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Kawataki S, Kubota Y, Katayama K, Imoto S, Takekawa M. GADD45β-MTK1 signaling axis mediates oncogenic stress-induced activation of the p38 and JNK pathways. Cancer Sci 2025; 116:128-142. [PMID: 39526327 PMCID: PMC11711059 DOI: 10.1111/cas.16389] [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: 09/23/2024] [Revised: 10/22/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
The ERK pathway governs essential biological processes such as cell proliferation and survival, and its hyperactivation by various oncogenes ultimately drives carcinogenesis. However, normal mammalian cells typically recognize aberrant ERK signaling as oncogenic stress and respond by inducing cell cycle arrest or apoptosis through activation of the p38 and JNK pathways. Despite the critical role of this response in preventing carcinogenesis, the precise molecular mechanisms underlying oncogene-induced, ERK-dependent activation of p38/JNK and its tumor-suppressive effects remain unclear. Here, we demonstrate that MAP three kinase 1 (MTK1), a stress-responsive MAPKKK, serves as a key mediator of p38/JNK activation induced by oncogenic ERK signaling. Mechanistically, aberrant ERK signaling induces sustained expression of the transcription factor early growth response protein 1 (EGR1), which promotes the production of the MTK1 activator GADD45β, leading to persistent activation of MTK1-p38/JNK signaling. Gene knockout and transcriptome analyses revealed that this GADD45β/MTK1-mediated cross-talk between the ERK and p38/JNK pathways preferentially upregulates a specific set of genes involved in apoptosis and the immune response. Notably, the expression of EGR1, GADD45β, and MTK1 is frequently downregulated in many cancers with high ERK activity, resulting in the disruption of the tumor-suppressive ERK-p38/JNK cross-talk. Restoring GADD45β expression in cancer cells reactivates p38/JNK signaling and suppresses tumorigenesis. Our findings delineate a molecular mechanism by which normal cells sense and respond to oncogenic stress to prevent abnormal growth, and highlight the significance of its dysregulation in cancer.
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Affiliation(s)
- Saeko Kawataki
- Division of Cell Signaling and Molecular Medicine, Institute of Medical ScienceThe University of TokyoTokyoJapan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoChibaJapan
| | - Yuji Kubota
- Division of Cell Signaling and Molecular Medicine, Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Kotoe Katayama
- Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Seiya Imoto
- Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical ScienceThe University of TokyoTokyoJapan
- Division of Health Medical Intelligence, Human Genome Center, Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Mutsuhiro Takekawa
- Division of Cell Signaling and Molecular Medicine, Institute of Medical ScienceThe University of TokyoTokyoJapan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoChibaJapan
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Singh B, Patwardhan RS, Pal D, Maurya DK, Singh BG, Checker R, Sharma D, Sandur SK. Repurposing of FDA approved kinase inhibitor bosutinib for mitigation of radiation induced damage via inhibition of JNK pathway. Toxicol Appl Pharmacol 2024; 482:116792. [PMID: 38142783 DOI: 10.1016/j.taap.2023.116792] [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: 10/20/2023] [Revised: 12/09/2023] [Accepted: 12/15/2023] [Indexed: 12/26/2023]
Abstract
Radiotherapy is a common modality for cancer treatment. However, it is often associated with normal tissue toxicity in 20-80% of the patients. Radioprotectors can improve the outcome of radiotherapy by selectively protecting normal cells against radiation toxicity. In the present study, compound libraries containing 54 kinase inhibitors and 80 FDA-approved drugs were screened for radioprotection of lymphocytes using high throughput cell analysis. A second-generation FDA-approved kinase inhibitor, bosutinib, was identified as a potential radioprotector for normal cells. The radioprotective efficacy of bosutinib was evinced from a reduction in radiation induced DNA damage, caspase-3 activation, DNA fragmentation and apoptosis. Oral administration of bosutinib protected mice against whole body irradiation (WBI) induced morbidity and mortality. Bosutinib also reduced radiation induced bone-marrow aplasia and hematopoietic damage in mice exposed to 4 Gy and 6 Gy dose of WBI. Mechanistic studies revealed that the radioprotective action of bosutinib involved interaction with cellular thiols and modulation of JNK pathway. The addition of glutathione and N-acetyl cysteine significantly reduced the radioprotective efficacy of bosutinib. Moreover, bosutinib did not protect cancer cells against radiation induced toxicity. On the contrary, bosutinib per se exhibited anticancer activity against human cancer cell lines. The results highlight possible use of bosutinib as a repurposable radioprotective agent for mitigation of radiation toxicity in cancer patients undergoing radiotherapy.
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Affiliation(s)
- Babita Singh
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - Raghavendra S Patwardhan
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
| | - Debojyoti Pal
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
| | - Dharmendra K Maurya
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - Beena G Singh
- Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India; Radiation and Photochemistry Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
| | - Rahul Checker
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - Deepak Sharma
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - Santosh K Sandur
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India.
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Ding L, Jiang L, Xing Z, Dai H, Wei J. Map4k4 is up-regulated and modulates granulosa cell injury and oxidative stress in polycystic ovary syndrome via activating JNK/c-JUN pathway: An experimental study. Int Immunopharmacol 2023; 124:110841. [PMID: 37647682 DOI: 10.1016/j.intimp.2023.110841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 08/18/2023] [Accepted: 08/19/2023] [Indexed: 09/01/2023]
Abstract
The regulatory mechanism on granulosa cells (GCs) oxidative injury is becoming increasingly important in polycystic ovary syndrome (PCOS) studies. Serine/threonine kinase mitogen-activated protein 4 kinase 4 (Map4k4) is linked with oxidative injury and possibly associated with premature ovarian failure and ovarian dysgenesis. Herein, we investigated the function and mechanism of Map4k4 in a PCOS rat model. A microarray from GEO database identified Map4k4 was up-regulated in the ovarian of PCOS rats, and functional enrichments suggested that oxidative stress-associated changes are involved. We verified the raised Map4k4 expression in an established PCOS rat model and also in the isolated PCOS-GCs, which were consistent with the microarray data. Map4k4 knockdown in vivo contributed to regular estrous cycle, restrained steroid concentrations and ovarian injury in PCOS rats. Both Map4k4 silencing in vivo and in vitro attenuated the PCOS-related GC oxidative stress and apoptosis. Mechanically, Map4k4 activated the JNK/c-JUN signaling pathway. Importantly, a JNK agonist restored the suppressive effects of Map4k4 silencing on PCOS-induced granulosa cell injury and oxidative stress. Besides, Map4k4 may be a target gene of miR-185-5p. In conclusion, Map4k4, a potential target of miR-185-5p, is up-regulated and induces ovarian GC oxidative injury by activating JNK/c-JUN pathway in PCOS. The Map4k4/JNK/c-JUN mechanism may provide a new idea on the treatment of PCOS.
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Affiliation(s)
- Lifeng Ding
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Lili Jiang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ze Xing
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Huixu Dai
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jingzan Wei
- Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
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4
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Kim EY, Ji Kim E, Park H, Lee Y, Kyung Kim D, Sohn Y, Jung HS. A study on specific factors related to inflammation and autophagy in BEAS-2B cells induced by urban particulate matter (PM, 1648a) and histological evaluation of PM-induced bronchial asthma model in mice. Int Immunopharmacol 2023; 123:110730. [PMID: 37543014 DOI: 10.1016/j.intimp.2023.110730] [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: 04/20/2023] [Revised: 07/13/2023] [Accepted: 07/27/2023] [Indexed: 08/07/2023]
Abstract
As particulate matter (PM) poses an increasing risk, research on its correlation with diseases is active. However, researchers often use their own PM, making it difficult to determine its components. To address this, we investigated the effects of PM with known constituents on BEAS-2B cells, examining cytokine levels, reactive oxygen species ROS production, DNA damage, and MAPK phosphorylation. Additionally, we evaluated the effects of PM on normal and OVA-induced asthmatic mice by measuring organ weight, cytokine levels, and inflammatory cells in bronchoalveolar lavage fluid, and examining histological changes. PM markedly increased levels of IL-6, GM-CSF, TNF-α, ROS, nitric oxide, and DNA damage, while surprisingly reducing IL-8 and MCP-1. Moreover, PM increased MAPK phosphorylation and inhibited mTOR and AKT phosphorylation. In vivo, lung and spleen weights, IgE, OVA-specific IgE, IL-4, IL-13, total cells, macrophages, lymphocytes, mucus generation, and LC3II were higher in the asthma group. PM treatment in asthmatic mice increased lung weight and macrophage infiltration, but decreased IL-4 and IL-13 in BALF. Meanwhile, PM treatment in the Nor group increased total cells, macrophages, lymphocytes, and mucus generation. Our study suggests that PM may induce and exacerbate lung disease by causing immune imbalance via the MAPK and autophagy pathways, resulting in decreased lung function due to increased smooth muscle thickness and mucus generation.
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Affiliation(s)
- Eun-Young Kim
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Eom Ji Kim
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Hoyeon Park
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Yujin Lee
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Do Kyung Kim
- Department of Anatomy, Konyang University College of Medicine, Daejeon 35365, Republic of Korea
| | - Youngjoo Sohn
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
| | - Hyuk-Sang Jung
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
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Ni C, Buszczak M. The homeostatic regulation of ribosome biogenesis. Semin Cell Dev Biol 2023; 136:13-26. [PMID: 35440410 PMCID: PMC9569395 DOI: 10.1016/j.semcdb.2022.03.043] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 12/22/2022]
Abstract
The continued integrity of biological systems depends on a balance between interdependent elements at the molecular, cellular, and organismal levels. This is particularly true for the generation of ribosomes, which influence almost every aspect of cell and organismal biology. Ribosome biogenesis (RiBi) is an energetically demanding process that involves all three RNA polymerases, numerous RNA processing factors, chaperones, and the coordinated expression of 79-80 ribosomal proteins (r-proteins). Work over the last several decades has revealed that the dynamic regulation of ribosome production represents a major mechanism by which cells maintain homeostasis in response to changing environmental conditions and acute stress. More recent studies suggest that cells and tissues within multicellular organisms exhibit dramatically different levels of ribosome production and protein synthesis, marked by the differential expression of RiBi factors. Thus, distinct bottlenecks in the RiBi process, downstream of rRNA transcription, may exist within different cell populations of multicellular organisms during development and in adulthood. This review will focus on our current understanding of the mechanisms that link the complex molecular process of ribosome biogenesis with cellular and organismal physiology. We will discuss diverse topics including how different steps in the RiBi process are coordinated with one another, how MYC and mTOR impact RiBi, and how RiBi levels change between stem cells and their differentiated progeny. In turn, we will also review how regulated changes in ribosome production itself can feedback to influence cell fate and function.
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Affiliation(s)
- Chunyang Ni
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
| | - Michael Buszczak
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
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6
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Hanson RL, Batchelor E. Coordination of MAPK and p53 dynamics in the cellular responses to DNA damage and oxidative stress. Mol Syst Biol 2022; 18:e11401. [PMID: 36472304 PMCID: PMC9724178 DOI: 10.15252/msb.202211401] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/01/2022] [Accepted: 11/07/2022] [Indexed: 12/12/2022] Open
Abstract
In response to different cellular stresses, the transcription factor p53 undergoes different dynamics. p53 dynamics, in turn, control cell fate. However, distinct stresses can generate the same p53 dynamics but different cell fate outcomes, suggesting integration of dynamic information from other pathways is important for cell fate regulation. To determine how MAPK activities affect p53-mediated responses to DNA breaks and oxidative stress, we simultaneously tracked p53 and either ERK, JNK, or p38 activities in single cells. While p53 dynamics were comparable between the stresses, cell fate outcomes were distinct. Combining MAPK dynamics with p53 dynamics was important for distinguishing between the stresses and for generating temporal ordering of cell fate pathways. Furthermore, cross-talk between MAPKs and p53 controlled the balance between proliferation and cell death. These findings provide insight into how cells integrate signaling pathways with distinct temporal patterns of activity to encode stress specificity and drive different cell fate decisions.
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Affiliation(s)
- Ryan L Hanson
- Department of Integrative Biology and PhysiologyUniversity of MinnesotaMinneapolisMNUSA
| | - Eric Batchelor
- Department of Integrative Biology and PhysiologyUniversity of MinnesotaMinneapolisMNUSA
- Masonic Cancer CenterUniversity of MinnesotaMinneapolisMNUSA
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7
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Acute cytotoxicity, genotoxicity, and apoptosis induced by petroleum VOC emissions in A549 cell line. Toxicol In Vitro 2022; 83:105409. [DOI: 10.1016/j.tiv.2022.105409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 04/28/2022] [Accepted: 05/30/2022] [Indexed: 11/27/2022]
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8
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Gehi BR, Gadhave K, Uversky VN, Giri R. Intrinsic disorder in proteins associated with oxidative stress-induced JNK signaling. Cell Mol Life Sci 2022; 79:202. [PMID: 35325330 PMCID: PMC11073203 DOI: 10.1007/s00018-022-04230-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 01/02/2023]
Abstract
The c-Jun N-terminal kinase (JNK) signaling cascade is a mitogen-activated protein kinase (MAPK) signaling pathway that can be activated in response to a wide range of environmental stimuli. Based on the type, degree, and duration of the stimulus, the JNK signaling cascade dictates the fate of the cell by influencing gene expression through its substrate transcription factors. Oxidative stress is a result of a disturbance in the pro-oxidant/antioxidant homeostasis of the cell and is associated with a large number of diseases, such as neurodegenerative disorders, cancer, diabetes, cardiovascular diseases, and disorders of the immune system, where it activates the JNK signaling pathway. Among different biological roles ascribed to the intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are signaling hub functions, as intrinsic disorder allows proteins to undertake multiple interactions, each with a different consequence. In order to ensure precise signaling, the cellular abundance of IDPs is highly regulated, and mutations or changes in abundance of IDPs/IDPRs are often associated with disease. In this study, we have used a combination of six disorder predictors to evaluate the presence of intrinsic disorder in proteins of the oxidative stress-induced JNK signaling cascade, and as per our findings, none of the 18 proteins involved in this pathway are ordered. The highest level of intrinsic disorder was observed in the scaffold proteins, JIP1, JIP2, JIP3; dual specificity phosphatases, MKP5, MKP7; 14-3-3ζ and transcription factor c-Jun. The MAP3Ks, MAP2Ks, MAPKs, TRAFs, and thioredoxin were the proteins that were predicted to be moderately disordered. Furthermore, to characterize the predicted IDPs/IDPRs in the proteins of the JNK signaling cascade, we identified the molecular recognition features (MoRFs), posttranslational modification (PTM) sites, and short linear motifs (SLiMs) associated with the disordered regions. These findings will serve as a foundation for experimental characterization of disordered regions in these proteins, which represents a crucial step for a better understanding of the roles of IDPRs in diseases associated with this important pathway.
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Affiliation(s)
- Bhuvaneshwari R Gehi
- School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, 175005, India
- Molecular Biophysics Unit (MBU), Indian Institute of Science, Bengaluru, 560012, India
| | - Kundlik Gadhave
- School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, 175005, India
| | - Vladimir N Uversky
- Department of Molecular Medicine and Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
- Laboratory of New Methods in Biology, Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", Pushchino, Moscow region, 142290, Russia.
| | - Rajanish Giri
- School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, 175005, India.
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9
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Phosphate Toxicity and Epithelial to Mesenchymal Transition. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1362:73-84. [DOI: 10.1007/978-3-030-91623-7_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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10
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Yamashita T, Kato T, Isogai T, Gu Y, Ito T, Ma N. Taurine Deficiency in Tissues Aggravates Radiation-Induced Gastrointestinal Syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1370:113-120. [DOI: 10.1007/978-3-030-93337-1_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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11
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Dent P. Cell Signaling and Translational Developmental Therapeutics. COMPREHENSIVE PHARMACOLOGY 2022. [PMCID: PMC7538147 DOI: 10.1016/b978-0-12-820472-6.00002-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
The relationships between drug pharmacodynamics and subsequent changes in cellular signaling processes are complex. Many in vitro cell signaling studies often use drug concentrations above physiologically safe drug levels achievable in a patient's plasma. Drug companies develop agents to inhibit or modify the activities of specific target enzymes, often without a full consideration that their compounds have additional unknown targets. These two negative sequelae, when published together, become impediments against successful developmental therapeutics and translation because this data distorts our understanding of signaling mechanisms and reduces the probability of successfully translating drug-based concepts from the bench to the bedside. This article will discuss cellular signaling in isolation and as it relates to extant single and combined therapeutic drug interventions. This will lead to a hypothetical series standardized sequential approaches describing a rigorous concept to drug development and clinical translation.
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12
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Sarma U, Maiti M, Nair A, Bhadange S, Bansode Y, Srivastava A, Saha B, Mukherjee D. Regulation of STAT3 signaling in IFNγ and IL10 pathways and in their cross-talk. Cytokine 2021; 148:155665. [PMID: 34366205 DOI: 10.1016/j.cyto.2021.155665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 11/17/2022]
Abstract
The pro-inflammatory IFNγ-STAT1 pathway and anti-inflammatory IL10-STAT3 pathway elicit cellular responses primarily utilizing their canonical STATs. However IL10 mediated STAT1 and IFNγ mediated STAT3 activation is also observed, suggesting crosstalk of these functionally opposing signaling pathways can potentially reshape the canonical dynamics both STATs and alter the expression of their target genes. Herein, we measured the dynamics of STATs in response to different doses of IL10 or IFNγ and in their co-stimulation and employed quantitative modeling to understand the regulatory mechanisms controlling signal responses in individual and co-simulation scenarios. Our experiments show, STAT3 in particular, exhibits a bell-shaped dose-response while treated with IFNγ or IL10 and our model quantiatively captured the dose-dependent dynamics of both the STATs in both pathways. The model next predicted and subsequent experiments validated that STAT3 dynamics would robustly remain IL10 specific when subjected to a co-stimulation of both IFNγ and IL10. Genes common to both pathways also exhibited IL10 specific expression during the co-stimulation. The findings thus uncover anovel feature of the IL10-STAT3 signaling axis during pathway crosstalk. Finally, parameter sampling coupled to information theory based analysis showed that bell-shaped signal-response of STAT3 in both pathways is primarily dependent on receptor concentration whereas robustness of IL10-STAT3 signaling axis in co-stimulation results from the negative regulation of the IFNγ pathway.
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Affiliation(s)
- U Sarma
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India.
| | - M Maiti
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - A Nair
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - S Bhadange
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - Y Bansode
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - A Srivastava
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - B Saha
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - D Mukherjee
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India.
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13
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Zhao X, Li L, Yuan S, Zhang Q, Jiang X, Luo T. SPIB acts as a tumor suppressor by activating the NFkB and JNK signaling pathways through MAP4K1 in colorectal cancer cells. Cell Signal 2021; 88:110148. [PMID: 34530056 DOI: 10.1016/j.cellsig.2021.110148] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 09/06/2021] [Accepted: 09/09/2021] [Indexed: 01/03/2023]
Abstract
Spi-B transcription factor (SPIB) is a member of the E-twenty-six (ETS) transcription factor family. Previous studies have shown that the expression of SPIB is downregulated in human colorectal cancer tissues. The purpose of our study was to explore the biological function and related mechanism of SPIB in colorectal cancer cells. Our study found that SPIB could inhibit the proliferation, migration and invasion of CRC cells; inhibit angiogenesis; and induce CRC cells cycle arrest in G2/M phase and promote the apoptosis of CRC cells. We also found that compared with the control group, the 50% inhibitory concentration (IC50) values of oxaliplatin and 5-FU in the SPIB overexpression group were significantly reduced. Western blot results showed that the overexpression of SPIB upregulated cleaved-PARP(c-PARP), nuclear factor kB p65 (NFkB p65), phospho-NFkB p65 (p-NFkB P65), JNK1, and C-Jun protein expression levels compared with the control group. The silence of SPIB downregulated c-PARP, NFκB p65, p-NFκB p65, JNK1, and C-Jun protein expression levels. A dual-luciferase reporter assay showed that SPIB could activate the promoter of MAP4K1 and enhance the expression of MAP4K1. After silencing MAP4K1, the protein expression levels of c-PARP, NFkB P65, p-NFkB P65, JNK1, and C-Jun were downregulated. In summary, we found that SPIB is a tumor suppressor in colorectal cancer cells and that SPIB sensitizes colorectal cancer cells to oxaliplatin and 5-FU, SPIB exerts its anti-colorectal cancer effect by activating the NFkB and JNK signaling pathways through MAP4K1. The above findings may provide a reference for new molecular markers and therapeutic targets for CRC.
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Affiliation(s)
- Xunping Zhao
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Lin Li
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Shiyun Yuan
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Qia Zhang
- Department of Medical Oncology, Yongchuan Hospital of Chongqing Medical University, Chongqing 404000, People's Republic of China
| | - Xianyao Jiang
- Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Tao Luo
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China.
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14
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Xie W, Xu R, Fan C, Yang C, Chen H, Cao Y. 900 MHz Radiofrequency Field Induces Mitochondrial Unfolded Protein Response in Mouse Bone Marrow Stem Cells. Front Public Health 2021; 9:724239. [PMID: 34513791 PMCID: PMC8428517 DOI: 10.3389/fpubh.2021.724239] [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: 06/12/2021] [Accepted: 08/04/2021] [Indexed: 01/29/2023] Open
Abstract
Objective: To examine whether exposure of mouse bone marrow stromal cells (BMSC) to 900 MHz radiofrequency fields used in mobile communication devices can induce mitochondrial unfolded protein response (UPRmt). Methods: BMSCs were exposed to continuous wave 900 MHz radiofrequency fields (RF) at 120 μW/cm2 power intensity for 4 h/d for 5 consecutive days. Cells in sham group (SH) were cultured in RF exposure system, but without RF radiation. The positive control cells were irradiated with 6 Gy X-ray at a dose rate of 1.103 Gy/min (XR). To inhibit the upstream molecular JNK2 of UPRmt, cells in siRNA + RF, and siRNA + XR group were also pretreated with 100 nM siRNA-JNK2 for 48 h before RF/XR exposure. Thirty minutes, 4 h, and 24 h post-RF/XR exposure, cells were collected, the level of ROS was measured with flow cytometry, the expression levels of UPRmt-related proteins were detected using western blot analysis. Results: Compared with Sham group, the level of ROS in RF and XR group was significantly increased 30 min and 4 h post-RF/XR exposure (P < 0.05), however, the RF/XR-induced increase of ROS level reversed 24 h post-RF/XR exposure. Compared with Sham group, the expression levels of HSP10/HSP60/ClpP proteins in cells of RF and XR group increased significantly 30 min and 4 h post-RF/XR exposure (P < 0.05), however, the RF/XR-induced increase of HSP10/HSP60/ClpP protein levels reversed 24 h post-RF exposure. After interfering with siRNA-JNK2, the RF/XR exposures could not induce the increase of HSP10/HSP60/ClpP protein levels any more. Conclusions: The exposure of 900 MHz RF at 120 μW/cm2 power flux density could increase ROS level and activate a transient UPRmt in BMSC cells. Mitochondrial homeostasis in term of protein folding ability is restored 24 h post-RF exposure. Exposure to RF in our experimental condition did not cause permanent and severe mitochondrial dysfunctions. However, the detailed underlying molecular mechanism of RF-induced UPRmt remains to be further studied.
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Affiliation(s)
- Wen Xie
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
| | - Rui Xu
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
| | - Caiyun Fan
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
| | - Chunyu Yang
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
| | - Haiyan Chen
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
| | - Yi Cao
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
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15
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Zhang Z, Oh M, Sasaki JI, Nör JE. Inverse and reciprocal regulation of p53/p21 and Bmi-1 modulates vasculogenic differentiation of dental pulp stem cells. Cell Death Dis 2021; 12:644. [PMID: 34168122 PMCID: PMC8225874 DOI: 10.1038/s41419-021-03925-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/20/2022]
Abstract
Dental pulp stem cells (DPSC) are capable of differentiating into vascular endothelial cells. Although the capacity of vascular endothelial growth factor (VEGF) to induce endothelial differentiation of stem cells is well established, mechanisms that maintain stemness and prevent vasculogenic differentiation remain unclear. Here, we tested the hypothesis that p53 signaling through p21 and Bmi-1 maintains stemness and inhibits vasculogenic differentiation. To address this hypothesis, we used primary human DPSC from permanent teeth and Stem cells from Human Exfoliated Deciduous (SHED) teeth as models of postnatal mesenchymal stem cells. DPSC seeded in biodegradable scaffolds and transplanted into immunodeficient mice generated mature human blood vessels invested with smooth muscle actin-positive mural cells. Knockdown of p53 was sufficient to induce vasculogenic differentiation of DPSC (without vasculogenic differentiation medium containing VEGF), as shown by increased expression of endothelial markers (VEGFR2, Tie-2, CD31, VE-cadherin), increased capillary sprouting in vitro; and increased DPSC-derived blood vessel density in vivo. Conversely, induction of p53 expression with small molecule inhibitors of the p53-MDM2 binding (MI-773, APG-115) was sufficient to inhibit VEGF-induced vasculogenic differentiation. Considering that p21 is a major downstream effector of p53, we knocked down p21 in DPSC and observed an increase in capillary sprouting that mimicked results observed when p53 was knocked down. Stabilization of ubiquitin activity was sufficient to induce p53 and p21 expression and reduce capillary sprouting. Interestingly, we observed an inverse and reciprocal correlation between p53/p21 and the expression of Bmi-1, a major regulator of stem cell self-renewal. Further, direct inhibition of Bmi-1 with PTC-209 resulted in blockade of capillary-like sprout formation. Collectively, these data demonstrate that p53/p21 functions through Bmi-1 to prevent the vasculogenic differentiation of DPSC.
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Affiliation(s)
- Zhaocheng Zhang
- Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Min Oh
- Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Jun-Ichi Sasaki
- Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Jacques E Nör
- Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA.
- Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA.
- Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
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16
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Drain AP, Zahir N, Northey JJ, Zhang H, Huang PJ, Maller O, Lakins JN, Yu X, Leight JL, Alston-Mills BP, Hwang ES, Chen YY, Park CC, Weaver VM. Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer. J Exp Med 2021; 218:e20191360. [PMID: 33822843 PMCID: PMC8025243 DOI: 10.1084/jem.20191360] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 12/07/2020] [Accepted: 02/12/2021] [Indexed: 01/10/2023] Open
Abstract
Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.
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Affiliation(s)
- Allison P. Drain
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA
- University of California, Berkeley–University of California, San Francisco Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA
| | - Nastaran Zahir
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
- Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA
| | - Jason J. Northey
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA
| | - Hui Zhang
- Department of Radiation Oncology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA
| | - Po-Jui Huang
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA
| | - Ori Maller
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA
| | - Johnathon N. Lakins
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA
| | - Xinmiao Yu
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA
| | - Jennifer L. Leight
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
- Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA
| | - Brenda P. Alston-Mills
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
- Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA
| | - E. Shelley Hwang
- Department of Surgery, Duke University Medical Center, Durham, NC
| | - Yunn-Yi Chen
- Department of Pathology, University of California, San Francisco, San Francisco, CA
| | - Catherine C. Park
- Department of Radiation Oncology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA
- University of California, San Francisco Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
| | - Valerie M. Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA
- University of California, San Francisco Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA
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17
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Wijaya DA, Louisa M, Wibowo H, Taslim A, Permata TBM, Handoko H, Nuryadi E, Kodrat H, Gondhowiardjo SA. The future potential of Annona muricata L. extract and its bioactive compounds as radiation sensitizing agent: proposed mechanisms based on a systematic review. JOURNAL OF HERBMED PHARMACOLOGY 2021. [DOI: 10.34172/jhp.2021.18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Despite technological advances in cancer treatment, especially in radiotherapy, many efforts are being made in improving cancer cell radio-sensitivity to increase therapeutic ratio and overcome cancer cell radio-resistance. In the present review, we evaluated the anticancer mechanism of Annona muricata L. (AM) leaves extract and its bioactive compounds such as annonaceous acetogenins, annomuricin, annonacin, or curcumin; and further correlated them with the potential of the mechanism to increase or to reduce cancer cells radio-sensitivity based on literature investigation. We see that AM has a promising future potential as a radio-sensitizer agent.
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Affiliation(s)
- David Andi Wijaya
- Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital - Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia
| | - Melva Louisa
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia
| | - Heri Wibowo
- Laboratorium Terpadu, Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia
| | - Aslim Taslim
- Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital - Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia
| | - Tiara Bunga Mayang Permata
- Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital - Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia
| | - Handoko Handoko
- Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital - Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia
| | - Endang Nuryadi
- Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital - Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia
| | - Henry Kodrat
- Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital - Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia
| | - Soehartati Argadikoesoema Gondhowiardjo
- Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital - Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia
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18
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Maharjan M, Tanvir RB, Chowdhury K, Duan W, Mondal AM. Computational identification of biomarker genes for lung cancer considering treatment and non-treatment studies. BMC Bioinformatics 2020; 21:218. [PMID: 33272232 PMCID: PMC7713218 DOI: 10.1186/s12859-020-3524-8] [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: 04/26/2020] [Accepted: 04/29/2020] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Lung cancer is the number one cancer killer in the world with more than 142,670 deaths estimated in the United States alone in the year 2019. Consequently, there is an overreaching need to identify the key biomarkers for lung cancer. The aim of this study is to computationally identify biomarker genes for lung cancer that can aid in its diagnosis and treatment. The gene expression profiles of two different types of studies, namely non-treatment and treatment, are considered for discovering biomarker genes. In non-treatment studies healthy samples are control and cancer samples are cases. Whereas, in treatment studies, controls are cancer cell lines without treatment and cases are cancer cell lines with treatment. RESULTS The Differentially Expressed Genes (DEGs) for lung cancer were isolated from Gene Expression Omnibus (GEO) database using R software tool GEO2R. A total of 407 DEGs (254 upregulated and 153 downregulated) from non-treatment studies and 547 DEGs (133 upregulated and 414 downregulated) from treatment studies were isolated. Two Cytoscape apps, namely, CytoHubba and MCODE, were used for identifying biomarker genes from functional networks developed using DEG genes. This study discovered two distinct sets of biomarker genes - one from non-treatment studies and the other from treatment studies, each set containing 16 genes. Survival analysis results show that most non-treatment biomarker genes have prognostic capability by indicating low-expression groups have higher chance of survival compare to high-expression groups. Whereas, most treatment biomarkers have prognostic capability by indicating high-expression groups have higher chance of survival compare to low-expression groups. CONCLUSION A computational framework is developed to identify biomarker genes for lung cancer using gene expression profiles. Two different types of studies - non-treatment and treatment - are considered for experiment. Most of the biomarker genes from non-treatment studies are part of mitosis and play vital role in DNA repair and cell-cycle regulation. Whereas, most of the biomarker genes from treatment studies are associated to ubiquitination and cellular response to stress. This study discovered a list of biomarkers, which would help experimental scientists to design a lab experiment for further exploration of detail dynamics of lung cancer development.
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Affiliation(s)
- Mona Maharjan
- School of Computing and Information Sciences, Florida International University, Miami, FL, USA
| | - Raihanul Bari Tanvir
- School of Computing and Information Sciences, Florida International University, Miami, FL, USA
| | - Kamal Chowdhury
- School of Natural Sciences and Mathematics, Claflin University, Orangeburg, SC, USA
| | - Wenrui Duan
- Department of Human & Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Ananda Mohan Mondal
- School of Computing and Information Sciences, Florida International University, Miami, FL, USA.
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19
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Yang CY, Chuang HC, Tsai CY, Xiao YZ, Yang JY, Huang RH, Shih YC, Tan TH. DUSP11 Attenuates Lipopolysaccharide-Induced Macrophage Activation by Targeting TAK1. THE JOURNAL OF IMMUNOLOGY 2020; 205:1644-1652. [PMID: 32796023 DOI: 10.4049/jimmunol.2000334] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/19/2020] [Indexed: 01/23/2023]
Abstract
Dual-specificity phosphatase 11 (DUSP11, also named as PIR1) is a member of the atypical DUSP protein tyrosine phosphatase family. DUSP11 is only known to be an RNA phosphatase that regulates noncoding RNA stability. To date, the role of DUSP11 in immune cell signaling and immune responses remains unknown. In this study, we generated and characterized the immune cell functions of DUSP11-deficient mice. We identified TGF-β-activated kinase 1 (TAK1) as a DUSP11-targeted protein. DUSP11 interacted directly with TAK1, and the DUSP11-TAK1 interaction was enhanced by LPS stimulation in bone marrow-derived macrophages. DUSP11 deficiency enhanced the LPS-induced TAK1 phosphorylation and cytokine production in bone marrow-derived macrophages. Furthermore, DUSP11-deficient mice were more susceptible to LPS-induced endotoxic shock. The LPS-induced serum levels of IL-1β, TNF-α, and IL-6 were significantly elevated in DUSP11-deficient mice compared with those of wild-type mice. The data indicate that DUSP11 inhibits LPS-induced macrophage activation by targeting TAK1.
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Affiliation(s)
- Chia-Yu Yang
- Immunology Research Center, National Health Research Institutes, 35053 Zhunan, Taiwan.,Department of Microbiology and Immunology, College of Medicine, Chang Gung University, 33302 Tao-Yuan, Taiwan; and
| | - Huai-Chia Chuang
- Immunology Research Center, National Health Research Institutes, 35053 Zhunan, Taiwan
| | - Ching-Yi Tsai
- Immunology Research Center, National Health Research Institutes, 35053 Zhunan, Taiwan
| | - Yu-Zhi Xiao
- Immunology Research Center, National Health Research Institutes, 35053 Zhunan, Taiwan
| | - Jhih-Yu Yang
- Immunology Research Center, National Health Research Institutes, 35053 Zhunan, Taiwan
| | - Rou-Huei Huang
- Immunology Research Center, National Health Research Institutes, 35053 Zhunan, Taiwan
| | - Ying-Chun Shih
- Immunology Research Center, National Health Research Institutes, 35053 Zhunan, Taiwan
| | - Tse-Hua Tan
- Immunology Research Center, National Health Research Institutes, 35053 Zhunan, Taiwan; .,Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030
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20
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Buljan M, Ciuffa R, van Drogen A, Vichalkovski A, Mehnert M, Rosenberger G, Lee S, Varjosalo M, Pernas LE, Spegg V, Snijder B, Aebersold R, Gstaiger M. Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Mol Cell 2020; 79:504-520.e9. [PMID: 32707033 PMCID: PMC7427327 DOI: 10.1016/j.molcel.2020.07.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 02/14/2020] [Accepted: 06/30/2020] [Indexed: 12/30/2022]
Abstract
Protein kinases are essential for signal transduction and control of most cellular processes, including metabolism, membrane transport, motility, and cell cycle. Despite the critical role of kinases in cells and their strong association with diseases, good coverage of their interactions is available for only a fraction of the 535 human kinases. Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. The interaction dataset is a high-quality resource with more than 5,000 previously unreported interactions. We extensively characterized the obtained network and were able to identify previously described, as well as predict new, kinase functional associations, including those of the less well-studied kinases PIM3 and protein O-mannose kinase (POMK). Importantly, the presented interaction map is a valuable resource for assisting biomedical studies. We uncover dozens of kinase-disease associations spanning from genetic disorders to complex diseases, including cancer.
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Affiliation(s)
- Marija Buljan
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland; Empa, Swiss Federal Laboratories for Materials Science and Technology, 9014 St. Gallen, Switzerland
| | - Rodolfo Ciuffa
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Audrey van Drogen
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Anton Vichalkovski
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Martin Mehnert
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - George Rosenberger
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland; Columbia University Department of Systems Biology, New York, NY 10032, USA
| | - Sohyon Lee
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Markku Varjosalo
- Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland
| | - Lucia Espona Pernas
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Vincent Spegg
- Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland
| | - Berend Snijder
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Ruedi Aebersold
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland; Faculty of Science, University of Zurich, Zurich, Switzerland.
| | - Matthias Gstaiger
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland.
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21
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Lipner MB, Peng XL, Jin C, Xu Y, Gao Y, East MP, Rashid NU, Moffitt RA, Herrera Loeza SG, Morrison AB, Golitz BT, Vaziri C, Graves LM, Johnson GL, Yeh JJ. Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy. JCI Insight 2020; 5:129905. [PMID: 32213714 DOI: 10.1172/jci.insight.129905] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 03/18/2020] [Indexed: 12/11/2022] Open
Abstract
Over 55,000 people in the United States are diagnosed with pancreatic ductal adenocarcinoma (PDAC) yearly, and fewer than 20% of these patients survive a year beyond diagnosis. Chemotherapies are considered or used in nearly every PDAC case, but there is limited understanding of the complex signaling responses underlying resistance to these common treatments. Here, we take an unbiased approach to study protein kinase network changes following chemotherapies in patient-derived xenograft (PDX) models of PDAC to facilitate design of rational drug combinations. Proteomics profiling following chemotherapy regimens reveals that activation of JNK-JUN signaling occurs after 5-fluorouracil plus leucovorin (5-FU + LEU) and FOLFOX (5-FU + LEU plus oxaliplatin [OX]), but not after OX alone or gemcitabine. Cell and tumor growth assays with the irreversible inhibitor JNK-IN-8 and genetic manipulations demonstrate that JNK and JUN each contribute to chemoresistance and cancer cell survival after FOLFOX. Active JNK1 and JUN are specifically implicated in these effects, and synergy with JNK-IN-8 is linked to FOLFOX-mediated JUN activation, cell cycle dysregulation, and DNA damage response. This study highlights the potential for JNK-IN-8 as a biological tool and potential combination therapy with FOLFOX in PDAC and reinforces the need to tailor treatment to functional characteristics of individual tumors.
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Affiliation(s)
- Matthew B Lipner
- Department of Pharmacology.,Lineberger Comprehensive Cancer Center
| | | | - Chong Jin
- Lineberger Comprehensive Cancer Center.,Department of Biostatistics
| | - Yi Xu
- Lineberger Comprehensive Cancer Center
| | - Yanzhe Gao
- Lineberger Comprehensive Cancer Center.,Department of Pathology, and
| | - Michael P East
- Department of Pharmacology.,Lineberger Comprehensive Cancer Center
| | - Naim U Rashid
- Lineberger Comprehensive Cancer Center.,Department of Biostatistics
| | | | | | | | | | - Cyrus Vaziri
- Lineberger Comprehensive Cancer Center.,Department of Pathology, and
| | - Lee M Graves
- Department of Pharmacology.,Lineberger Comprehensive Cancer Center
| | - Gary L Johnson
- Department of Pharmacology.,Lineberger Comprehensive Cancer Center
| | - Jen Jen Yeh
- Department of Pharmacology.,Lineberger Comprehensive Cancer Center.,Department of Surgery, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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22
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Liao C, Cai B, Feng Y, Chen J, Wu Y, Zhuang J, Liu Z, Wu Y. Activation of JNK signaling promotes all- trans-retinal-induced photoreceptor apoptosis in mice. J Biol Chem 2020; 295:6958-6971. [PMID: 32265302 DOI: 10.1074/jbc.ra120.013189] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 04/02/2020] [Indexed: 11/06/2022] Open
Abstract
Disrupted clearance of all-trans-retinal (atRAL), a component of the visual (retinoid) cycle in the retina, may cause photoreceptor atrophy in autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD). However, the mechanisms underlying atRAL-induced photoreceptor loss remain elusive. Here, we report that atRAL activates c-Jun N-terminal kinase (JNK) signaling at least partially through reactive oxygen species production, which promoted mitochondria-mediated caspase- and DNA damage-dependent apoptosis in photoreceptor cells. Damage to mitochondria in atRAL-exposed photoreceptor cells resulted from JNK activation, leading to decreased expression of Bcl2 apoptosis regulator (Bcl2), increased Bcl2 antagonist/killer (Bak) levels, and cytochrome c (Cyt c) release into the cytosol. Cytosolic Cyt c specifically provoked caspase-9 and caspase-3 activation and thereby initiated apoptosis. Phosphorylation of JNK in atRAL-loaded photoreceptor cells induced the appearance of γH2AX, a sensitive marker for DNA damage, and was also associated with apoptosis onset. Suppression of JNK signaling protected photoreceptor cells against atRAL-induced apoptosis. Moreover, photoreceptor cells lacking Jnk1 and Jnk2 genes were more resistant to atRAL-associated cytotoxicity. The Abca4 -/- Rdh8 -/- mouse model displays defects in atRAL clearance that are characteristic of STGD1 and dry AMD. We found that JNK signaling was activated in the neural retina of light-exposed Abca4 -/- Rdh8 -/- mice. Of note, intraperitoneal administration of JNK-IN-8, which inhibits JNK signaling, effectively ameliorated photoreceptor degeneration and apoptosis in light-exposed Abca4 -/- Rdh8 -/- mice. We propose that pharmacological inhibition of JNK signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload.
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Affiliation(s)
- Chunyan Liao
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen City, FJ 361102, China
| | - Binxiang Cai
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen City, FJ 361102, China
| | - Yufeng Feng
- Department of Anesthesiology, First Affiliated Hospital of Xiamen University, Xiamen City, FJ 361003, China
| | - Jingmeng Chen
- School of Medicine, Xiamen University, Xiamen City, FJ 361102, China
| | - Yiping Wu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen City, FJ 361102, China
| | - Jingbin Zhuang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen City, FJ 361102, China
| | - Zuguo Liu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen City, FJ 361102, China
| | - Yalin Wu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen City, FJ 361102, China .,Xiamen Eye Center of Xiamen University, Xiamen City, FJ 361001, China.,Shenzhen Research Institute of Xiamen University, Shenzhen City, GD 518063, China
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Zhou R, Gao J, Xiang C, Liu Z, Zhang Y, Zhang J, Yang H. Salvianolic acid A attenuated myocardial infarction–induced apoptosis and inflammation by activating Trx. Naunyn Schmiedebergs Arch Pharmacol 2019; 393:991-1002. [DOI: 10.1007/s00210-019-01766-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 11/08/2019] [Indexed: 01/30/2023]
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Miura H, Kondo Y, Matsuda M, Aoki K. Cell-to-Cell Heterogeneity in p38-Mediated Cross-Inhibition of JNK Causes Stochastic Cell Death. Cell Rep 2019; 24:2658-2668. [PMID: 30184500 DOI: 10.1016/j.celrep.2018.08.020] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 07/17/2018] [Accepted: 08/07/2018] [Indexed: 12/30/2022] Open
Abstract
The stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38 are important players in cell-fate decisions in response to environmental stress signals. Crosstalk signaling between JNK and p38 is emerging as an important regulatory mechanism in inflammatory and stress responses. However, it is unknown how this crosstalk affects signaling dynamics, cell-to-cell variation, and cellular responses at the single-cell level. We established a multiplexed live-cell imaging system based on kinase translocation reporters to simultaneously monitor JNK and p38 activities with high specificity and sensitivity at single-cell resolution. Various stresses activated JNK and p38 with various dynamics. In all cases, p38 suppressed JNK activity in a cross-inhibitory manner. We demonstrate that p38 antagonizes JNK through both transcriptional and post-translational mechanisms. This cross-inhibition generates cellular heterogeneity in JNK activity after stress exposure. Our data indicate that this heterogeneity in JNK activity plays a role in fractional killing in response to UV stress.
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Affiliation(s)
- Haruko Miura
- Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Quantitative Biology Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan; Division of Quantitative Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan
| | - Yohei Kondo
- Quantitative Biology Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan; Division of Quantitative Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan; Department of Basic Biology, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan
| | - Michiyuki Matsuda
- Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Kazuhiro Aoki
- Quantitative Biology Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan; Division of Quantitative Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan; Department of Basic Biology, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan.
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Chuang HC, Tan TH. MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus. Cells 2019; 8:cells8111433. [PMID: 31766293 PMCID: PMC6912701 DOI: 10.3390/cells8111433] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 11/08/2019] [Accepted: 11/11/2019] [Indexed: 12/21/2022] Open
Abstract
T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt–AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt–AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE.
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Chuang HC, Tan TH. MAP4K3/GLK in autoimmune disease, cancer and aging. J Biomed Sci 2019; 26:82. [PMID: 31640697 PMCID: PMC6806545 DOI: 10.1186/s12929-019-0570-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 10/01/2019] [Indexed: 01/01/2023] Open
Abstract
MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22 years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor TFEB and retains TFEB in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKCθ through phosphorylating PKCθ at Ser-538 residue, leading to activation of IKK/NF-κB. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients; the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-RORγt complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer; the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates IQGAP1, resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. Due to the inhibitory function of HPK1/MAP4K1 in T-cell activation and the promoting effects of GLK on tumorigenesis, HPK1 and GLK dual inhibitors could be useful therapeutic drugs for cancer immunotherapy. In addition, GLK deficiency results in extension of lifespan in Caenorhabditis elegans and mice. Taken together, targeting MAP4K3 (GLK) may be useful for treating/preventing autoimmune disease, cancer metastasis/recurrence, and aging.
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Affiliation(s)
- Huai-Chia Chuang
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053, Taiwan
| | - Tse-Hua Tan
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053, Taiwan. .,Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, 77030, USA.
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Zhu H, Chen Y, Bai LC, Cao XR, Xu R. Different Effects of Melatonin on X-Rays-Irradiated Cancer Cells in a Dose-Dependent Manner. Dose Response 2019; 17:1559325819877271. [PMID: 31579126 PMCID: PMC6759722 DOI: 10.1177/1559325819877271] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/18/2018] [Accepted: 08/20/2019] [Indexed: 11/17/2022] Open
Abstract
The purpose of this study is to investigate the effects of melatonin on the radiosensitivity of HeLa cells. Concentration from 10 to 1000 µM of melatonin was used on HeLa cells before X-rays irradiation (IR). The cellular inactivation effect was analyzed by clonogenic assay, and cell growth was measured by MTT assay at various concentrations. Ten micrometer melatonin promoted the cell-killing effects of IR, while 1000-µM melatonin prevented IR-induced cellular inactivation. Further analysis revealed that 1000-µM melatonin protected the cells from IR-induced reactive oxygen species damage, as the oxidative stress measured by fluorescent microscopy and fluorescence-activated cell sorting using 2,7-dichlorofluorescein diacetate staining. This is further confirmed by melatonin receptor agonist, which has no antioxidant capacity. A 10-µM melatonin, on the contrary, enhanced the cell-killing effects of IR by activating c-Jun NH2-terminal kinase (JNK) signaling. c-Jun NH2-terminal kinase signaling activation was indicated by Western blot of phosphorylated JNK. We used JNK inhibitor to further confirm the involvement of JNK signaling in the cell-killing enhancement of 10-µM melatonin administration. Our results suggest the importance of dose-dependent effects in melatonin application for radiotherapy.
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Affiliation(s)
- Hao Zhu
- Radiology Department, Lanzhou University Second Hospital, Lanzhou, China
| | - Yong Chen
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Liang-Cai Bai
- Radiology Department, Lanzhou University Second Hospital, Lanzhou, China
| | - Xiang-Rong Cao
- Radiology Department, Lanzhou University Second Hospital, Lanzhou, China
| | - Rui Xu
- Radiology Department, Lanzhou University Second Hospital, Lanzhou, China
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Li Y, Xia YZ, Hu SM, Kong LY, Yang L. Tooniliatone A sensitizes multidrug resistant cancer cells by decreasing Bcl-xL via activation of JNK MAPK signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 62:152947. [PMID: 31102887 DOI: 10.1016/j.phymed.2019.152947] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/28/2019] [Accepted: 05/04/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND Multidrug resistance (MDR) refers to the phenotype of tumor cells that are resistant to various chemotherapeutic drugs with different structures and functions, which is clearly disadvantageous for patients. Finding a natural product that can effectively reverse the MDR of tumor cells is important for the treatment of patients. PURPOSE To prove that tooniliatone A (TA), a novel typical limonoid, can effectively reverse the MDR of tumor cells and to explore its mechanism of action. METHODS The MTT, CCK-8 and monoclonal formation assays, as well as flow cytometry, were used to evaluate the role of TA in reversing tumor multidrug resistance; then the mechanism of action for TA was explored by western blotting and real-time fluorescent quantitative PCR. RESULTS TA significantly reversed the MDR of the K562/MDR and MCF-7/MDR cell lines. TA can inhibit the anti-apoptotic protein Bcl-xL to make cells sensitive to common chemotherapeutic drugs and activate the SAPK/JNK pathway to promote phosphorylation of JNK and its downstream cJun protein. Small interfering RNA-mediated knockdown of JNK and cJun could antagonize the MDR reversal effect of TA and the inhibition of Bcl-xL by TA. Therefore, we hypothesized that TA activates the JNK pathway to increase the transcription of the proapoptotic protein Bim, thereby inhibiting Bcl-xL and reversing MDR in tumor cells. CONCLUSION Our study suggests that TA reverses tumor MDR by activating the SAPK/JNK pathway to inhibit the action of Bcl-xL. TA may be an effective tumor MDR reversal agent.
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Affiliation(s)
- Yun Li
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, China
| | - Yuan-Zheng Xia
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, China
| | - Sheng-Mou Hu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, China
| | - Ling-Yi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, China.
| | - Lei Yang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, China.
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An oral 2-hydroxypropyl-β-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma. Pharmacol Res 2019; 148:104400. [PMID: 31425749 DOI: 10.1016/j.phrs.2019.104400] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 08/12/2019] [Accepted: 08/13/2019] [Indexed: 11/21/2022]
Abstract
Validation of a small molecular compound targeting the oncogenic pathways is the primary approach for the development of the anti-cancer drugs. In the present study, we employed the computational mimic drug targets prediction software to foresee the molecular targets of a series of spirooxindole-pyrrolizidine derivatives, which were synthesized by our laboratory viatargeted combinational chemistry. We found that CPHSP, a novel spirooxindole-pyrrolizidine derivative, can target the MDM2/p53 signaling that is essential for the tumorigenesis of hepatocellular carcinoma (HCC). To validate its anti-tumoral function, we firstly established the soluble receipt of CPHSP through 2-hydroxypropyl-β-cyclodextrin (HBC) loading and showed that oral administration of HBC-loaded CPHSP significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice in the subcutaneously human hepatoma cells-xenografted nude mouse model of HCC. Immunohistochemistry staining showed that HBC-loaded CPHSP treatment suppressed the proliferation and induced apoptosis of tumor cells in this model. Our mechanistic studies showed that CPHSP treatment inhibited MDM2 protein expression and up-regulated p53 activity and activated MKK4/MKK7/JNK1/2/C-Jun signaling pathway, which resulted in cell cycle arrest and apoptosis of HepG2 cells in vitro. Moreover, we showed that JNK1/2 activation could also up-regulate p53 expression in CPHSP-treated HepG2 cells. Finally, we documented the antitumor activities of oral administration of the HBC-loaded CPHSP in the ML-1 bearing orthotopic mouse model. In summary, this study suggests that oral administration of HBC-loaded CPHSP is a safe and effective treatment for HCC, of which the clinical potency for patients with HCC warrants further studies.
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Wu S, Ma S, Yin X, Yi P, Liu J. An integrated PKD1-dependent signaling network amplifies IRE1 prosurvival signaling. J Biol Chem 2019; 294:11119-11130. [PMID: 31167779 DOI: 10.1074/jbc.ra118.003311] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 03/21/2019] [Indexed: 12/13/2022] Open
Abstract
Following the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), a condition known as ER stress in this compartment triggers an adaptive signaling pathway referred to as the unfolded protein response (UPR). The UPR aims at restoring ER homeostasis; if the ER stress cannot be resolved, apoptosis is triggered. However, the mechanisms responsible for regulating the balance between cell life and death decisions that occur after exposure to ER stress remain unclear. Protein kinase D1 (PKD1) has been reported to initiate protective signaling against oxidative stress or ischemia, two conditions that impinge on the induction of ER stress. In addition, the high levels of expression of PKD1, observed in highly proliferative cancers and tumors with poor prognosis, contribute to enhanced resistance to chemotherapy. In this study, we show that the ER stress inducers tunicamycin and thapsigargin lead to the activation of PKD1 in human prostate cancer PC-3 cells and in hepatoma HepG2 cells through a PKCδ-dependent mechanism. Moreover, our data indicate that PKD1 is required for the stabilization of inositol-requiring enzyme 1 (IRE1) and the subsequent regulation of its activity. PKD1 activation contributes to the phosphorylation of mitogen-activated protein kinase phosphatase 1, resulting in decreased IRE1-mediated c-Jun N-terminal kinase activation. This study unveils the existence of a novel PKD1-dependent prosurvival mechanism that is activated upon ER stress and selectively enhances IRE1 prosurvival signaling.
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Affiliation(s)
- Shiyong Wu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, Hubei, China
| | - Shumin Ma
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, Hubei, China
| | - Xueliang Yin
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, Hubei, China
| | - Ping Yi
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, Hubei, China
| | - Jianfeng Liu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, Hubei, China
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Regulation of Dual-Specificity Phosphatase (DUSP) Ubiquitination and Protein Stability. Int J Mol Sci 2019; 20:ijms20112668. [PMID: 31151270 PMCID: PMC6600639 DOI: 10.3390/ijms20112668] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 12/21/2022] Open
Abstract
Mitogen-activated protein kinases (MAPKs) are key regulators of signal transduction and cell responses. Abnormalities in MAPKs are associated with multiple diseases. Dual-specificity phosphatases (DUSPs) dephosphorylate many key signaling molecules, including MAPKs, leading to the regulation of duration, magnitude, or spatiotemporal profiles of MAPK activities. Hence, DUSPs need to be properly controlled. Protein post-translational modifications, such as ubiquitination, phosphorylation, methylation, and acetylation, play important roles in the regulation of protein stability and activity. Ubiquitination is critical for controlling protein degradation, activation, and interaction. For DUSPs, ubiquitination induces degradation of eight DUSPs, namely, DUSP1, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, and DUSP16. In addition, protein stability of DUSP2 and DUSP10 is enhanced by phosphorylation. Methylation-induced ubiquitination of DUSP14 stimulates its phosphatase activity. In this review, we summarize the knowledge of the regulation of DUSP stability and ubiquitination through post-translational modifications.
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Yang SA, Portilla JM, Mihailovic S, Huang YC, Deng WM. Oncogenic Notch Triggers Neoplastic Tumorigenesis in a Transition-Zone-like Tissue Microenvironment. Dev Cell 2019; 49:461-472.e5. [PMID: 30982664 PMCID: PMC6504601 DOI: 10.1016/j.devcel.2019.03.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 01/24/2019] [Accepted: 03/15/2019] [Indexed: 12/30/2022]
Abstract
During the initial stages of tumorigenesis, the tissue microenvironment where the pro-tumor cells reside plays a crucial role in determining the fate of these cells. Transition zones, where two types of epithelial cells meet, are high-risk sites for carcinogenesis, but the underlying mechanism remains largely unclear. Here, we show that persistent upregulation of Notch signaling induces neoplastic tumorigenesis in a transition zone between the salivary gland imaginal ring cells and the giant cells in Drosophila larvae. In this region, local endogenous JAK-STAT and JNK signaling creates a tissue microenvironment that is susceptible to oncogenic-Notch-induced tumorigenesis, whereas the rest of the salivary gland imaginal ring is refractory to Notch-induced tumor transformation. JNK signaling activates a matrix metalloprotease (MMP1) to promote Notch-induced tumorigenesis at the transition zone. These findings illustrate the significance of local endogenous inflammatory signaling in primary tumor formation.
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Affiliation(s)
- Sheng-An Yang
- Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA
| | - Juan-Martin Portilla
- Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA
| | - Sonja Mihailovic
- Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA
| | - Yi-Chun Huang
- Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA
| | - Wu-Min Deng
- Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA.
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Baltriukiene D, Kalvelyte A, Bukelskiene V. Induction of Apoptosis and Activation of JNK and p38 MAPK Pathways in Deoxynivalenol-Treated Cell Lines. Altern Lab Anim 2019; 35:53-9. [PMID: 17411352 DOI: 10.1177/026119290703500101] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Deoxynivalenol (DON) is a mycotoxin produced by what are thought to be the most prevalent toxin-producing fungi of the Fusarium genus. Here, we present the results of apoptosis induction, phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs), and expression of the c-Jun protein after DON treatment, in a pre-B lymphocyte REH cell line. In addition, human pre-T lymphocyte Jurkat, hamster kidney-derived BHK21 and mouse hepatoma MH-22a cells were used in comparative experiments in vitro. We found that the DON effect was cell origin-dependent and dose-dependent, with a significant slow-down of cell proliferation and increase of apoptotic cells in blood cell lines. BHK21 and MH-22a cells were less sensitive to the DON effect. In blood-derived REH and Jurkat cells, DON-induced apoptotic changes were preceded by an increase in JNK and p38 MAPKs phosphorylation, as well as in c-Jun expression. However, the activation of JNK phosphorylation and c-Jun expression were transient, but did not coincide with each other. An inhibitor of JNK1/2, SP600125, had a negligible negative effect on REH cell viability after DON treatment, demonstrating that JNK does not contribute to DON-induced apoptosis. In contrast, studies on the role of p38 MAPK revealed that p38 signalling is required for DON-induced apoptosis in REH cells.
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Lane K, Andres-Terre M, Kudo T, Monack DM, Covert MW. Escalating Threat Levels of Bacterial Infection Can Be Discriminated by Distinct MAPK and NF-κB Signaling Dynamics in Single Host Cells. Cell Syst 2019; 8:183-196.e4. [DOI: 10.1016/j.cels.2019.02.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 10/08/2018] [Accepted: 02/26/2019] [Indexed: 12/18/2022]
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35
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Watson CS, Koong L, Jeng YJ, Vinas R. Xenoestrogen interference with nongenomic signaling actions of physiological estrogens in endocrine cancer cells. Steroids 2019; 142:84-93. [PMID: 30012504 PMCID: PMC6339598 DOI: 10.1016/j.steroids.2018.06.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 06/15/2018] [Accepted: 06/27/2018] [Indexed: 11/20/2022]
Abstract
Rapid nongenomic signaling by estrogens (Es), initiated near the cell membrane, provides new explanations for the potent actions of environmental chemicals that imperfectly mimic physiological Es. These pathways can affect tumor growth, stabilization, or shrinkage via a number of signaling streams such as activation/inactivation of mitogen-activated protein kinases and caspases, generation of second messengers, and phospho-triggering of cyclin instability. Though prostate cancers are better known for their responsiveness to androgen deprivation, ∼17% of late stage tumors regress in response to high dose natural or pharmaceutical Es; however, the mechanisms at the cellular level are not understood. More accurate recent measurements show that estradiol (E2) levels decline in aging men, leading to the hypothesis that maintaining young male levels of E2 may prevent the growth of prostate cancers. Major contributions to reducing prostate cancer cell numbers included low E2 concentrations producing sustained ERK phospho-activation correlated with generation of reactive oxygen species causing cancer cell death, and phospho-activation of cyclin D1 triggering its rapid degradation by interrupting cell cycle progression. These therapeutic actions were stronger in early stage tumor cells (with higher membrane estrogen receptor levels), and E2 was far more effective compared to diethylstilbestrol (the most frequently prescribed E treatment). Xenoestrogens (XEs) exacerbated the growth of prostate cancer cells, and as we know from previous studies in pituitary cancer cells, can interfere with the nongenomic signaling actions of endogenous Es. Therefore, nongenomic actions of physiological levels of E2 may be important deterrents to the growth of prostate cancers, which could be undermined by the actions of XEs.
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Affiliation(s)
- Cheryl S Watson
- Biochemistry & Molecular Biology Dept., University of Texas Medical Branch, Galveston, TX 77555, United States.
| | - Luke Koong
- Biochemistry & Molecular Biology Dept., University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Yow-Jiun Jeng
- Biochemistry & Molecular Biology Dept., University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Rene Vinas
- Biochemistry & Molecular Biology Dept., University of Texas Medical Branch, Galveston, TX 77555, United States
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Bylicky MA, Mueller GP, Day RM. Radiation resistance of normal human astrocytes: the role of non-homologous end joining DNA repair activity. JOURNAL OF RADIATION RESEARCH 2019; 60:37-50. [PMID: 30423138 PMCID: PMC6373697 DOI: 10.1093/jrr/rry084] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/03/2018] [Indexed: 05/27/2023]
Abstract
Radiotherapy is a common modality for treatment of brain cancers, but it can induce long-term physiological and cognitive deficits. The responses of normal human brain cells to radiation is not well understood. Astrocytes have been shown to have a variety of protective mechanisms against oxidative stress and have been shown to protect neurons. We investigated the response of cultured normal human astrocytes (NHAs) to X-ray irradiation. Following exposure to 10 Gy X-irradiation, NHAs exhibited DNA damage as indicated by the formation of γ-H2AX foci. Western blotting showed that NHAs displayed a robust increase in expression of non-homologous end joining DNA repair enzymes within 15 min post-irradiation and increased expression of homologous recombination DNA repair enzymes ~2 h post-irradiation. The cell cycle checkpoint protein p21/waf1 was upregulated from 6-24 h, and then returned to baseline. Levels of DNA repair enzymes returned to basal ~48 h post-irradiation. NHAs re-entered the cell cycle and proliferation was observed at 6 days. In contrast, normal human mesenchymal stem cells (MSCs) failed to upregulate DNA repair enzymes and instead displayed sustained upregulation of p21/waf1, a cell cycle checkpoint marker for senescence. Ectopic overexpression of Ku70 was sufficient to protect MSCs from sustained upregulation of p21/waf1 induced by 10 Gy X-rays. These findings suggest that increased expression of Ku70 may be a key mechanism for the radioresistance of NHAs, preventing their accelerated senescence from high-dose radiation. These results may have implications for the development of novel targets for radiation countermeasure development.
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Affiliation(s)
- Michelle A Bylicky
- Department of Anatomy, Physiology, and Genetics, The Uniformed Services University of the Health Sciences, Jones Bridge Road, Bethesda, MD, USA
| | - Gregory P Mueller
- Department of Anatomy, Physiology, and Genetics, The Uniformed Services University of the Health Sciences, Jones Bridge Road, Bethesda, MD, USA
| | - Regina M Day
- Department of Pharmacology and Molecular Therapeutics, The Uniformed Services University of the Health Sciences, Jones Bridge Road, Bethesda, MD, USA
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Chatterjee J, Nairy RK, Langhnoja J, Tripathi A, Patil RK, Pillai PP, Mustak MS. ER stress and genomic instability induced by gamma radiation in mice primary cultured glial cells. Metab Brain Dis 2018; 33:855-868. [PMID: 29429012 DOI: 10.1007/s11011-018-0183-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Accepted: 01/04/2018] [Indexed: 11/28/2022]
Abstract
Ionizing radiation induces various pathophysiological conditions by altering central nervous system (CNS) homeostasis, leading to neurodegenerative diseases. However, the potential effect of ionizing radiation response on cellular physiology in glial cells is unclear. In the present study, micronucleus test, comet assay, and RT-PCR were performed to investigate the potential effect of gamma radiation in cultured oligodendrocytes and astrocytes with respect to genomic instability, Endoplasmic Reticulum (ER) stress, and inflammation. Further, we studied the effect of alteration in ER stress specific gene expression in cortex post whole body radiation in mice. Results showed that exposure of gamma radiation of 2Gy in-vitro cultured astrocytes and oligodendrocytes and 7Gy in-vivo induced ER stress and Inflammation along with profuse DNA damage and Chromosomal abnormality. Additionally, we observed downregulation of myelin basic protein levels in cultured oligodendrocytes exposed to radiation. The present data suggests that ER stress and pro inflammatory cytokines serve as the major players in inducing glial cell dysfunction post gamma irradiation along with induction of genomic instability. Taken together, these results indicate that ER stress, DNA damage, and inflammatory pathways may be critical events leading to glial cell dysfunction and subsequent cell death following exposure to ionizing radiation.
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Affiliation(s)
- Jit Chatterjee
- Department of Applied Zoology, Mangalore University, Mangalagangotri, Mangalore, Karnataka State, 574199, India
| | - Rajesha K Nairy
- Department of Physics, P.A College of Engineering, Mangalore, 574153, India
| | - Jaldeep Langhnoja
- Division of Neurobiology, Department of Zoology, Maharaja Sayajirao University of Baroda, Vadodara, 390002, India
| | - Ashutosh Tripathi
- Division of Neurobiology, Department of Zoology, Maharaja Sayajirao University of Baroda, Vadodara, 390002, India
| | - Rajashekhar K Patil
- Department of Applied Zoology, Mangalore University, Mangalagangotri, Mangalore, Karnataka State, 574199, India
| | - Prakash P Pillai
- Division of Neurobiology, Department of Zoology, Maharaja Sayajirao University of Baroda, Vadodara, 390002, India
| | - Mohammed S Mustak
- Department of Applied Zoology, Mangalore University, Mangalagangotri, Mangalore, Karnataka State, 574199, India.
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38
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Chen H, Liu RH. Potential Mechanisms of Action of Dietary Phytochemicals for Cancer Prevention by Targeting Cellular Signaling Transduction Pathways. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:3260-3276. [PMID: 29498272 DOI: 10.1021/acs.jafc.7b04975] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Cancer is a severe health problem that significantly undermines life span and quality. Dietary approach helps provide preventive, nontoxic, and economical strategies against cancer. Increased intake of fruits, vegetables, and whole grains are linked to reduced risk of cancer and other chronic diseases. The anticancer activities of plant-based foods are related to the actions of phytochemicals. One potential mechanism of action of anticancer phytochemicals is that they regulate cellular signal transduction pathways and hence affects cancer cell behaviors such as proliferation, apoptosis, and invasion. Recent publications have reported phytochemicals to have anticancer activities through targeting a wide variety of cell signaling pathways at different levels, such as transcriptional or post-transcriptional regulation, protein activation and intercellular messaging. In this review, we discuss major groups of phytochemicals and their regulation on cell signaling transduction against carcinogenesis via key participators, such as Nrf2, CYP450, MAPK, Akt, JAK/STAT, Wnt/β-catenin, p53, NF-κB, and cancer-related miRNAs.
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Affiliation(s)
- Hongyu Chen
- Department of Food Science , Cornell University , Ithaca , New York 14853-7201 , United States
- Institute of Edible Fungi , Shanghai Academy of Agriculture Science , Shanghai 201403 , China
| | - Rui Hai Liu
- Department of Food Science , Cornell University , Ithaca , New York 14853-7201 , United States
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39
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Wang X, Beute WK, Harrison JS, Studzinski GP. JNK1 as a signaling node in VDR-BRAF induction of cell death in AML. J Steroid Biochem Mol Biol 2018; 177:149-154. [PMID: 28765039 PMCID: PMC5788744 DOI: 10.1016/j.jsbmb.2017.07.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/15/2017] [Accepted: 07/07/2017] [Indexed: 12/12/2022]
Abstract
Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant diseases. However, given the strong preclinical evidence of anti-neoplastic activity and the epidemiological associations suggesting that vitamin D compounds may have a place in cancer therapy, attempts are continuing to devise new approaches to their therapeutic use. This laboratory has developed a strategy to enhance the effectiveness of the currently standard therapy of Acute Myeloid Leukemia (AML) by the immediate addition of the vitamin D2 analog Doxercalciferol combined with the plant polyphenol-derived Carnosic acid to AML cells previously treated with Cytarabine (AraC). Enhancement of AML cell death was noted to be dependent on VDR and BRAF kinase. Here we document that the stress-related kinase JNK is an important additional component of cell death enhancement in this protocol. Either the Knock-down or the inhibition of JNK activity reduced the enhancement of AraC-induced cell death, and we show that JNK signaling to the apoptosis regulator BIM and Caspase executioners of cell death are downstream of VDR and BRAF. A clear understanding of the molecular basis for the increased efficacy of AraC in the therapy of AML is expected to bring this regimen to a clinical trial.
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Affiliation(s)
- Xuening Wang
- Department of Pathology & Laboratory Medicine, New Jersey Medical School, Rutgers, Newark, NJ, 07103, USA
| | - William K Beute
- Department of Pathology & Laboratory Medicine, New Jersey Medical School, Rutgers, Newark, NJ, 07103, USA
| | - Jonathan S Harrison
- Department of Medicine, University of Connecticut, Farmington, CT, 06030, USA
| | - George P Studzinski
- Department of Pathology & Laboratory Medicine, New Jersey Medical School, Rutgers, Newark, NJ, 07103, USA.
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40
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Xiao H, Liu X, Wang Y, Wang G, Yin C. Angiotensin‑(1‑7) prevents lipopolysaccharide‑induced hepatocellular inflammatory response by inhibiting the p38MAPK/AP‑1 signaling pathway. Mol Med Rep 2018; 17:5492-5497. [PMID: 29393446 DOI: 10.3892/mmr.2018.8527] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 09/26/2017] [Indexed: 11/06/2022] Open
Abstract
The pathological mechanism of lipopolysaccharide (LPS)‑induced liver injury involves a number of inflammatory mediators and cytokines. Angiotensin (Ang)‑(1‑7), a ligand for the proto‑oncogene Mas (Mas) receptor, antagonizes the actions of Ang II in the renin angiotensin system and exerts an anti‑inflammatory effect on LPS‑induced macrophages. The present study investigated the potential role of Ang‑(1‑7) in the regulation of inflammatory responses in LPS‑induced hepatocytes using the rat liver BRL cell line. The results of the present study demonstrated that the inflammatory mediator, tumor necrosis factor (TNF)‑α, its upstream transcriptional regulatory factor activator protein (AP)‑1 and p38 mitogen activated protein kinase (MAPK) which were detected by reverse transcription‑quantitative polymerase chain reaction and western blotting were upregulated in LPS‑induced hepatic cells in a time‑dependent manner, peaking 12 h following LPS stimulation. By contrast, treatment with Ang‑(1‑7) significantly attenuated the expression of TNF‑α, AP‑1 and p38MAPK in a concentration‑dependent manner. The anti‑inflammatory effect of Ang‑(1‑7) was reversed by the Mas receptor selective antagonist, A779, in BRL cells. Furthermore, the p38MAPK inhibitor, SB 203580, abolished the protective effects of Ang‑(1‑7), suggesting the involvement of the p38MAPK pathway in the anti‑inflammatory activity of Ang‑(1‑7). The results of the present study indicated that Ang‑(1‑7) may serve an anti‑inflammatory role in LPS‑induced hepatocyte injury via the regulation of the p38MAPK/AP‑1 signaling pathway.
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Affiliation(s)
- Hongli Xiao
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Xiaoya Liu
- Department of Internal Medicine, Beijing Obstetrics and Gynaecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Yan Wang
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Guoxing Wang
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Chenghong Yin
- Department of Internal Medicine, Beijing Obstetrics and Gynaecology Hospital, Capital Medical University, Beijing 100026, P.R. China
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41
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Rusin A, Seymour C, Mothersill C. Chronic fatigue and immune deficiency syndrome (CFIDS), cellular metabolism, and ionizing radiation: a review of contemporary scientific literature and suggested directions for future research. Int J Radiat Biol 2018; 94:212-228. [DOI: 10.1080/09553002.2018.1422871] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Andrej Rusin
- Department of Biology, McMaster University, Hamilton, Canada
| | - Colin Seymour
- Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Canada
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42
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Jia M, Zhu M, Wang M, Sun M, Qian J, Ding F, Chang J, Wei Q. Genetic variants of GADD45A, GADD45B and MAPK14 predict platinum-based chemotherapy-induced toxicities in Chinese patients with non-small cell lung cancer. Oncotarget 2018; 7:25291-303. [PMID: 26993769 PMCID: PMC5041904 DOI: 10.18632/oncotarget.8052] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/29/2016] [Indexed: 12/23/2022] Open
Abstract
The JNK and P38α pathways play a crucial role in tissue homeostasis, apoptosis and autophagy under genotoxic stresses, but it is unclear whether single nucleotide polymorphisms (SNPs) of genes in these pathways play a role in platinum-based chemotherapy-induced toxicities in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 11 selected, independent, potentially functional SNPs of nine genes in the JNK and P38α pathways in 689 patients with advanced NSCLC treated with platinum-combination chemotherapy regimens. Associations between these SNPs and chemotherapy toxicities were tested in a discovery group of 345 patients and then validated in a replication group of 344 patients. In both discovery and validation groups as well as their pooled analysis, carriers of GADD45B rs2024144T variant allele had a significantly higher risk for severe hematologic toxicity and carriers of MAPK14 rs3804451A variant allele had a significantly higher risk for both overall toxicity and gastrointestinal toxicity. In addition, carriers of GADD45A rs581000C had a lower risk of anemia, while carriers of GADD45B rs2024144T had a significantly higher risk for leukocytopenia or agranulocytosis. The present study provides evidence that genetic variants in genes involved in the JNK and P38α pathways may predict platinum-based chemotherapy toxicity outcomes in patients with advanced NSCLC. Larger studies of other patient populations are needed to validate our findings.
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Affiliation(s)
- Ming Jia
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Meiling Zhu
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China
| | - Mengyun Wang
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Menghong Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Ji Qian
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Fudan University, Shanghai, 200032, China
| | - Fei Ding
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Jianhua Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Qingyi Wei
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, 27710, USA
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43
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Xiao B, Li L, Xu C, Zhao S, Lin L, Cheng J, Yang W, Cong W, Kan G, Cui S. Transcriptome sequencing of the naked mole rat ( Heterocephalus glaber) and identification of hypoxia tolerance genes. Biol Open 2017; 6:1904-1912. [PMID: 29138211 PMCID: PMC5769652 DOI: 10.1242/bio.028548] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The naked mole rat (NMR; Heterocephalus glaber) is a small rodent species found in regions of Kenya, Ethiopia and Somalia. It has a high tolerance for hypoxia and is thus considered one of the most important natural models for studying hypoxia tolerance mechanisms. The various mechanisms underlying the NMR's hypoxia tolerance are beginning to be understood at different levels of organization, and next-generation sequencing methods promise to expand this understanding to the level of gene expression. In this study, we examined the sequence and transcript abundance data of the muscle transcriptome of NMRs exposed to hypoxia using the Illumina HiSeq 2500 system to clarify the possible genomic adaptive responses to the hypoxic underground surroundings. The RNA-seq raw FastQ data were mapped against the NMR genome. We identified 2337 differentially expressed genes (DEGs) by comparison of the hypoxic and control groups. Functional annotation of the DEGs by gene ontology (GO) analysis revealed enrichment of hypoxia stress-related GO categories, including ‘biological regulation’, ‘cellular process’, ‘ion transport’ and ‘cell-cell signaling’. Enrichment of DEGs in signaling pathways was analyzed against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to identify possible interactions between DEGs. The results revealed significant enrichment of DEGs in focal adhesion, the mitogen-activated protein kinase (MAPK) signaling pathway and the glycine, serine and threonine metabolism pathway. Furthermore, inhibition of DEGs (STMN1, MAPK8IP1 and MAPK10) expression induced apoptosis and arrested cell growth in NMR fibroblasts following hypoxia. Thus, this global transcriptome analysis of NMRs can provide an important genetic resource for the study of hypoxia tolerance in mammals. Furthermore, the identified DEGs may provide important molecular targets for biomedical research into therapeutic strategies for stroke and cardiovascular diseases. Summary: The identified differentially expressed genes in naked mole rat exposed to hypoxia may provide an important genetic resource for further analyses of mammalian tolerance to hypoxia and molecular targets for the prevention of ischemic diseases. This article has an associated First Person interview with the first author of the paper as part of the supplementary information.
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Affiliation(s)
- Bang Xiao
- Laboratory Animal Centre, The Second Military Medical University, Shanghai 200433, China
| | - Li Li
- Department of Training, The Second Military Medical University, Shanghai 20043, China
| | - Chang Xu
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Shanmin Zhao
- Laboratory Animal Centre, The Second Military Medical University, Shanghai 200433, China
| | - Lifang Lin
- Laboratory Animal Centre, The Second Military Medical University, Shanghai 200433, China
| | - Jishuai Cheng
- Laboratory Animal Centre, The Second Military Medical University, Shanghai 200433, China
| | - Wenjing Yang
- Laboratory Animal Centre, The Second Military Medical University, Shanghai 200433, China
| | - Wei Cong
- Laboratory Animal Centre, The Second Military Medical University, Shanghai 200433, China
| | - Guanghan Kan
- China Astronaut Research and Training Center, Beijing 100094, China
| | - Shufang Cui
- Laboratory Animal Centre, The Second Military Medical University, Shanghai 200433, China
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44
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Gao G, Zhang T, Wang Q, Reddy K, Chen H, Yao K, Wang K, Roh E, Zykova T, Ma W, Ryu J, Curiel-Lewandrowski C, Alberts D, Dickinson SE, Bode AM, Xing Y, Dong Z. ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK. Mol Cancer Ther 2017; 16:1843-1854. [PMID: 28655782 DOI: 10.1158/1535-7163.mct-17-0212] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 05/12/2017] [Accepted: 06/13/2017] [Indexed: 01/09/2023]
Abstract
Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. Mol Cancer Ther; 16(9); 1843-54. ©2017 AACR.
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Affiliation(s)
- Ge Gao
- The Hormel Institute, University of Minnesota, Austin, Minnesota.,School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Tianshun Zhang
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Qiushi Wang
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Kanamata Reddy
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Hanyong Chen
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Ke Yao
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Keke Wang
- The Hormel Institute, University of Minnesota, Austin, Minnesota.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, P.R. China
| | - Eunmiri Roh
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Tatyana Zykova
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Weiya Ma
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Joohyun Ryu
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | | | - David Alberts
- The University of Arizona Cancer Center, Tucson, Arizona
| | | | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Ying Xing
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China.
| | - Zigang Dong
- The Hormel Institute, University of Minnesota, Austin, Minnesota. .,China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, P.R. China
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Fischer S, Marquart KF, Pieper LA, Fieder J, Gamer M, Gorr I, Schulz P, Bradl H. miRNA engineering of CHO cells facilitates production of difficult-to-express proteins and increases success in cell line development. Biotechnol Bioeng 2017; 114:1495-1510. [PMID: 28262952 PMCID: PMC6084326 DOI: 10.1002/bit.26280] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 01/25/2017] [Accepted: 03/01/2017] [Indexed: 01/05/2023]
Abstract
In recent years, coherent with growing biologics portfolios also the number of complex and thus difficult-to-express (DTE) therapeutic proteins has increased considerably. DTE proteins challenge bioprocess development and can include various therapeutic protein formats such as monoclonal antibodies (mAbs), multi-specific affinity scaffolds (e.g., bispecific antibodies), cytokines, or fusion proteins. Hence, the availability of robust and versatile Chinese hamster ovary (CHO) host cell factories is fundamental for high-yielding bioprocesses. MicroRNAs (miRNAs) have emerged as potent cell engineering tools to improve process performance of CHO manufacturing cell lines. However, there has not been any report demonstrating the impact of beneficial miRNAs on industrial cell line development (CLD) yet. To address this question, we established novel CHO host cells constitutively expressing a pro-productive miRNA: miR-557. Novel host cells were tested in two independent CLD campaigns using two different mAb candidates including a normal as well as a DTE antibody. Presence of miR-557 significantly enhanced each process step during CLD in a product independent manner. Stable expression of miR-557 increased the probability to identify high-producing cell clones. Furthermore, production cell lines derived from miR-557 expressing host cells exhibited significantly increased final product yields in fed-batch cultivation processes without compromising product quality. Strikingly, cells co-expressing miR-557 and a DTE antibody achieved a twofold increase in product titer compared to clones co-expressing a negative control miRNA. Thus, host cell engineering using miRNAs represents a promising tool to overcome limitations in industrial CLD especially with regard to DTE proteins. Biotechnol. Bioeng. 2017;114: 1495-1510. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Simon Fischer
- Early Stage Bioprocess Development, Boehringer Ingelheim GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach, Germany.,Cell Culture Development CMB, Boehringer Ingelheim GmbH & Co. KG, Biberach, Germany
| | - Kim F Marquart
- Early Stage Bioprocess Development, Boehringer Ingelheim GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach, Germany
| | - Lisa A Pieper
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Juergen Fieder
- Early Stage Bioprocess Development, Boehringer Ingelheim GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach, Germany
| | - Martin Gamer
- Early Stage Bioprocess Development, Boehringer Ingelheim GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach, Germany
| | - Ingo Gorr
- Early Stage Bioprocess Development, Boehringer Ingelheim GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach, Germany
| | - Patrick Schulz
- Cell Culture Development CMB, Boehringer Ingelheim GmbH & Co. KG, Biberach, Germany
| | - Harald Bradl
- Cell Culture Development CMB, Boehringer Ingelheim GmbH & Co. KG, Biberach, Germany
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Houng JY, Tai TS, Hsu SC, Hsu HF, Hwang TS, Lin CJ, Fang LW. Glossogyne tenuifolia ( Hsiang-ju) extract suppresses T cell activation by inhibiting activation of c-Jun N-terminal kinase. Chin Med 2017; 12:9. [PMID: 28400856 PMCID: PMC5387255 DOI: 10.1186/s13020-017-0130-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 03/17/2017] [Indexed: 11/30/2022] Open
Abstract
Background Glossogyne tenuifolia (GT) (Hsiang-ju) is a Chinese herbal medicine previously exhibited an anti-inflammatory activity. This study aimed to investigate the effect of GT ethanol extract (GTE) on T cell-mediated adaptive immunity. Methods Human peripheral blood mononuclear cells (PBMCs) and Jurkat T cells were activated by phytohemagglutinin in the presence of various doses (3.13–50 μg/mL) of GTE. The effect of GTE on T cell activation was examined by a proliferation assay of activated PBMCs and the level of the activation marker CD69 on the surface of activated Jurkat T cells. Apoptosis was determined by propidium iodide staining in hypotonic solution. Signaling pathway molecules were assessed by western blotting. Results Glossogyne tenuifolia ethanol extract was demonstrated to inhibit T cell activation, not only in the proliferation of human PBMCs at the concentrations of 12.5, 25 and 50 μg/mL (P = 0.0118, 0.0030 and 0.0021) but also in the CD69 expression in Jurkat cells, which was not due to the cytotoxicity of GTE. The presence of GTE did not change the activity of nuclear factor kappa-light-chain-enhancer of activated B cells or extracellular signal-regulated kinase upon T cell activation. In addition, GTE significantly reduced activation of c-Jun N-terminal kinase (JNK) (P = 0.0167) and p38 (P = 0.0278). Furthermore, decreased JNK activation mediated the preventive effect of GTE on T cell activation-induced cell death (AICD). Conclusion Glossogyne tenuifolia ethanol extract inhibited T cell activation of Jurkat cells and freshly prepared human PBMCs due to suppression of JNK activity. Furthermore, GTE inhibited AICD by blocking prolonged JNK phosphorylation in activated T cells. Taken together, the anti-inflammatory effects exerted by GTE were mediated via suppression of JNK phosphorylation in T cell activation. Electronic supplementary material The online version of this article (doi:10.1186/s13020-017-0130-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jer-Yiing Houng
- Department of Nutrition, I-Shou University, No.8, Yida Rd., Yanchao District, Kaohsiung City, 82445 Taiwan
| | - Tzong-Shyuan Tai
- Department of Medical Research, E-Da Hospital, Kaohsiung City, 82445 Taiwan.,School of Medicine for International Students, I-Shou University, Kaohsiung City, 82445 Taiwan
| | - Shu-Ching Hsu
- National Institute of Infectious Diseases and Vaccinology, NHRI, Miaoli County, 35053 Taiwan.,Department of Medical Research, Show-Chwan Memorial Hospital, Changhua County, 50008 Taiwan
| | - Hsia-Fen Hsu
- Department of Nutrition, I-Shou University, No.8, Yida Rd., Yanchao District, Kaohsiung City, 82445 Taiwan
| | - Tzann-Shun Hwang
- Graduate Institute of Biotechnology, Chinese Culture University, Taipei City, 11114 Taiwan
| | - Chih-Jiun Lin
- Department of Leisure and Recreation Management, Da-Yeh University, Changhua County, 51591 Taiwan
| | - Li-Wen Fang
- Department of Nutrition, I-Shou University, No.8, Yida Rd., Yanchao District, Kaohsiung City, 82445 Taiwan
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Solinas G, Becattini B. JNK at the crossroad of obesity, insulin resistance, and cell stress response. Mol Metab 2016; 6:174-184. [PMID: 28180059 PMCID: PMC5279903 DOI: 10.1016/j.molmet.2016.12.001] [Citation(s) in RCA: 280] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 11/28/2016] [Accepted: 12/02/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The cJun-N-terminal-kinase (JNK) plays a central role in the cell stress response, with outcomes ranging from cell death to cell proliferation and survival, depending on the specific context. JNK is also one of the most investigated signal transducers in obesity and insulin resistance, and studies have identified new molecular mechanisms linking obesity and insulin resistance. Emerging evidence indicates that whereas JNK1 and JNK2 isoforms promote the development of obesity and insulin resistance, JNK3 activity protects from excessive adiposity. Furthermore, current evidence indicates that JNK activity within specific cell types may, in specific stages of disease progression, promote cell tolerance to the stress associated with obesity and type-2 diabetes. SCOPE OF REVIEW This review provides an overview of the current literature on the role of JNK in the progression from obesity to insulin resistance, NAFLD, type-2 diabetes, and diabetes complications. MAJOR CONCLUSION Whereas current evidence indicates that JNK1/2 inhibition may improve insulin sensitivity in obesity, the role of JNK in the progression from insulin resistance to diabetes, and its complications is largely unresolved. A better understanding of the role of JNK in the stress response to obesity and type-2 diabetes, and the development of isoform-specific inhibitors with specific tissue distribution will be necessary to exploit JNK as possible drug target for the treatment of type-2 diabetes.
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Affiliation(s)
- Giovanni Solinas
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden.
| | - Barbara Becattini
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden
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Liu Y, Jiang L, Li X. κ-carrageenan-derived pentasaccharide attenuates Aβ25–35-induced apoptosis in SH-SY5Y cells via suppression of the JNK signaling pathway. Mol Med Rep 2016; 15:285-290. [DOI: 10.3892/mmr.2016.6006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 09/15/2016] [Indexed: 11/05/2022] Open
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Jia M, Xu Y, Zhu M, Wang M, Sun M, Qian J, Chang J, Wei Q. The P38α rs3804451 Variant Predicts Chemotherapy Response and Survival of Patients with Non-Small Cell Lung Cancer Treated with Platinum-Based Chemotherapy. Transl Oncol 2016; 9:531-539. [PMID: 27835790 PMCID: PMC5109261 DOI: 10.1016/j.tranon.2016.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 09/16/2016] [Accepted: 09/19/2016] [Indexed: 01/01/2023] Open
Abstract
The JNK and P38α pathways play an important role in the sensitivity and outcomes of chemotherapy. We hypothesize that functional single nucleotide polymorphisms (SNPs) of genes of these pathways modulate outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy (PBC). We selectively genotyped 11 independent, potentially functional SNPs of 9 genes in the JNK and P38α pathways first in a discovery group of 355 patients with advanced NSCLC treated with PBC, and we evaluated their associations with progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards regression analysis. Then, resultant significant SNPs were further validated in a replication group of 355 patients. In both discovery and validation groups as well as their combined analysis, the MAPK14 rs3804451GA/AA genotypes showed a strong association with a reduced PFS (adjusted hazards ratio [HR]=1.39; 95% confidence interval [CI]=1.16-1.66; P=.0003) and OS (adjusted HR=1.41; 95% CI=1.11-1.80; P=.005) compared with the wild-type GG genotype. In contrast, patients with or without the MAPK14 rs3804451A allele had no significant difference in OS in response to tyrosine-kinase inhibitor treatment (adjusted HR=0.86; 95% CI=0.56-1.33; P=.505). The present study provides evidence that the MAPK14 rs3804451 G>A variant may modulate survival outcomes in patients with advanced NSCLC treated with PBC. Larger studies of additional patient populations are needed to validate our findings.
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Affiliation(s)
- Ming Jia
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, 270 Dongan Road, Xuhui, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Xuhui, Shanghai, 200032, China.
| | - Yuan Xu
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, 270 Dongan Road, Xuhui, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Xuhui, Shanghai, 200032, China.
| | - Meiling Zhu
- Department of Oncology, Xinhua Hospital affiliated to Shanghai Jiaotong University, School of Medicine, No. 1665, Kong Jiang Road, Shanghai, 200092, China.
| | - Mengyun Wang
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, 270 Dongan Road, Xuhui, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Xuhui, Shanghai, 200032, China.
| | - Menghong Sun
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Xuhui, Shanghai, 200032, China; Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Xuhui, Shanghai, 200032, China.
| | - Ji Qian
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Fudan University, Shanghai, 200032, China.
| | - Jianhua Chang
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Xuhui, Shanghai, 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Xuhui, Shanghai, 200032, China.
| | - Qingyi Wei
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, 270 Dongan Road, Xuhui, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Xuhui, Shanghai, 200032, China; Duke Cancer Institute, Duke University Medical Center, and Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA.
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Ren Y, Yeoh KW, Hao P, Kon OL, Sze SK. Irradiation of Epithelial Carcinoma Cells Upregulates Calcium-Binding Proteins That Promote Survival under Hypoxic Conditions. J Proteome Res 2016; 15:4258-4264. [PMID: 27790916 DOI: 10.1021/acs.jproteome.6b00340] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Hypoxia is thought to promote tumor radio-resistance via effects on gene expression in cancer cells that modulate their metabolism, proliferation, and DNA repair pathways to enhance survival. Here we demonstrate for the first time that under hypoxic condition A431 epithelial carcinoma cells exhibit increased viability when exposed to low-dose γ-irradiation, indicating that radiotherapy can promote tumor cell survival when oxygen supply is limited. When assessed using iTRAQ quantitative proteomics and Western blotting, irradiated tumor cells were observed to significantly up-regulate the expression of calcium-binding proteins CALM1, CALU, and RCN1, suggesting important roles for these mediators in promoting tumor cell survival during hypoxia. Accordingly, shRNA-knockdown of CALM1, CALU, and RCN1 expression reduced hypoxic tumor cell resistance to low-dose radiation and increased apoptosis. These data indicate that γ-irradiation of hypoxic tumor cells induces up-regulation of calcium-binding proteins that promote cancer cell survival and may limit the efficacy of radiotherapy in the clinic.
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Affiliation(s)
- Yan Ren
- School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551.,BGI-Shenzhen , Yantian District Beishan Industrial Zone 11th building, Shenzhen, China 518083
| | - Kheng Wei Yeoh
- National Cancer Centre Singapore , Department of Radiation Oncology, 11 Hospital Drive, Singapore 169610
| | - Piliang Hao
- School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551
| | - Oi Lian Kon
- National Cancer Centre Singapore , Division of Medical Sciences, 11 Hospital Drive, Singapore 169610
| | - Siu Kwan Sze
- School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551
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