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Kundu G, Ghasemi M, Yim S, Rohil A, Xin C, Ren L, Srivastava S, Akinfolarin A, Kumar S, Srivastava GP, Sabbisetti VS, Murugaiyan G, Ajay AK. STAT3 Protein-Protein Interaction Analysis Finds P300 as a Regulator of STAT3 and Histone 3 Lysine 27 Acetylation in Pericytes. Biomedicines 2024; 12:2102. [PMID: 39335615 PMCID: PMC11428717 DOI: 10.3390/biomedicines12092102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Signal transducer and activator of transcription 3 (STAT3) is a member of the cytoplasmic inducible transcription factors and plays an important role in mediating signals from cytokines, chemokines, and growth factors. We and others have found that STAT3 directly regulates pro-fibrotic signaling in the kidney. The STAT3 protein-protein interaction plays an important role in activating its transcriptional activity. It is necessary to identify these interactions to investigate their function in kidney disease. Here, we investigated the protein-protein interaction among three species to find crucial interactions that can be targeted to alleviate kidney disease. METHOD In this study, we examined common protein-protein interactions leading to the activation or downregulation of STAT3 among three different species: humans (Homo sapiens), mice (Mus musculus), and rabbits (Oryctolagus cuniculus). Further, we chose to investigate the P300 and STAT3 interaction and performed studies of the activation of STAT3 using IL-6 and inhibition of the P300 by its specific inhibitor A-485 in pericytes. Next, we performed immunoprecipitation to confirm whether A-485 inhibits the binding of P300 to STAT3. RESULTS Using the STRING application from ExPASy, we found that six proteins, including PIAS3, JAK1, JAK2, EGFR, SRC, and EP300, showed highly confident interactions with STAT3 in humans, mice, and rabbits. We also found that IL-6 treatment increased the acetylation of STAT3 and increased histone 3 lysine acetylation (H3K27ac). Furthermore, we found that the disruption of STAT3 and P300 interaction by the P300 inhibitor A-485 decreased STAT3 acetylation and H3K27ac. Finally, we confirmed that the P300 inhibitor A-485 inhibited the binding of STAT3 with P300, which inhibited its transcriptional activity by reducing the expression of Ccnd1 (Cyclin D1). CONCLUSIONS Targeting the P300 protein interaction with STAT3 may alleviate STAT3-mediated fibrotic signaling in humans and other species.
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Affiliation(s)
- Gautam Kundu
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- US Military HIV Research Program (MHRP), Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA
| | - Maryam Ghasemi
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Seungbin Yim
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Ayanna Rohil
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Cuiyan Xin
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Leo Ren
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | | | - Akinwande Akinfolarin
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Subodh Kumar
- Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Gyan P. Srivastava
- Department of Electrical Engineering & Computer Science, University of Missouri, Columbia, MO 65211, USA
| | - Venkata S. Sabbisetti
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Gopal Murugaiyan
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Amrendra K. Ajay
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Center for Polycystic Kidney Disease, Harvard Medical School, Boston, MA 02115, USA
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Tahmasebi Dehkordi H, Khaledi F, Ghasemi S. Immunological processes of enhancers and suppressors of long non-coding RNAs associated with brain tumors and inflammation. Int Rev Immunol 2024; 43:178-196. [PMID: 37974420 DOI: 10.1080/08830185.2023.2280581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 11/02/2023] [Indexed: 11/19/2023]
Abstract
Immunological processes, such as inflammation, can both cause tumor suppression and cancer progression. Moreover, deregulated levels of long non-coding RNA (lncRNA) expression in the brain may cause inflammation and lead to the growth of tumors. Like other biological processes, the immune system's role in cancer is complicated, varies, and can help or hurt the cancer's maintenance. According to research, inflammation and brain cancer are correlated via several signaling pathways. A variety of lncRNAs have recently been revealed to influence cancer by modulating inflammatory pathways. As a result, lncRNAs have the potential to influence carcinogenesis, tumor formation, or tumor suppression via an increase or decrease in inflammation functions. Although the study and targeting of lncRNAs have made great progress in the treatment of cancer, there are definitely limitations and challenges. Using new technologies like nanocarriers and cell-penetrating peptides (CPPs) to target treatments without hurting healthy body tissues has shown to be very effective. In this review article, we have collected significantly related lncRNAs and their inhibitory or stimulating roles in inflammation and brain cancer for the first time. However, there are limitations, such as side effects and damage to normal tissues. With the advancement of new targeting technologies, these lncRNAs may be candidates for the specific targeting therapy of brain cancers by limiting inflammation or stimulating the immune system against them in the future.
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Affiliation(s)
- Hossein Tahmasebi Dehkordi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Fatemeh Khaledi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sorayya Ghasemi
- Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Chen Y, Zhai N, Zhu Y, Yue P, Verma N, Brotherton-Pleiss C, Fu W, Nakamura K, Chen W, Kawakami J, Murali R, Tius MA, Lopez-Tapia F, Turkson J. Azetidine ring, salicylic acid, and salicylic acid bioisosteres as determinants of the binding characteristics of novel potent compounds to Stat3. Bioorg Med Chem Lett 2024; 97:129565. [PMID: 38008341 DOI: 10.1016/j.bmcl.2023.129565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 11/08/2023] [Accepted: 11/22/2023] [Indexed: 11/28/2023]
Affiliation(s)
- Yue Chen
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
| | - Ning Zhai
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
| | - Yinsong Zhu
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
| | - Peibin Yue
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
| | - Nagendra Verma
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
| | - Christine Brotherton-Pleiss
- Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, 701 Ilalo St., Honolulu, HI 96813, USA; Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI 96825, USA
| | - Wenzhen Fu
- Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, 701 Ilalo St., Honolulu, HI 96813, USA; Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI 96825, USA
| | - Kayo Nakamura
- Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI 96825, USA
| | - Weiliang Chen
- Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI 96825, USA
| | - Joel Kawakami
- Department of Natural Sciences and Mathematics, Chaminade University, 3140 Waialae Avenue, Honolulu, HI 96816, USA
| | - Ramachandran Murali
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
| | - Marcus A Tius
- Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, 701 Ilalo St., Honolulu, HI 96813, USA; Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI 96825, USA
| | - Francisco Lopez-Tapia
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
| | - James Turkson
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
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Wang W, Lopez McDonald MC, Kim C, Ma M, Pan Z(T, Kaufmann C, Frank DA. The complementary roles of STAT3 and STAT1 in cancer biology: insights into tumor pathogenesis and therapeutic strategies. Front Immunol 2023; 14:1265818. [PMID: 38022653 PMCID: PMC10663227 DOI: 10.3389/fimmu.2023.1265818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
STATs are a family of transcription factors that regulate many critical cellular processes such as proliferation, apoptosis, and differentiation. Dysregulation of STATs is frequently observed in tumors and can directly drive cancer pathogenesis. STAT1 and STAT3 are generally viewed as mediating opposite roles in cancer development, with STAT1 suppressing tumorigenesis and STAT3 promoting oncogenesis. In this review, we investigate the specific roles of STAT1 and STAT3 in normal physiology and cancer biology, explore their interactions with each other, and offer insights into therapeutic strategies through modulating their transcriptional activity.
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Affiliation(s)
| | | | | | | | | | | | - David A. Frank
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, United States
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Ajith A, Subbiah U. In silico prediction of deleterious non-synonymous SNPs in STAT3. ASIAN BIOMED 2023; 17:185-199. [PMID: 37860678 PMCID: PMC10584383 DOI: 10.2478/abm-2023-0059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2023]
Abstract
Background STAT3, a pleiotropic transcription factor, plays a critical role in the pathogenesis of autoimmunity, cancer, and many aspects of the immune system, as well as having a link with inflammatory bowel disease. Changes caused by non-synonymous single nucleotide polymorphisms (nsSNPs) have the potential to damage the protein's structure and function. Objective We identified disease susceptible single nucleotide polymorphisms (SNPs) in STAT3 and predicted structural changes associated with mutants that disrupt normal protein-protein interactions using different computational algorithms. Methods Several in silico tools, such as SIFT, PolyPhen v2, PROVEAN, PhD-SNP, and SNPs&GO, were used to determine nsSNPs of the STAT3. Further, the potentially deleterious SNPs were evaluated using I-Mutant, ConSurf, and other computational tools like DynaMut for structural prediction. Result 417 nsSNPs of STAT3 were identified, 6 of which are considered deleterious by in silico SNP prediction algorithms. Amino acid changes in V507F, R335W, E415K, K591M, F561Y, and Q32K were identified as the most deleterious nsSNPs based on the conservation profile, structural conformation, relative solvent accessibility, secondary structure prediction, and protein-protein interaction tools. Conclusion The in silico prediction analysis could be beneficial as a diagnostic tool for both genetic counseling and mutation confirmation. The 6 deleterious nsSNPs of STAT3 may serve as potential targets for different proteomic studies, large population-based studies, diagnoses, and therapeutic interventions.
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Affiliation(s)
- Athira Ajith
- Human Genetics Research Centre, Sree Balaji Dental College and Hospital, Bharath Institute of Higher Education and Research, Chennai600100, Tamil Nadu, India
| | - Usha Subbiah
- Human Genetics Research Centre, Sree Balaji Dental College and Hospital, Bharath Institute of Higher Education and Research, Chennai600100, Tamil Nadu, India
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Faida P, Attiogbe MKI, Majeed U, Zhao J, Qu L, Fan D. Lung cancer treatment potential and limits associated with the STAT family of transcription factors. Cell Signal 2023:110797. [PMID: 37423343 DOI: 10.1016/j.cellsig.2023.110797] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/19/2023] [Accepted: 07/04/2023] [Indexed: 07/11/2023]
Abstract
Lung cancer is one of the mortal cancers and the leading cause of cancer-related mortality, with a cancer survival rate of fewer than 5% in developing nations. This low survival rate can be linked to things like late-stage detection, quick postoperative recurrences in patients receiving therapy, and chemoresistance developing against various lung cancer treatments. Signal transducer and activator of transcription (STAT) family of transcription factors are involved in lung cancer cell proliferation, metastasis, immunological control, and treatment resistance. By interacting with specific DNA sequences, STAT proteins trigger the production of particular genes, which in turn result in adaptive and incredibly specific biological responses. In the human genome, seven STAT proteins have been discovered (STAT1 to STAT6, including STAT5a and STAT5b). Many external signaling proteins can activate unphosphorylated STATs (uSTATs), which are found inactively in the cytoplasm. When STAT proteins are activated, they can increase the transcription of several target genes, which leads to unchecked cellular proliferation, anti-apoptotic reactions, and angiogenesis. The effects of STAT transcription factors on lung cancer are variable; some are either pro- or anti-tumorigenic, while others maintain dual, context-dependent activities. Here, we give a succinct summary of the various functions that each member of the STAT family plays in lung cancer and go into more detail about the advantages and disadvantages of pharmacologically targeting STAT proteins and their upstream activators in the context of lung cancer treatment.
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Affiliation(s)
- Paison Faida
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Mawusse K I Attiogbe
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Usman Majeed
- College of Food Science and Technology, Northwest University, Xi'an, Shaanxi 710069, China
| | - Jing Zhao
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Linlin Qu
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China.
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Yue P, Zhu Y, Brotherton-Pleiss C, Fu W, Verma N, Chen J, Nakamura K, Chen W, Chen Y, Alonso-Valenteen F, Mikhael S, Medina-Kauwe L, Kershaw KM, Celeridad M, Pan S, Limpert AS, Sheffler DJ, Cosford NDP, Shiao SL, Tius MA, Lopez-Tapia F, Turkson J. Novel potent azetidine-based compounds irreversibly inhibit Stat3 activation and induce antitumor response against human breast tumor growth in vivo. Cancer Lett 2022; 534:215613. [PMID: 35276290 PMCID: PMC9867837 DOI: 10.1016/j.canlet.2022.215613] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/09/2022] [Accepted: 02/27/2022] [Indexed: 01/26/2023]
Abstract
Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC50 0.38-0.98 μM) over Stat1 or Stat5 (IC50 > 15.8 μM) in vitro. Mass spectrometry detected the Stat3 cysteine peptides covalently bound to the azetidine compounds, and the key residues, Cys426 and Cys468, essential for the high potency inhibition, were confirmed by site-directed mutagenesis. In triple-negative breast cancer (TNBC) models, treatment with the azetidine compounds inhibited constitutive and ligand-induced Stat3 signaling, and induced loss of viable cells and tumor cell death, compared to no effect on the induction of Janus kinase (JAK)2, Src, epidermal growth factor receptor (EGFR), and other proteins, or weak effects on cells that do not harbor aberrantly-active Stat3. H120 (8e) and H182 as a single agent inhibited growth of TNBC xenografts, and H278 (hydrochloric acid salt of H182) in combination with radiation completely blocked mouse TNBC growth and improved survival in syngeneic models. We identify potent azetidine-based, selective, irreversible Stat3 inhibitors that inhibit TNBC growth in vivo.
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Affiliation(s)
- Peibin Yue
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA,Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Yinsong Zhu
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA,Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Christine Brotherton-Pleiss
- Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA,Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI, 96825, USA
| | - Wenzhen Fu
- Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA,Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI, 96825, USA
| | - Nagendra Verma
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA,Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Jasmine Chen
- Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA
| | - Kayo Nakamura
- Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI, 96825, USA
| | - Weiliang Chen
- Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI, 96825, USA
| | - Yue Chen
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA,Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Felix Alonso-Valenteen
- Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA,Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Simoun Mikhael
- Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA,Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Lali Medina-Kauwe
- Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA,Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Kathleen M. Kershaw
- Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA,Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Maria Celeridad
- Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA
| | - Songqin Pan
- W. M. Keck Proteomics Laboratory, University of California, Riverside, CA, 92521, USA
| | - Allison S. Limpert
- Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA
| | - Douglas J. Sheffler
- Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA
| | - Nicholas D. P. Cosford
- Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA
| | - Stephen L. Shiao
- Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA,Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Marcus A. Tius
- Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA,Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI, 96825, USA
| | - Francisco Lopez-Tapia
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA,Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA,Corresponding author. Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA. (J. Turkson)
| | - James Turkson
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
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Tošić I, Frank DA. STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications. Neoplasia 2021; 23:1167-1178. [PMID: 34731785 PMCID: PMC8569436 DOI: 10.1016/j.neo.2021.10.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/16/2021] [Accepted: 10/17/2021] [Indexed: 02/07/2023] Open
Abstract
The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is activated constitutively in a wide array of human cancers. It is an appealing molecular target for novel therapy as it directly regulates expression of genes involved in cell proliferation, survival, angiogenesis, chemoresistance and immune responsiveness. In addition to these well-established oncogenic roles, STAT3 has also been found to mediate a wide array of functions in modulating cellular behavior. The transcriptional function of STAT3 is canonically regulated through tyrosine phosphorylation. However, STAT3 phosphorylated at a single serine residue can allow incorporation of this protein into the inner mitochondrial membrane to support oxidative phosphorylation (OXPHOS) and maximize the utility of glucose sources. Conflictingly, its canonical transcriptional activity suppresses OXPHOS and favors aerobic glycolysis to promote oncogenic behavior. Apart from mediating the energy metabolism and controversial effects on ATP production, STAT3 signaling modulates lipid metabolism of cancer cells. By mediating fatty acid synthesis and beta oxidation, STAT3 promotes employment of available resources and supports survival in the conditions of metabolic stress. Thus, the functions of STAT3 extend beyond regulation of oncogenic genes expression to pleiotropic effects on a spectrum of essential cellular processes. In this review, we dissect the current knowledge on activity and mechanisms of STAT3 involvement in transcriptional regulation, mitochondrial function, energy production and lipid metabolism of malignant cells, and its implications to cancer pathogenesis and therapy.
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Affiliation(s)
- Isidora Tošić
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - David A Frank
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
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Liu S, Gandler HI, Tošić I, Ye DQ, Giaccone ZT, Frank DA. Mutant KRAS Downregulates the Receptor for Leukemia Inhibitory Factor (LIF) to Enhance a Signature of Glycolysis in Pancreatic Cancer and Lung Cancer. Mol Cancer Res 2021; 19:1283-1295. [PMID: 33931487 PMCID: PMC8349878 DOI: 10.1158/1541-7786.mcr-20-0633] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 03/06/2021] [Accepted: 04/23/2021] [Indexed: 01/11/2023]
Abstract
Pancreatic cancer is characterized by aberrant activity of oncogenic KRAS, which is mutated in 90% of pancreatic adenocarcinomas. Because KRAS itself is a challenging therapeutic target, we focused on understanding key signaling pathways driven by KRAS as a way to reveal dependencies that are amenable to therapeutic intervention. Analyses in primary human pancreatic cancers and model systems revealed that the receptor for the cytokine leukemia inhibitory factor (LIF) is downregulated by mutant KRAS. Furthermore, downregulation of the LIF receptor (LIFR) is necessary for KRAS-mediated neoplastic transformation. We found LIFR exerts inhibitory effects on KRAS-mediated transformation by inhibiting expression of the glucose transporter GLUT1, a key mediator of the enhanced glycolysis found in KRAS-driven malignancies. Decreased LIFR expression leads to increased GLUT1 as well as increases in glycolysis and mitochondrial respiration. The repression of GLUT1 by LIFR is mediated by the transcription factor STAT3, indicating a tumor-suppressive role for STAT3 within cancer cells with mutated KRAS. Finally, reflecting a clinically important tumor-suppressive role of LIFR, decreased LIFR expression correlates with shorter survival in pancreatic cancer patients with mutated KRAS. Similar findings were found in non-small cell lung cancers driven by mutated KRAS, suggesting that silencing LIFR is a generalized mechanism of KRAS-mediated cellular transformation. These results indicate that the LIFR/STAT3 pathway may mediate either tumor-promoting or tumor-suppressive signaling pathways depending on the genetic background of tumor cells, and may play diverse roles within other cells in the tumor microenvironment. IMPLICATIONS: Mutant KRAS drives downregulation of the receptor for LIF, thereby allowing an increase in expression of the glucose transporter GLUT1 and increases in glycolysis and mitochondrial respiration.
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Affiliation(s)
- Suhu Liu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Helen I Gandler
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Isidora Tošić
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Darwin Q Ye
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Zachary T Giaccone
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - David A Frank
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
- Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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10
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Diallo M, Herrera F. The role of understudied post-translational modifications for the behavior and function of Signal Transducer and Activator of Transcription 3. FEBS J 2021; 289:6235-6255. [PMID: 34235865 DOI: 10.1111/febs.16116] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 12/19/2022]
Abstract
The Signal Transducer and Activator of Transcription (STAT) family of transcription factors is involved in inflammation, immunity, development, cancer, and response to injury, among other biological phenomena. Canonical STAT signaling is often represented as a 3-step pathway involving the sequential activation of a membrane receptor, an intermediate kinase, and a STAT transcription factor. The rate-limiting phosphorylation at a highly conserved C-terminal tyrosine residue determines the nuclear translocation and transcriptional activity of STATs. This apparent simplicity is actually misleading and can hardly explain the pleiotropic nature of STATs, the existence of various noncanonical STAT pathways, or the key role of the N-terminal domain in STAT functions. More than 80 post-translational modifications (PTMs) have been identified for STAT3, but their functions remain barely understood. Here, we provide a brief but comprehensive overview of these underexplored PTMs and their role on STAT3 canonical and noncanonical functions. A less tyrosine-centric point of view may be required to advance our understanding of STAT signaling.
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Affiliation(s)
- Mickael Diallo
- Faculdade de Ciências da Universidade de Lisboa, Cell Structure and Dynamics Laboratory, BioISI - Instituto de Biosistemas e Ciências integrativas, Lisbon, Portugal.,MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Federico Herrera
- Faculdade de Ciências da Universidade de Lisboa, Cell Structure and Dynamics Laboratory, BioISI - Instituto de Biosistemas e Ciências integrativas, Lisbon, Portugal.,MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
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11
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STAT3β is a tumor suppressor in acute myeloid leukemia. Blood Adv 2020; 3:1989-2002. [PMID: 31270081 DOI: 10.1182/bloodadvances.2018026385] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 05/04/2019] [Indexed: 12/17/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3α and STAT3β. Although truncated STAT3β was originally postulated to act as a dominant-negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3β gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3β in AML remains elusive. Therefore, we analyzed the STAT3β/α messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3β/α mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3β in AML, we engineered a transgenic mouse allowing for balanced Stat3β expression. Transgenic Stat3β expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9-dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3β depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3β plays an essential tumor-suppressive role in AML.
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12
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Qin J, Shen X, Zhang J, Jia D. Allosteric inhibitors of the STAT3 signaling pathway. Eur J Med Chem 2020; 190:112122. [DOI: 10.1016/j.ejmech.2020.112122] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/04/2020] [Accepted: 02/04/2020] [Indexed: 01/13/2023]
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13
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Pyrimethamine conjugated histone deacetylase inhibitors: Design, synthesis and evidence for triple negative breast cancer selective cytotoxicity. Bioorg Med Chem 2020; 28:115345. [DOI: 10.1016/j.bmc.2020.115345] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/12/2020] [Accepted: 01/22/2020] [Indexed: 12/25/2022]
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14
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DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells. Oncogenesis 2020; 9:1. [PMID: 31900385 PMCID: PMC6949220 DOI: 10.1038/s41389-019-0187-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 12/02/2019] [Accepted: 12/10/2019] [Indexed: 12/15/2022] Open
Abstract
DNA damage-induced apoptosis suppressor (DDIAS) regulates cancer cell survival. Here we investigated the involvement of DDIAS in IL-6-mediated signaling to understand the mechanism underlying the role of DDIAS in lung cancer malignancy. We showed that DDIAS promotes tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in malignant cancers. Interestingly, siRNA protein tyrosine phosphatase (PTP) library screening revealed protein tyrosine phosphatase receptor mu (PTPRM) as a novel STAT3 PTP. PTPRM knockdown rescued the DDIAS-knockdown-mediated decrease in STAT3 Y705 phosphorylation in the presence of IL-6. However, PTPRM overexpression decreased STAT3 Y705 phosphorylation. Moreover, endogenous PTPRM interacted with endogenous STAT3 for dephosphorylation at Y705 following IL-6 treatment. As expected, PTPRM bound to wild-type STAT3 but not the STAT3 Y705F mutant. PTPRM dephosphorylated STAT3 in the absence of DDIAS, suggesting that DDIAS hampers PTPRM/STAT3 interaction. In fact, DDIAS bound to the STAT3 transactivation domain (TAD), which competes with PTPRM to recruit STAT3 for dephosphorylation. Thus we show that DDIAS prevents PTPRM/STAT3 binding and blocks STAT3 Y705 dephosphorylation, thereby sustaining STAT3 activation in lung cancer. DDIAS expression strongly correlates with STAT3 phosphorylation in human lung cancer cell lines and tissues. Thus DDIAS may be considered as a potential biomarker and therapeutic target in malignant lung cancer cells with aberrant STAT3 activation.
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15
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Pivotal Role of STAT3 in Shaping Glioblastoma Immune Microenvironment. Cells 2019; 8:cells8111398. [PMID: 31698775 PMCID: PMC6912524 DOI: 10.3390/cells8111398] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/02/2019] [Accepted: 11/04/2019] [Indexed: 12/03/2022] Open
Abstract
Glioblastoma belongs to the most malignant intracranial tumors characterized by indispensable growth and aggressiveness that highly associates with dismal prognosis and therapy resistance. Tumor heterogeneity that often challenges therapeutic schemes is largely attributed to the complex interaction of neoplastic cells with tumor microenvironment (TME). Soluble immunoregulatory molecules secreted by glioma cells attract astrocytes, circulating stem cells and a range of immune cells to TME, inducing a local production of cytokines, chemokines and growth factors that reprogram immune cells to inflammatory phenotypes and manipulate host’s immune response in favor of cancer growth and metastasis. Accumulating evidence indicates that these tolerogenic properties are highly regulated by the constitutive and persistent activation of the oncogenic signal transducer and activator of transcription 3 (STAT3) protein, which impairs anti-tumor immunity and enhances tumor progression. Herein, we discuss current experimental and clinical evidence that highlights the pivotal role of STAT3 in glioma tumorigenesis and particularly in shaping tumor immune microenvironment in an effort to justify the high need of selective targeting for glioma immunotherapy.
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16
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Shen X, Zhao L, Chen P, Gong Y, Liu D, Zhang X, Dai L, Sun Q, Lou J, Jin Z, Zhang B, Niu D, Chen C, Qi X, Jia D. A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3. J Biol Chem 2019; 294:17471-17486. [PMID: 31594861 DOI: 10.1074/jbc.ra119.009801] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 09/25/2019] [Indexed: 12/25/2022] Open
Abstract
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in ∼70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy. However, specific direct STAT3 inhibitors remain to be developed. Oridonin is an ent-kaurane plant-derived diterpenoid with anti-cancer and anti-inflammatory activities. Here, using an array of cell-based and biochemical approaches, including cell proliferation and apoptosis assays, pulldown and reporter gene assays, site-directed mutagenesis, and molecular dynamics analyses, we report that a thiazole-derived oridonin analogue, CYD0618, potently and directly inhibits STAT3. We found that CYD0618 covalently binds to Cys-542 in STAT3 and suppresses its activity through an allosteric effect, effectively reducing STAT3 dimerization and nuclear translocation, as well as decreasing expression of STAT3-targeted oncogenes. Remarkably, CYD0618 not only strongly inhibited growth of multiple cancer cell lines that harbor constitutive STAT3 activation, but it also suppressed in vivo tumor growth via STAT3 inhibition. Taken together, our findings suggest Cys-542 as a druggable site for selectively inhibiting STAT3 and indicate that CYD0618 represents a promising lead compound for developing therapeutic agents against STAT3-driven diseases.
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Affiliation(s)
- Xiaofei Shen
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
| | - Lin Zhao
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
| | - Peihao Chen
- School of Life Science, Peking University, Beijing 100084, China.,National Institute of Biological Sciences (NIBS), Beijing 102206, China
| | - Yanqiu Gong
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
| | - Dingdong Liu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
| | - Xia Zhang
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
| | - Lunzhi Dai
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
| | - Qingxiang Sun
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
| | - Jizhong Lou
- Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhong Jin
- Computer Network Information Center and Center of Scientific Computing Applications and Research, Chinese Academy of Sciences, Beijing 100190, China
| | - Baohua Zhang
- Computer Network Information Center and Center of Scientific Computing Applications and Research, Chinese Academy of Sciences, Beijing 100190, China
| | - Dawen Niu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming 650223, China
| | - Xiangbing Qi
- National Institute of Biological Sciences (NIBS), Beijing 102206, China
| | - Da Jia
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
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17
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Chen W, Wu G, Zhu Y, Zhang W, Zhang H, Zhou Y, Sun P. HOXA10 deteriorates gastric cancer through activating JAK1/STAT3 signaling pathway. Cancer Manag Res 2019; 11:6625-6635. [PMID: 31406476 PMCID: PMC6642621 DOI: 10.2147/cmar.s201342] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Accepted: 05/29/2019] [Indexed: 12/13/2022] Open
Abstract
Background: HOXA10 has been reported to be deregulated in many kinds of cancers including gastric cancer. But its role in gastric cancer progression is controversial. Therefore, the current study was performed to explore the role and mechanism of HOXA10 in gastric cancer. Materials and methods: IHC and Western blotting assays were used to assess HOXA10 expression in gastric cancer tissues and cells. Lentivirus infection was used to alter HOXA10, STAT3 and JAK1 expression in gastric cancer NCI-N87 and MKN28 cells. MTT, cloning formation, flow cytometry and in vivo xenotransplantation experiments were carried out to assess cell proliferation, cloning formation, apoptosis and tumorigenesis. Results: HOXA10 expression was obviously increased in gastric cancer tissues and cells when compared with the normal gastric tissue samples and cells. Upregulation of HOXA10 significantly enhanced cell proliferation, cloning formation and tumorigenesis abilities and reduced cell apoptosis in gastric cancer, and promoted the activation of JAK1/STAT3 signaling. In addition, we showed that the effects of HOXA10 on the promotion of cell viability and tumorigenesis and cell apoptosis repression were all weakened when JAK1 or STAT3 was downregulated. Conclusion: This study demonstrates that HOXA10 functions as an oncogene in gastric cancer through activating JAK1/STAT3 signaling.
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Affiliation(s)
- Wenchao Chen
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, People's Republic of China
| | - Gang Wu
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, People's Republic of China
| | - Yuanzeng Zhu
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, People's Republic of China
| | - Wei Zhang
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, People's Republic of China
| | - Han Zhang
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, People's Republic of China
| | - Yang Zhou
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, People's Republic of China
| | - Peichun Sun
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, People's Republic of China
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18
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STAT3 isoforms: Alternative fates in cancer? Cytokine 2019; 118:27-34. [DOI: 10.1016/j.cyto.2018.07.014] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 07/10/2018] [Accepted: 07/11/2018] [Indexed: 02/04/2023]
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19
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Jiang LH, Hao YL, Zhu JW. Expression and prognostic value of HER-2/neu, STAT3 and SOCS3 in hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2019; 43:282-291. [PMID: 30385249 DOI: 10.1016/j.clinre.2018.09.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/18/2018] [Accepted: 09/28/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations, while the viral-chemical etiology along with molecular mechanisms of HCC pathogenesis remains largely unknown. This study aimed to determine expression profile and prognostic value of HER-2/neu, STAT3 and SOCS3 in HCC. METHODS Immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to evaluate the expression of HER-2/neu, STAT3 and SOCS3 in HCC tissues and adjacent normal tissues collected from 176 HCC patients. RESULTS HER-2/neu and STAT3 levels were higher and SOCS3 expression was lower in HCC tissues than in adjacent normal tissues. HER-2/neu, STAT3 and SOCS3 levels were associated with histological grade, tumor diameter, TNM stage, vascular invasion, lymph node metastasis and distant metastasis in HCC. SOCS3 expression was negatively associated with HER-2/neu and STAT3 expression. HCC patients with higher HER-2/neu and STAT3 levels had shorter overall, disease-free and disease-specific survival, whereas the opposite was found in patients with higher SOCS3 expression. In Cox regression analysis, tumor size, TNM stage, and STAT3 expression were identified as independent prognostic factors of HCC. CONCLUSION Taken together, these observations suggest that HER-2/neu, STAT3 and, SOCS3 are related to the aggressive tumor behavior and STAT3 has potential value as a prognostic factor for HCC.
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Affiliation(s)
- Li-Hua Jiang
- Department of Clinical Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuhuangding East Road, Yantai 264000, Shandong Province, PR China
| | - Ying-Li Hao
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai 264001, Shandong Province, PR China
| | - Jing-Wei Zhu
- Department of Clinical Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuhuangding East Road, Yantai 264000, Shandong Province, PR China.
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20
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Abstract
Cervical cancer is the third most common gynecological cancer and the fourth leading cause of cancer-related deaths in women around the world. Substantial evidence has demonstrated that microRNA (miRNA) expression is disordered in many malignant tumors. The dysregulation of miRNAs has been suggested to be involved in the tumorigenesis and tumor development of cervical cancer. Therefore, identification of miRNAs and their biological roles and targets involved in tumor pathology would provide valuable insight into the diagnosis and treatment of patients with cervical cancer. MicroRNA-411 (miR-411) has been reported to play an important role in several types of human cancer. However, the expression level, role, and underlying molecular mechanisms of miR-411 in cervical cancer remain unclear. Therefore, the objectives of this study were to investigate the expression pattern and clinical significance of miR-411 in cervical cancer and to evaluate its role and underlying mechanisms in this disease. In this study, we confirmed that the expression of miR-411 was significantly downregulated in both cervical cancer tissues and cell lines. Low expression of miR-411 was associated with tumor size, FIGO stage, lymph node metastasis, and distant metastasis. Additionally, miR-411 overexpression inhibited cell proliferation and invasion in cervical cancer. Furthermore, signal transducer and activator of transcription 3 (STAT3) was identified as a direct target of miR-411 in this disease. In clinical samples, miR-411 expression levels were inversely correlated with STAT3, which was significantly upregulated in cervical cancer. Restored STAT3 expression abolished the tumor-suppressing effects of miR-411 overexpression on the proliferation and invasion of cervical cancer cells. In conclusion, our data demonstrated that miR-411 inhibited cervical cancer progression by directly targeting STAT3 and may represent a novel potential therapeutic target and prognostic marker for patients with this disease.
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Affiliation(s)
- Dan Shan
- Department of Obstetrics and Gynecology, Tianjin Hospital, Tianjin, P.R. China
| | - Yumin Shang
- Department of Obstetrics and Gynecology, Tianjin Hospital, Tianjin, P.R. China
| | - Tongxiu Hu
- Department of Obstetrics and Gynecology, Tianjin Hospital, Tianjin, P.R. China
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21
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Zhou Y, Yang J, Zhang Q, Xu Q, Lu L, Wang J, Xia W. P4HB knockdown induces human HT29 colon cancer cell apoptosis through the generation of reactive oxygen species and inactivation of STAT3 signaling. Mol Med Rep 2018; 19:231-237. [PMID: 30431122 PMCID: PMC6297753 DOI: 10.3892/mmr.2018.9660] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 05/10/2018] [Indexed: 12/11/2022] Open
Abstract
Colon cancer is the second most lethal malignancy worldwide. A better understanding of colon cancer at the molecular level may increase overall survival rates. Previous studies have indicated that prolyl 4-hydroxylase, β polypeptide (P4HB) is associated with tumorigenesis in colon cancer; however, its role and molecular mechanisms in colon cancer remain unclear. In the present study, the cellular responses to P4HB in human colon cancer cell lines were investigated by proliferation and apoptosis assays, western blotting, and immunohistochemistry. The results showed that expression of P4HB was higher in colon cancer tissues compared within adjacent normal tissues. P4HB knockdown increased the apoptosis of human HT29 cells. Furthermore, P4HB knockdown reduced the activation of signal transducer and activator of transcription 3 (STAT3) and promoted accumulation of reactive oxygen species (ROS). Inhibiting the accumulation of ROS abrogated the increased cell apoptosis induced by P4HB knockdown. Notably, decreased ROS levels effectively antagonized the effects of P4HB on STAT3 inactivation. In conclusion, these findings suggested that P4HB knockdown may induce HT29 human colon cancer cell apoptosis through the generation of ROS and inactivation of the STAT3 signaling pathway.
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Affiliation(s)
- Ying Zhou
- Department of Gastroenterology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Jing Yang
- Department of General Surgery, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Qilin Zhang
- Department of Neurosurgery, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Qihua Xu
- Department of Gastroenterology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Lihua Lu
- Department of Gastroenterology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Jiening Wang
- Department of Integrated TCM and Western Medicine, President's Office, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Wei Xia
- Department of Nuclear Medicine, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
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22
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Nucleus, Mitochondrion, or Reticulum? STAT3 à La Carte. Int J Mol Sci 2018; 19:ijms19092820. [PMID: 30231582 PMCID: PMC6164042 DOI: 10.3390/ijms19092820] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 09/12/2018] [Accepted: 09/14/2018] [Indexed: 12/12/2022] Open
Abstract
The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of an oncogene, contributing in multiple ways to tumor transformation, growth, and progression. For this reason, many laboratories and pharmaceutical companies are making efforts to develop specific inhibitors. However, STAT3 has also been shown to act as a tumor suppressor in a number of cases, suggesting that its activity is strongly context-specific. Here, we discuss the bases that can explain the multiple roles of this factor in both physiological and pathological contexts. In particular, we focus on the following four features: (i) the distinct properties of the STAT3α and β isoforms; (ii) the multiple post-translational modifications (phosphorylation on tyrosine or serine, acetylation and methylation on different residues, and oxidation and glutathionylation) that can affect its activities downstream of multiple different signals; (iii) the non-canonical functions in the mitochondria, contributing to the maintenance of energy homeostasis under stress conditions; and (iv) the recently discovered functions in the endoplasmic reticulum, where STAT3 contributes to the regulation of calcium homeostasis, energy production, and apoptosis.
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23
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Wu S, Qiu Y, Shao Y, Yin S, Wang R, Pang X, Ma J, Zhang C, Wu B, Koo S, Han L, Zhang Y, Gao X, Wang T, Yu H. Lycorine Displays Potent Antitumor Efficacy in Colon Carcinoma by Targeting STAT3. Front Pharmacol 2018; 9:881. [PMID: 30135654 PMCID: PMC6092588 DOI: 10.3389/fphar.2018.00881] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 07/20/2018] [Indexed: 11/13/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is an attractive therapeutic target for cancer treatment. In this study, we identify lycorine is an effective inhibitor of STAT3, leading to repression of multiple oncogenic processes in colon carcinoma. Lycorine selectively inactivates phospho-STAT3 (Tyr-705), and subsequent molecular docking uncovers that lycorine directly binds to the SH2 domain of STAT3. Consequently, we find that lycorine exhibits anti-proliferative activity and induces cell apoptosis on human colorectal cancer (CRC) in vitro. Lycorine induces the activation of the caspase-dependent mitochondrial apoptotic pathway, as indicated by activation of caspase and increase of the ratio of Bax/Bcl-2 and mitochondrial depolarization. Overexpressing STAT3 greatly blocks these effects by lycorine in CRC cells. Finally, lycorine exhibits a potential therapeutic effect in xenograft colorectal tumors by targeting STAT3 without observed toxicity. Taken together, the present study indicates that lycorine acts as a promising inhibitor of STAT3, which blocks tumorigenesis in colon carcinoma.
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Affiliation(s)
- Song Wu
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuling Qiu
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Yingying Shao
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shuangshuang Yin
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Rui Wang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xu Pang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Junhong Ma
- Department of Gastrointestinal Surgery, Nankai Hospital, Tianjin, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Bo Wu
- School of Fundamental Sciences, China Medical University, Shenyang, China
| | - Sangho Koo
- Department of Chemistry, Myongji University, Seoul, South Korea
| | - Lifeng Han
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yi Zhang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiumei Gao
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tao Wang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Haiyang Yu
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Chen L, Lu Z, Yang Y, Du L, Zhou X, Chen Y. Effects of purified Omphalia lapidescens protein on metastasis, cell cycle, apoptosis and the JAK-STAT signaling pathway in SGC-7901 human gastric cells. Oncol Lett 2018. [PMID: 29541181 PMCID: PMC5835924 DOI: 10.3892/ol.2018.7830] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer is one of the most common cancers globally with high rates of morbidity and mortality. Purified Omphalia lapidescens protein (pPeOp) is a protein extracted from the sclerotium of Omphalia lapidescens. The present study aimed to investigate the effects of pPeOp on the viability, migration, cell cycle progression and apoptosis of SGC-7901 cells. The expression of numerous proteins, namely matrix metallopeptidase (MMP)2, MMP9, p53, caspase-3, B-cell lymphoma (Bcl)-2, cyclin A2, cyclin B1, cyclin D1, cyclin dependent kinase (CDK)1, CDK2 and CDK4, were investigated using western blot analysis and reverse transcription-quantitative polymerase chain reaction. The results of the present study demonstrated that treating SGC-7901 cells with pPeOp markedly suppressed their migration, induced their apoptosis and arrested their progression in S phase. pPeOp also downregulated the expression of migration-associated proteins (MMP2 and MMP9) and cyclin-associated proteins (cyclin A2, cyclin B1, cyclin D1, CDK1, CDK2 and CDK4) in a dose-dependent manner. Cells treated with pPeOp significantly upregulated caspase-3 and p53 and downregulated Bcl-2. Finally, the impact of pPeOp on three key nodes of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway were investigated and it was revealed that expression levels of JAK1, JAK2 and STAT3 were significantly downregulated following treatment. Together, the results of the present study suggested that pPeOp suppresses metastasis, arrests cell cycle, induces apoptosis and inhibits the JAK-STAT signaling pathway in SGC-7901 cells. Therefore, pPeOp may serve as a novel therapeutic agent for patients with gastric cancer.
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Affiliation(s)
- Luchao Chen
- Microbiology and Immunology Laboratory, College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Zhongxia Lu
- Microbiology and Immunology Laboratory, College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Yongle Yang
- Institute of Preventive and Veterinary Medicine and The Key Laboratory of Animal Virology of Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
| | - Lijun Du
- Microbiology and Immunology Laboratory, College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Xiaofang Zhou
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Yitao Chen
- Microbiology and Immunology Laboratory, College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
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25
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PUM1 promotes ovarian cancer proliferation, migration and invasion. Biochem Biophys Res Commun 2018; 497:313-318. [DOI: 10.1016/j.bbrc.2018.02.078] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 02/07/2018] [Indexed: 01/30/2023]
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26
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Wang Y, Shao F, Chen L. ALDH1A2 suppresses epithelial ovarian cancer cell proliferation and migration by downregulating STAT3. Onco Targets Ther 2018; 11:599-608. [PMID: 29430185 PMCID: PMC5797454 DOI: 10.2147/ott.s145864] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Epithelial ovarian cancer is the deadliest gynecological malignancy worldwide. A better understanding of epithelial ovarian cancer pathogenesis and the molecular mechanism underlying its metastasis may increase overall survival rates. Previous studies have indicated that aldehyde dehydrogenase 1 family member A2 (ALDH1A2) is a candidate tumor suppressor in epithelial ovarian cancer. However, the potential role of ALDH1A2 in the molecular mechanisms of epithelial ovarian cancer remains largely unclear. In the present study, we found lower expression of ALDH1A2 in high-grade epithelial ovarian cancer tissues than in low-grade epithelial ovarian cancer tissues. Overexpression of ALDH1A2 decreased the proliferation and migration of epithelial ovarian cancer cell lines, whereas ALDH1A2 knockdown significantly increased cell growth and migration. Moreover, upregulation of ALDH1A2 also reduced the activation of signal transducer and activator of transcription 3 (STAT3). In conclusion, these findings suggest that ALDH1A2 suppresses epithelial ovarian cancer cell proliferation and migration by downregulating STAT3.
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Affiliation(s)
- Yichen Wang
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Feng Shao
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Lu Chen
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou, China
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27
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Shanmugam MK, Arfuso F, Kumar AP, Wang L, Goh BC, Ahn KS, Bishayee A, Sethi G. Modulation of diverse oncogenic transcription factors by thymoquinone, an essential oil compound isolated from the seeds of Nigella sativa Linn. Pharmacol Res 2017; 129:357-364. [PMID: 29162539 DOI: 10.1016/j.phrs.2017.11.023] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/17/2017] [Accepted: 11/17/2017] [Indexed: 12/14/2022]
Abstract
Thymoquinone (TQ), isolated almost fifty years ago, is the main bioactive constituent of black seed essential oil extracted from the seed of Nigella sativa. TQ has been shown to have promising effects against a variety of inflammatory diseases and cancer. Cancer development is a multistep process where normal cells acquire qualities that enable the cells to proliferate continuously and migrate to distant sites in the human body. Drugs that interfere with this process are considered potential anti-cancer therapeutics, which may ultimately result in their clinical usage. TQ is once such compound which has been reported to modulate several major signaling pathways and key oncogenic molecules that play a prominent role in cancer initiation, progression, invasion, metastasis, and angiogenesis. Various studies have reported that TQ can enhance the anti-cancer potential when co-administered with several chemotherapeutic agents while reducing their toxic side effects. In addition, TQ has been shown to inhibit the growth of breast, prostate, pancreatic, colon, lung, and hematological malignancies in different mouse models of cancer. This review focuses on TQ's chemical and pharmacological properties, its diverse molecular targets and also provides clear evidence on its promising potential under preclinical and clinical settings.
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Affiliation(s)
- Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Frank Arfuso
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6009, Australia
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; Cancer Science Institute of Singapore, National University of Singapore, 117600, Singapore; Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6009, Australia; National University Cancer Institute, National University Health System, 117600, Singapore; Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA
| | - Lingzhi Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; Cancer Science Institute of Singapore, National University of Singapore, 117600, Singapore
| | - Boon Cher Goh
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; Cancer Science Institute of Singapore, National University of Singapore, 117600, Singapore; Department of Haematology-Oncology, National University Health System, 119228, Singapore
| | - Kwang Seok Ahn
- College of Korean Medicine, Kyung Hee University, Kyungheedae-gil, Dongdaemoon-gu, Seoul 130-701, South Korea, South Korea
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, 18301 N. Miami Avenue, Miami, FL 33169, USA
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6009, Australia.
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28
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Lu R, Zhang YG, Sun J. STAT3 activation in infection and infection-associated cancer. Mol Cell Endocrinol 2017; 451:80-87. [PMID: 28223148 PMCID: PMC5469714 DOI: 10.1016/j.mce.2017.02.023] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 02/14/2017] [Indexed: 12/23/2022]
Abstract
The Janus kinase/signal transducers and activators for transcription (JAK/STAT) pathway plays crucial roles in regulating apoptosis, proliferation, differentiation, and the inflammatory response. The JAK/STAT families are composed of four JAK family members and seven STAT family members. STAT3 plays a key role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment. Recent evidence suggests that STAT3 regulates diverse biological functions in pathogenesis of diseases, such as infection and cancer. In the current review, we will summarize the research progress of STAT3 activation in infection and cancers. We highlight our recent study on the novel role of STAT3 in Salmonella infection-associated colon cancer. Infection with bacterial AvrA-expressing Salmonella activates the STAT3 pathway, which induces the β-catenin signals and enhances colonic tumorigenesis. STAT3 may be a promising target in developing prevention and treatment for infectious diseases and infection-associated cancers.
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Affiliation(s)
- Rong Lu
- Division of Gastroenterology and Hepatology, Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Yong-Guo Zhang
- Division of Gastroenterology and Hepatology, Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Jun Sun
- Division of Gastroenterology and Hepatology, Medicine, University of Illinois at Chicago, Chicago, IL, USA.
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29
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Cocchiola R, Romaniello D, Grillo C, Altieri F, Liberti M, Magliocca FM, Chichiarelli S, Marrocco I, Borgoni G, Perugia G, Eufemi M. Analysis of STAT3 post-translational modifications (PTMs) in human prostate cancer with different Gleason Score. Oncotarget 2017; 8:42560-42570. [PMID: 28489571 PMCID: PMC5522088 DOI: 10.18632/oncotarget.17245] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 04/05/2017] [Indexed: 01/09/2023] Open
Abstract
Prostate Cancer (PCa) is a complex and heterogeneous disease. The androgen receptor (AR) and the signal transducer and activator of transcription 3 (STAT3) could be effective targets for PCa therapy. STAT3, a cytoplasmatic latent transcription factor, is a hub protein for several oncogenic signalling pathways and up-regulates the expression of numerous genes involved in tumor cell proliferation, angiogenesis, metastasis and cell survival. STAT3 activity can be modulated by several Post-Translational Modifications (PTMs) which reflect particular cell conditions and may be implicated in PCa development and progression. The aim of this work was to analyze STAT3 PTMs at different tumor stages and their relationship with STAT3 cellular functions. For this purpose, sixty-five prostatectomy, Formalin-fixed paraffin-embedded (FFPE) specimens, classified with different Gleason Scores, were subjected to immunoblotting, immunofluorescence staining and RT-PCR analysis. All experiments were carried out in matched non-neoplastic and neoplastic tissues. Data obtained showed different STAT3 PTMs profiles among the analyzed tumor grades which correlate with differences in the amount and distribution of specific STAT3 interactors as well as the expression of STAT3 target genes. These results highlight the importance of PTMs as an additional biomarker for the exactly evaluation of the PCa stage and the optimal treatment of this disease.
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Affiliation(s)
- Rossana Cocchiola
- Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
- Istituto Pasteur, Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, Rome, Italy
- Fondazione Enrico ed Enrica Sovena, Rome, Italy
| | - Donatella Romaniello
- Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
- Istituto Pasteur, Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, Rome, Italy
| | - Caterina Grillo
- Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
- Istituto Pasteur, Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, Rome, Italy
| | - Fabio Altieri
- Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
- Istituto Pasteur, Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, Rome, Italy
| | - Marcello Liberti
- Department of Gynecological-Obstretic Science and Urologic Sciences, Sapienza University of Rome, Rome, Italy
| | - Fabio Massimo Magliocca
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Silvia Chichiarelli
- Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
- Istituto Pasteur, Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, Rome, Italy
| | - Ilaria Marrocco
- Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
- Istituto Pasteur, Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, Rome, Italy
| | - Giuseppe Borgoni
- Department of Gynecological-Obstretic Science and Urologic Sciences, Sapienza University of Rome, Rome, Italy
| | - Giacomo Perugia
- Department of Gynecological-Obstretic Science and Urologic Sciences, Sapienza University of Rome, Rome, Italy
| | - Margherita Eufemi
- Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
- Istituto Pasteur, Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, Rome, Italy
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30
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Avalle L, Camporeale A, Camperi A, Poli V. STAT3 in cancer: A double edged sword. Cytokine 2017; 98:42-50. [PMID: 28579221 DOI: 10.1016/j.cyto.2017.03.018] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 03/14/2017] [Accepted: 03/31/2017] [Indexed: 12/11/2022]
Abstract
The transcription factor signal transducer and activator of transcription (STAT) 3 is activated downstream of cytokines, growth factors and oncogenes to mediate their functions under both physiological and pathological conditions. In particular, aberrant/unrestrained STAT3 activity is detected in a wide variety of tumors, driving multiple pro-oncogenic functions. For that, STAT3 is widely considered as an oncogene and is the object of intense translational studies. One of the distinctive features of this factor is however, its ability to elicit different and sometimes contrasting effects under different conditions. In particular, STAT3 activities have been shown to be either pro-oncogenic or tumor-suppressive according to the tumor aetiology/mutational landscape, suggesting that the molecular bases underlining its functions are still incompletely understood. Here we discuss some of the properties that may provide the bases to explain STAT3 heterogeneous functions, and in particular how post-translational modifications contribute shaping its sub-cellular localization and activities, the cross talk between these activities and cell metabolic conditions, and finally how its functions can control the behaviour of both tumor and tumor microenvironment cell populations.
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Affiliation(s)
- Lidia Avalle
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, 10126 Turin, Italy
| | - Annalisa Camporeale
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, 10126 Turin, Italy
| | - Andrea Camperi
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, 10126 Turin, Italy
| | - Valeria Poli
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, 10126 Turin, Italy.
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31
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Ren Z, Zou W, Cui J, Liu L, Qing Y, Li Y. Geraniin suppresses tumor cell growth and triggers apoptosis in human glioma via inhibition of STAT3 signaling. Cytotechnology 2017; 69:765-773. [PMID: 28374108 DOI: 10.1007/s10616-017-0085-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 03/17/2017] [Indexed: 01/28/2023] Open
Abstract
Natural phytochemicals are attracting increasing interest as anticancer agents. The aim of this study is to evaluate the therapeutic potential of geraniin, a major ellagitannin extracted from Geranium sibiricum L., in human glioma. Human U87 and LN229 glioma cells were treated with different concentrations of geraniin, and cell viability, apoptosis, and gene expression were assessed. The involvement of STAT3 signaling in the action of geraniin was examined. We found that geraniin treatment for 48 h significantly (P < 0.05) impaired the phosphorylation of STAT3 and reduced the expression of downstream target genes Bcl-xL, Mcl-1, Bcl-2, and cyclin D1. Exposure to geraniin led to a concentration-dependent decline in cell viability and increase in apoptosis in glioma cells, but had no significant impact on the viability of normal human astrocytes. Measurement of caspase-3 activity showed that geraniin-treated U87 and LN229 cells showed a 1.8-2.5-fold higher caspase-3 activity than control cells. Overexpression of constitutively active STAT3 significantly (P < 0.05) reversed geraniin-mediated growth suppression and apoptosis, which was accompanied by restoration of Bcl-xL, Mcl-1, Bcl-2, and cyclin D1 expression. In an xenograft tumor mouse model, geraniin treatment significantly retarded tumor growth and induced apoptosis. Western blot analysis confirmed the suppression of STAT3 phosphorylation in glioma xenograft tumors by geraniin. Taken together, these data suggest that geraniin exerts growth-suppressive and pro-apoptotic effects on glioma cells via inhibition of STAT3 signaling and may have therapeutic benefits in malignant gliomas.
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Affiliation(s)
- Zhong Ren
- Encephalopathy Division, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China
| | - Wenshuang Zou
- Liver Disease Division, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China
| | - Junfeng Cui
- Clinical Training Center, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China
| | - Luping Liu
- Department of Orthopaedic Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yang Qing
- Department of Nuclear Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yongmei Li
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China.
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Wang J, Guo XJ, Ding YM, Jiang JX. miR-1181 inhibits invasion and proliferation via STAT3 in pancreatic cancer. World J Gastroenterol 2017; 23:1594-1601. [PMID: 28321160 PMCID: PMC5340811 DOI: 10.3748/wjg.v23.i9.1594] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 10/09/2016] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the role of microRNA 1181 (miR-1181) in invasion and proliferation in pancreatic cancer.
METHODS We analyzed the expression of miR-1181 in several pancreatic cancer cell lines and generated stable MIA-PaCa-2 and PANC-1 cell lines with up-regulated miR-1181 expression using an adenovirus delivery system. We then investigated miR-1181's effect on invasion and proliferation of pancreatic cancer cells by transwell assay, wound healing assay, cell counting kit-8 assay and colony-forming assay, and explored any underlying mechanisms by western bolt. Beyond that, we observed the change of the PANC-1 cell's cytoskeleton by immunofluorescence staining.
RESULTS Our data showed that miR-1181 was relatively down-regulated in pancreatic cancer cell lines compared with normal pancreatic ductal epithelial cells. And miR-1181 inhibited the migration, invasion and proliferation activities of MIA-PaCa-2 and PANC-1 cells. Notably, after over-expressing of miR-1181 in PANC-1 cells, F-actin depolymerized. Immunofluorescence staining shows decreased F-actin and β-tubulin expression in PANC-1 cells over-expressing miR-1181 compared with the control cells. Furthermore, we found that over-expressing miR-1181 inhibited the expression of signal transducer and activator of transcription 3 (STAT3) while knocking-down miR-1181 up-regulated the expression of STAT3. Knocking-down miR-1181 promoted the invasion and proliferation of pancreatic cancer cells. And inhibition of STAT3 blocked the promotion effects of knocking-down miR-1181 on proliferation and invasion in pancreatic cancer.
CONCLUSION Together our findings suggest that miR-1181 may be involved in pancreatic cancer cell invasion and proliferation by targeting STAT3 and indicate that miR-1181 may be a potential therapeutic agent for pancreatic cancer.
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Liu R, Tang C, Shen A, Luo H, Wei X, Zheng D, Sun C, Li Z, Zhu D, Li T, Wu Z. IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling. Oncotarget 2016; 7:85079-85096. [PMID: 27835881 PMCID: PMC5356721 DOI: 10.18632/oncotarget.13196] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 10/26/2016] [Indexed: 12/31/2022] Open
Abstract
IL-37 has been characterized as a fundamental inhibitor of innate immunity and a tumor suppressor in several cancers. However, the molecular mechanism of IL-37 in hepatocellular carcinoma (HCC) is largely unclear. In this study we found IL-37 expression was down-regulated in human HCC tissues and cell lines, and was negatively correlated with tumor size, vascular invasion, as well as overall-survial and disease-free survival (OS and DFS) of HCC. Multivariate Cox analysis revealed that IL-37 was an independent prognostic indicator for OS and DFS in HCC. Functional studies further showed that IL-37 overexpression significantly suppressed tumor growth by confining HCC to G2/M cell cycle arrest in vitro and in vivo. Mechanistically, we determined that IL-37 promoted Smad3 phospho-isoform signaling conversion from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/p21 tumor-suppressive signaling. Consistently, we detected a significant negative correlation between IL-37 expression and pSmad3L levels in a cohort of HCC biopsies; and the expression of pSmad3L predicted poorer outcome. These data highlight the importance of IL-37 in the cell proliferation and progression of HCC, and suggests that IL-37 may be a valuable biomarker for HCC prognosis.
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Affiliation(s)
- Rui Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Chengyong Tang
- Department of Clinical Pharmacology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ai Shen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Hepatobiliary Surgery, Chongqing Cancer Institute, Chongqing 400030, China
| | - Huating Luo
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xufu Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Daofeng Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Chao Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zhongtang Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Di Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Tingting Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Hua B, Li W, Chen C, Liu Z. Targeting Signal Transducer and Activator of Transcription 3 for Colorectal Cancer Prevention and Treatment with Natural Products. CANCER TRANSLATIONAL MEDICINE 2016. [DOI: 10.4103/2395-3977.181435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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