplified the anti-tumor activity of SMI-4a in melanoma cells via strengthening autophagy. Conclusions Our results suggested that SMI-4a could enhance autophagy-inducing apoptosis by inhibiting AKT/mTOR signaling pathway in melanoma cells, and G-Rh2 could enhance the effects of SMI-4a against melanoma cancer via amplifying autophagy induction. This study demonstrates that combined SMI-4a and G-Rh2 might be a novel alternative strategy for melanoma treatment. Electronic supplementary material The online version of this article (10.1186/s13020-018-0168-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Da-Lun Lv
- 1Department of Burn and Plastic Surgery, First Affiliated Hospital of Wannan Medical College, Jinghu District, Wuhu, 241000 Anhui China
| | - Lei Chen
- 1Department of Burn and Plastic Surgery, First Affiliated Hospital of Wannan Medical College, Jinghu District, Wuhu, 241000 Anhui China
| | - Wei Ding
- 1Department of Burn and Plastic Surgery, First Affiliated Hospital of Wannan Medical College, Jinghu District, Wuhu, 241000 Anhui China
| | - Wei Zhang
- 1Department of Burn and Plastic Surgery, First Affiliated Hospital of Wannan Medical College, Jinghu District, Wuhu, 241000 Anhui China
| | - He-Li Wang
- 1Department of Burn and Plastic Surgery, First Affiliated Hospital of Wannan Medical College, Jinghu District, Wuhu, 241000 Anhui China
| | - Shuai Wang
- 1Department of Burn and Plastic Surgery, First Affiliated Hospital of Wannan Medical College, Jinghu District, Wuhu, 241000 Anhui China
| | - Wen-Bei Liu
- 2Dermatological Department, First Affiliated Hospital of Wannan Medical College, Jinghu District, Wuhu, 241000 Anhui China
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High PIM1 expression is a biomarker of T-cell acute lymphoblastic leukemia with JAK/STAT activation or t(6;7)(p21;q34)/TRB@-PIM1 rearrangement. Leukemia 2018; 32:1807-1810. [PMID: 29479063 DOI: 10.1038/s41375-018-0031-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 01/10/2018] [Indexed: 02/06/2023]
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Asati V, Bharti SK. Design, synthesis and molecular modeling studies of novel thiazolidine-2,4-dione derivatives as potential anti-cancer agents. J Mol Struct 2018. [DOI: 10.1016/j.molstruc.2017.10.077] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Insulin receptor substrate 1 is a substrate of the Pim protein kinases. Oncotarget 2018; 7:20152-65. [PMID: 26956053 PMCID: PMC4991444 DOI: 10.18632/oncotarget.7918] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 02/14/2016] [Indexed: 01/05/2023] Open
Abstract
The Pim family of serine/threonine protein kinases (Pim 1, 2, and 3) contribute to cellular transformation by regulating glucose metabolism, protein synthesis, and mitochondrial oxidative phosphorylation. Drugs targeting the Pim protein kinases are being tested in phase I/II clinical trials for the treatment of hematopoietic malignancies. The goal of these studies was to identify Pim substrate(s) that could help define the pathway regulated by these enzymes and potentially serve as a biomarker of Pim activity. To identify novel substrates, bioinformatics analysis was carried out to identify proteins containing a consensus Pim phosphorylation site. This analysis identified the insulin receptor substrate 1 and 2 (IRS1/2) as potential Pim substrates. Experiments were carried out in tissue culture, animals, and human samples from phase I trials to validate this observation and define the biologic readout of this phosphorylation. Our study demonstrates in both malignant and normal cells using either genetic or pharmacological inhibition of the Pim kinases or overexpression of this family of enzymes that human IRS1S1101 and IRS2S1149 are Pim substrates. In xenograft tumor experiments and in a human phase I clinical trial, a pan-Pim inhibitor administered in vivo to animals or humans decreased IRS1S1101 phosphorylation in tumor tissues. This phosphorylation was shown to have effects on the half-life of the IRS family of proteins, suggesting a role in insulin or IGF signaling. These results demonstrate that IRS1S1101 is a novel substrate for the Pim kinases and provide a novel marker for evaluation of Pim inhibitor therapy.
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Asati V, Thakur SS, Upmanyu N, Bharti SK. Virtual Screening, Molecular Docking, and DFT Studies of Some Thiazolidine-2,4-diones as Potential PIM-1 Kinase Inhibitors. ChemistrySelect 2018. [DOI: 10.1002/slct.201702392] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Vivek Asati
- Institute of Pharmaceutical Sciences, Guru; Ghasidas Vishwavidyalaya (A Central University); Bilaspur- 495009 Chhattisgarh India
- NRI Institute of Pharmaceutical Sciences; Bhopal, MP India
| | - Santosh S. Thakur
- Department of Chemistry; Guru Ghasidas Vishwavidyalaya (A Central University); Bilaspur- 495009 Chhattisgarh India
| | - Neeraj Upmanyu
- School of Pharmacy & Research; People's University; Bhopal, MP India
| | - Sanjay K. Bharti
- Institute of Pharmaceutical Sciences, Guru; Ghasidas Vishwavidyalaya (A Central University); Bilaspur- 495009 Chhattisgarh India
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Fan RF, Lu Y, Fang ZG, Guo XY, Chen YX, Xu YC, Lei YM, Liu KF, Lin DJ, Liu LL, Liu XF. PIM-1 kinase inhibitor SMI-4a exerts antitumor effects in chronic myeloid leukemia cells by enhancing the activity of glycogen synthase kinase 3β. Mol Med Rep 2017; 16:4603-4612. [PMID: 28849186 PMCID: PMC5647015 DOI: 10.3892/mmr.2017.7215] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 08/02/2017] [Indexed: 12/11/2022] Open
Abstract
The development of targeted tyrosine kinase inhibitors (TKIs) has succeeded in altering the course of chronic myeloid leukemia (CML). However, a number of patients have failed to respond or experienced disease relapse following TKI treatment. Proviral integration site for moloney murine leukemia virus-1 (PIM-1) is a serine/threonine kinase that participates in regulating apoptosis, cell cycle, signal transduction and transcriptional pathways, which are associated with tumor progression, and poor prognosis. SMI-4a is a selective PIM-1 kinase inhibitor that inhibits PIM-1 kinase activity in vivo and in vitro. The present study aimed to explore the mechanism underlying the antitumor effect of SMI-4a in K562 and imatinib-resistant K562 (K562/G) cell lines. It was demonstrated that SMI-4a inhibited the proliferation of K562 and K562/G cells using a WST-8 assay. The Annexin V-propidium iodide assay demonstrated that SMI-4a induced apoptosis of K562 and K562/G cells in a dose-, and time-dependent manner. Furthermore, Hoechst 33342 staining was used to verify the apoptosis rate. The clone formation assay revealed that SMI-4a significantly inhibited the colony formation capacity of K562 and K562/G cells. Western blot analysis demonstrated that SMI-4a decreased phosphorylated (p)-Ser9-glycogen synthase kinase (GSK) 3β/pGSK3β and inhibited the translocation of β-catenin. In addition, the downstream gene expression of apoptosis regulator Bax and poly(ADP-ribose) polymerase-1 was upregulated, and apoptosis regulator Bcl-2 and Myc proto-oncogene protein expression levels were downregulated. Immunofluorescence results demonstrated changes in the expression level of β-catenin in the plasma and nucleus. The results of the present study suggest that SMI-4a is an effective drug to use in combination with current chemotherapeutics for the treatment of imatinib-resistant CML.
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Affiliation(s)
- Rui-Fang Fan
- Department of Hematology, Sun Yat‑sen Institute of Hematology, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ying Lu
- Department of Blood Transfusion, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhi-Gang Fang
- Department of Hematology, Sun Yat‑sen Institute of Hematology, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiao-Yan Guo
- Department of Pediatrics, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510100, P.R. China
| | - Yu-Xin Chen
- Department of Hematology, Sun Yat‑sen Institute of Hematology, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yi-Chuan Xu
- Department of Hematology, Sun Yat‑sen Institute of Hematology, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ya-Mei Lei
- Department of Hematology, Sun Yat‑sen Institute of Hematology, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ke-Fang Liu
- Logistics Management Office, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Dong-Jun Lin
- Department of Hematology, Sun Yat‑sen Institute of Hematology, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ling-Ling Liu
- Department of Hematology, Sun Yat‑sen Institute of Hematology, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiang-Fu Liu
- Department of Blood Transfusion, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
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Wang K, Deng X, Shen Z, Jia Y, Ding R, Li R, Liao X, Wang S, Ha Y, Kong Y, Wu Y, Guo J, Jie W. High glucose promotes vascular smooth muscle cell proliferation by upregulating proto-oncogene serine/threonine-protein kinase Pim-1 expression. Oncotarget 2017; 8:88320-88331. [PMID: 29179437 PMCID: PMC5687607 DOI: 10.18632/oncotarget.19368] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 06/28/2017] [Indexed: 02/06/2023] Open
Abstract
Serine/threonine kinase proviral integration site for Moloney murine leukemia virus 1 (Pim-1) plays an essential role in arterial wall cell proliferation and associated vascular diseases, including pulmonary arterial hypertension and aortic wall neointima formation. Here we tested a role of Pim-1 in high-glucose (HG)-mediated vascular smooth muscle cell (VSMC) proliferation. Pim-1 and proliferating cell nuclear antigen (PCNA) expression levels in arterial samples from streptozotocin-induced hyperglycemia rats were increased, compared with their weak expression in normoglycemic groups. In cultured rat VSMCs, HG led to transient Pim-1 expression decline, followed by sustained expression increase at both transcriptional and translational levels. Immunoblot analysis demonstrated that HG increased the expression of the 33-kDa isoform of Pim-1, but at much less extent to its 44-kDa plasma membrane isoform. D-glucose at a concentration of 25 mmol/L showed highest activity in stimulating Pim-1 expression. Both Pim-1 inhibitor quercetagetin and STAT3 inhibitor stattic significantly attenuated HG-induced VSMC proliferation and arrested cell cycle progression at the G1 phase. Quercetagetin showed no effect on Pim-1 expression but decreased the phosphorylated-Bad (T112)/Bad ratio in HG-treated VSMCs. However, stattic decreased phosphorylated-STAT3 (Y705) levels and caused transcriptional and translational down-regulation of Pim-1 in HG-treated VSMCs. Our findings suggest HG-mediated Pim-1 expression contributes to VSMC proliferation, which may be partly due to the activation of STAT3/Pim-1 signaling.
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Affiliation(s)
- Keke Wang
- Department of Pathology, School of Basic medicine Sciences, Guangdong Medical University, Zhanjiang, P.R. China
| | - Xiaojiang Deng
- Department of Cardiovascular, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Zhihua Shen
- Department of Pathology, School of Basic medicine Sciences, Guangdong Medical University, Zhanjiang, P.R. China
| | - Yanan Jia
- Department of Pathology, School of Basic medicine Sciences, Guangdong Medical University, Zhanjiang, P.R. China
| | - Ranran Ding
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Rujia Li
- Department of Pathology, School of Basic medicine Sciences, Guangdong Medical University, Zhanjiang, P.R. China
| | - Xiaomin Liao
- Department of Pathology, School of Basic medicine Sciences, Guangdong Medical University, Zhanjiang, P.R. China
| | - Sisi Wang
- Department of Pathology, School of Basic medicine Sciences, Guangdong Medical University, Zhanjiang, P.R. China
| | - Yanping Ha
- Department of Pathology, School of Basic medicine Sciences, Guangdong Medical University, Zhanjiang, P.R. China
| | - Yueqiong Kong
- Cardiovascular Institute of 1st Affiliated Hospital & Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, P.R. China
| | - Yuyou Wu
- Cardiovascular Institute of 1st Affiliated Hospital & Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, P.R. China
| | - Junli Guo
- Cardiovascular Institute of 1st Affiliated Hospital & Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, P.R. China
| | - Wei Jie
- Department of Pathology, School of Basic medicine Sciences, Guangdong Medical University, Zhanjiang, P.R. China
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Asati V, Bharti SK, Budhwani AK. 3D-QSAR and virtual screening studies of thiazolidine-2,4-dione analogs: Validation of experimental inhibitory potencies towards PIM-1 kinase. J Mol Struct 2017. [DOI: 10.1016/j.molstruc.2016.12.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Bataille CJR, Brennan MB, Byrne S, Davies SG, Durbin M, Fedorov O, Huber KVM, Jones AM, Knapp S, Liu G, Nadali A, Quevedo CE, Russell AJ, Walker RG, Westwood R, Wynne GM. Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family. Bioorg Med Chem 2017; 25:2657-2665. [PMID: 28341403 DOI: 10.1016/j.bmc.2017.02.056] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 02/23/2017] [Accepted: 02/25/2017] [Indexed: 12/31/2022]
Abstract
The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.
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Affiliation(s)
- Carole J R Bataille
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
| | - Méabh B Brennan
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
| | - Simon Byrne
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
| | - Stephen G Davies
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
| | - Matthew Durbin
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
| | - Oleg Fedorov
- Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK
| | - Kilian V M Huber
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
| | - Alan M Jones
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
| | - Stefan Knapp
- Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK
| | - Gu Liu
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
| | - Anna Nadali
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
| | - Camilo E Quevedo
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
| | - Angela J Russell
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
| | - Roderick G Walker
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
| | - Robert Westwood
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
| | - Graham M Wynne
- Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
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Wu J, Zhang Q, Wuu YR, Zou S, Hei TK. Cytoplasmic Irradiation Induces Metabolic Shift in Human Small Airway Epithelial Cells via Activation of Pim-1 Kinase. Radiat Res 2017; 187:441-453. [PMID: 28170315 DOI: 10.1667/rr0006cc.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The unique cellular and molecular consequences of cytoplasmic damage caused by ionizing radiation were studied using a precision microbeam irradiator. Our results indicated that targeted cytoplasmic irradiation induced metabolic shift from an oxidative to glycolytic phenotype in human small airway epithelial cells (SAE). At 24 h postirradiation, there was an increase in the mRNA expression level of key glycolytic enzymes as well as lactate secretion in SAE cells. Using RNA-sequencing analysis to compare genes that were responsive to cytoplasmic versus nuclear irradiation, we found a glycolysis related gene, Pim-1, was significantly upregulated only in cytoplasmic irradiated SAE cells. Inhibition of Pim-1 activity using the selective pharmaceutic inhibitor Smi-4a significantly reduced the level of lactate production and glucose uptake after cytoplasmic irradiation. In addition, Pim-1 also inhibited AMPK activity, which is a well-characterized negative regulator of glycolysis. Distinct from the glycolysis induced by cytoplasmic irradiation, targeted nuclear irradiation also induced a transient and minimal increase in glycolysis that correlated with increased expression of Hif-1α. In an effort to explore the underline mechanism, we found that inhibition of mitochondria fission using the cell-permeable inhibitor mdivi-1 suppressed the induction of Pim-1, thus confirming Pim-1 upregulation as a downstream effect of mitochondrial dysfunction. Our data show and, for the first time, that cytoplasmic irradiation mediate expression level of Pim-1, which lead to glycolytic shift in SAE cells. Additionally, since glycolysis is frequently linked to cancer cell metabolism, our findings further suggest a role of cytoplasmic damage in promoting neoplastic changes.
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Affiliation(s)
- Jinhua Wu
- a Center for Radiological Research, College of Physicians and Surgeons; Columbia University, New York, New York 10032.,d Institute of Plasma Physics, Chinese Academy of Sciences, Hefei, Anhui, China 230031
| | - Qin Zhang
- c Department of Environmental Health and Occupational Medicine, West China School of Public Health, Sichuan University. Chengdu, Sichuan, China 610041; and
| | - Yen-Ruh Wuu
- a Center for Radiological Research, College of Physicians and Surgeons; Columbia University, New York, New York 10032
| | - Sirui Zou
- a Center for Radiological Research, College of Physicians and Surgeons; Columbia University, New York, New York 10032
| | - Tom K Hei
- a Center for Radiological Research, College of Physicians and Surgeons; Columbia University, New York, New York 10032.,b Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032
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Laurenzana I, Caivano A, La Rocca F, Trino S, De Luca L, D'Alessio F, Schenone S, Falco G, Botta M, Del Vecchio L, Musto P. A Pyrazolo[3,4- d]pyrimidine Compound Reduces Cell Viability and Induces Apoptosis in Different Hematological Malignancies. Front Pharmacol 2016; 7:416. [PMID: 27872592 PMCID: PMC5098387 DOI: 10.3389/fphar.2016.00416] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 10/20/2016] [Indexed: 12/19/2022] Open
Abstract
Molecular targeted therapies are based upon drugs acting on tumors by interfering with specific targets involved in growth and spread of cancer. Many targeted therapies were approved by Food and Drug Administration as standard treatment, others were introduced into preclinical or clinical studies on hematological malignancies (HMs). The development of drug-resistance in some HMs and the lack of effective treatments in other ones emphasized the need for searching new molecular targets and therapeutic agents. The aim of this study was to evaluate the effects of 4c pyrazolo[3,4-d]pyrimidine compound, a Src inhibitor, on lymphoid and myeloid neoplasms. Here, we demonstrated its ability to reduce cell viability, induce apoptosis and cell cycle arrest in lymphoid cell lines such as Jurkat, SKMM1, Derl-2/7, and myeloid cell lines, such as Jurl-MK1. Moreover, we reported a high expression of a Src kinase, Fyn, in these cell lines compared to healthy subjects. This study was a starting point to investigate 4c pyrazolo[3,4-d]pyrimidine compound as a drug for HMs and Src kinases as its potential molecular targets.
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Affiliation(s)
- Ilaria Laurenzana
- Laboratory of Preclinical and Translational Research, IRCCS - Referral Cancer Center of Basilicata (CROB), Rionero in Vulture Potenza, Italy
| | - Antonella Caivano
- Laboratory of Preclinical and Translational Research, IRCCS - Referral Cancer Center of Basilicata (CROB), Rionero in Vulture Potenza, Italy
| | - Francesco La Rocca
- Laboratory of Preclinical and Translational Research, IRCCS - Referral Cancer Center of Basilicata (CROB), Rionero in Vulture Potenza, Italy
| | - Stefania Trino
- Laboratory of Preclinical and Translational Research, IRCCS - Referral Cancer Center of Basilicata (CROB), Rionero in Vulture Potenza, Italy
| | - Luciana De Luca
- Laboratory of Preclinical and Translational Research, IRCCS - Referral Cancer Center of Basilicata (CROB), Rionero in Vulture Potenza, Italy
| | | | | | - Geppino Falco
- Department of Biology, University of Naples Federico II Naples, Italy
| | - Maurizio Botta
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena Siena, Italy
| | - Luigi Del Vecchio
- Biotecnologie Avanzate s.c.a.r.l., CEINGENapoli, Italy; Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico IINaples, Italy
| | - Pellegrino Musto
- Scientific Direction, IRCCS - Referral Cancer Center of Basilicata (CROB), Rionero in Vulture Potenza, Italy
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