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1
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Malone K, LaCasse E, Beug ST. Cell death in glioblastoma and the central nervous system. Cell Oncol (Dordr) 2025; 48:313-349. [PMID: 39503973 PMCID: PMC11997006 DOI: 10.1007/s13402-024-01007-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2024] [Indexed: 04/15/2025] Open
Abstract
Glioblastoma is the commonest and deadliest primary brain tumor. Glioblastoma is characterized by significant intra- and inter-tumoral heterogeneity, resistance to treatment and dismal prognoses despite decades of research in understanding its biological underpinnings. Encompassed within this heterogeneity and therapy resistance are severely dysregulated programmed cell death pathways. Glioblastomas recapitulate many neurodevelopmental and neural injury responses; in addition, glioblastoma cells are composed of multiple different transformed versions of CNS cell types. To obtain a greater understanding of the features underlying cell death regulation in glioblastoma, it is important to understand the control of cell death within the healthy CNS during homeostatic and neurodegenerative conditions. Herein, we review apoptotic control within neural stem cells, astrocytes, oligodendrocytes and neurons and compare them to glioblastoma apoptotic control. Specific focus is paid to the Inhibitor of Apoptosis proteins, which play key roles in neuroinflammation, CNS cell survival and gliomagenesis. This review will help in understanding glioblastoma as a transformed version of a heterogeneous organ composed of multiple varied cell types performing different functions and possessing different means of apoptotic control. Further, this review will help in developing more glioblastoma-specific treatment approaches and will better inform treatments looking at more direct brain delivery of therapeutic agents.
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Affiliation(s)
- Kyle Malone
- Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Eric LaCasse
- Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Shawn T Beug
- Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
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2
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Nishii T, Osuka K, Nishimura Y, Ohmichi Y, Ohmichi M, Suzuki C, Nagashima Y, Oyama T, Abe T, Kato H, Saito R. Protective Mechanism of Stem Cells from Human Exfoliated Deciduous Teeth in Treating Spinal Cord Injury. J Neurotrauma 2024; 41:1196-1210. [PMID: 38185837 DOI: 10.1089/neu.2023.0251] [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] [Indexed: 01/09/2024] Open
Abstract
Spinal cord injury (SCI) induces devastating permanent deficits. Recently, cell transplantation therapy has become a notable treatment for SCI. Although stem cells from human exfoliated deciduous teeth (SHED) are an attractive therapy, their precise mechanism of action remains to be elucidated. In this study, we explored one of the neuroprotective mechanisms of SHED treatment at the subacute stage after SCI. We used a rat clip compression SCI model. The animals were randomly divided into three groups: SCI, SCI + phosphate-buffered saline (PBS), and SCI + SHED. The SHED or PBS intramedullary injection was administered immediately after SCI. After SCI, we explored the effects of SHED on motor function, as assessed by the Basso-Beattie-Bresnahan score and the inclined plane method, the signal transduction pathway, especially the Janus kinase (JAK) and the signal transducer and activator of transcription 3 (STAT3) pathway, the apoptotic pathway, and the expression of neurocan, one of the chondroitin sulfate proteoglycans. SHED treatment significantly improved functional recovery from Day 14 relative to the controls. Western blot analysis showed that SHED significantly reduced the expression of glial fibrillary acidic protein (GFAP) and phosphorylated STAT3 (p-STAT3) at Tyr705 on Day 10 but not on Day 5. However, SHED had no effect on the expression levels of Iba-1 on Days 5 or 10. Immunohistochemistry revealed that p-STAT3 at Tyr705 was mainly expressed in GFAP-positive astrocytes on Day 10 after SCI, and its expression was reduced by administration of SHED. Moreover, SHED treatment significantly induced expression of cleaved caspase 3 in GFAP-positive astrocytes only in the epicenter lesions on Day 10 after SCI but not on Day 5. The expression of neurocan was also significantly reduced by SHED injection on Day 10 after SCI. Our results show that SHED plays an important role in reducing astrogliosis and glial scar formation between Days 5 and 10 after SCI, possibly via apoptosis of astrocytes, ultimately resulting in improvement in neurological functions thereafter. Our data revealed one of the neuroprotective mechanisms of SHED at the subacute stage after SCI, which improved functional recovery after SCI, a serious condition.
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Affiliation(s)
- Tomoya Nishii
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Koji Osuka
- Department of Neurological Surgery, Aichi Medical University, Aichi, Japan
| | - Yusuke Nishimura
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusuke Ohmichi
- Department of Anatomy II, Kanazawa Medical University, Ishikawa, Japan
| | - Mika Ohmichi
- Department of Anatomy II, Kanazawa Medical University, Ishikawa, Japan
| | - Chiharu Suzuki
- Department of Neurological Surgery, Aichi Medical University, Aichi, Japan
| | - Yoshitaka Nagashima
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahiro Oyama
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Abe
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Kato
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ryuta Saito
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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3
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Adesoye T, Tripathy D, Hunt KK, Keyomarsi K. Exploring Novel Frontiers: Leveraging STAT3 Signaling for Advanced Cancer Therapeutics. Cancers (Basel) 2024; 16:492. [PMID: 38339245 PMCID: PMC10854592 DOI: 10.3390/cancers16030492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 02/12/2024] Open
Abstract
Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling pathways with ligand binding to receptor and non-receptor-linked kinases. Through downstream deregulation of target genes, aberrations in STAT3 activation are implicated in tumorigenesis, metastasis, and recurrence in multiple cancers. While there have been extensive efforts to develop direct and indirect STAT3 inhibitors using novel drugs as a therapeutic strategy, direct clinical application remains in evolution. In this review, we outline the mechanisms of STAT3 activation, the resulting downstream effects in physiologic and malignant settings, and therapeutic strategies for targeting STAT3. We also summarize the pre-clinical and clinical evidence of novel drug therapies targeting STAT3 and discuss the challenges of establishing their therapeutic efficacy in the current clinical landscape.
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Affiliation(s)
- Taiwo Adesoye
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Debasish Tripathy
- Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Kelly K. Hunt
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Khandan Keyomarsi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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4
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Molenda S, Sikorska A, Florczak A, Lorenc P, Dams-Kozlowska H. Oligonucleotide-Based Therapeutics for STAT3 Targeting in Cancer-Drug Carriers Matter. Cancers (Basel) 2023; 15:5647. [PMID: 38067351 PMCID: PMC10705165 DOI: 10.3390/cancers15235647] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 09/08/2024] Open
Abstract
High expression and phosphorylation of signal transducer and transcription activator 3 (STAT3) are correlated with progression and poor prognosis in various types of cancer. The constitutive activation of STAT3 in cancer affects processes such as cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. The importance of STAT3 in cancer makes it a potential therapeutic target. Various methods of directly and indirectly blocking STAT3 activity at different steps of the STAT3 pathway have been investigated. However, the outcome has been limited, mainly by the number of upstream proteins that can reactivate STAT3 or the relatively low specificity of the inhibitors. A new branch of molecules with significant therapeutic potential has emerged thanks to recent developments in the regulatory function of non-coding nucleic acids. Oligonucleotide-based therapeutics can silence target transcripts or edit genes, leading to the modification of gene expression profiles, causing cell death or restoring cell function. Moreover, they can reach untreatable targets, such as transcription factors. This review briefly describes oligonucleotide-based therapeutics that found application to target STAT3 activity in cancer. Additionally, this review comprehensively summarizes how the inhibition of STAT3 activity by nucleic acid-based therapeutics such as siRNA, shRNA, ASO, and ODN-decoy affected the therapy of different types of cancer in preclinical and clinical studies. Moreover, due to some limitations of oligonucleotide-based therapeutics, the importance of carriers that can deliver nucleic acid molecules to affect the STAT3 in cancer cells and cells of the tumor microenvironment (TME) was pointed out. Combining a high specificity of oligonucleotide-based therapeutics toward their targets and functionalized nanoparticles toward cell type can generate very efficient formulations.
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Affiliation(s)
- Sara Molenda
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Agata Sikorska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Anna Florczak
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Patryk Lorenc
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Hanna Dams-Kozlowska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
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Kawauchi D, Takahashi M, Satomi K, Yamamuro S, Kobayashi T, Uchida E, Honda-Kitahara M, Narita Y, Iwadate Y, Ichimura K, Tomiyama A. The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death. Cancer Sci 2021; 112:2442-2453. [PMID: 33728771 PMCID: PMC8177803 DOI: 10.1111/cas.14885] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/11/2021] [Accepted: 03/14/2021] [Indexed: 12/20/2022] Open
Abstract
Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second‐generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase‐dependent/‐independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second‐generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM.
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Affiliation(s)
- Daisuke Kawauchi
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.,Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masamichi Takahashi
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.,Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kaishi Satomi
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.,Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Shun Yamamuro
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.,Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Tatsuya Kobayashi
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.,Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Eita Uchida
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.,Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka-City, Japan
| | - Mai Honda-Kitahara
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan
| | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yasuo Iwadate
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Koichi Ichimura
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan
| | - Arata Tomiyama
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.,Department of Neurosurgery, National Defense Medical College, Tokorozawa, Japan
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6
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Razavi ZS, Tajiknia V, Majidi S, Ghandali M, Mirzaei HR, Rahimian N, Hamblin MR, Mirzaei H. Gynecologic cancers and non-coding RNAs: Epigenetic regulators with emerging roles. Crit Rev Oncol Hematol 2020; 157:103192. [PMID: 33290823 DOI: 10.1016/j.critrevonc.2020.103192] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 12/24/2022] Open
Abstract
Gynecologic cancers involve the female genital organs, such as the vulva, vagina, cervix, endometrium, ovaries, and fallopian tubes. The occurrence and frequency of gynecologic cancer depends on personal lifestyle, history of exposure to viruses or carcinogens, genetics, body shape, and geographical habitat. For a long time, research into the molecular biology of cancer was broadly restricted to protein-coding genes. Recently it has been realized that non-coding RNAs (ncRNA), including long noncoding RNAs (LncRNAs), microRNAs, circular RNAs and piRNAs (PIWI-interacting RNAs), can all play a role in the regulation of cellular function within gynecological cancer. It is now known that ncRNAs are able to play dual roles, i.e. can exert both oncogenic or tumor suppressive functions in gynecological cancer. Moreover, several clinical trials are underway looking at the biomarker and therapeutic roles of ncRNAs. These efforts may provide a new horizon for the diagnosis and treatment of gynecological cancer. Herein, we summarize some of the ncRNAs that have been shown to be important in gynecological cancers.
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Affiliation(s)
| | - Vida Tajiknia
- Department of Surgery, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shahab Majidi
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran
| | - Maryam Ghandali
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, 02114, USA; Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA; Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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7
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Khalil M, Khalifeh H, Baldini F, Serale N, Parodi A, Voci A, Vergani L, Daher A. Antitumor Activity of Ethanolic Extract from Thymbra Spicata L. aerial Parts: Effects on Cell Viability and Proliferation, Apoptosis Induction, STAT3, and NF-kB Signaling. Nutr Cancer 2020; 73:1193-1206. [PMID: 32696667 DOI: 10.1080/01635581.2020.1792517] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Thyme-like plants including Thymbra spicata L. are widely used as food and folk medicinal remedies in the Mediterranean area. This study aimed to explore the in vitro antitumor potential of polyphenol-enriched extracts from aerial parts of T. spicata. The ethanolic extract significantly inhibited proliferation of different human tumor cell lines, without significant effects on non-neoplastic cells. A deeper investigation of the molecular mechanism sustaining the in vitro antitumor activity of the extract was carried on the human breast cancer cells MCF-7 in comparison with the normal breast cells MCF-10A. The effects on MCF-7 cells were associated with the following: (i) production of reactive oxygen species (ROS) and release of nitric oxide; (ii) apoptosis induction; and (iii) reduction in STAT3 and NF-kB phosphorylation. The ethanolic extract from T. spicata leaves might represent a novel therapeutic tool in combination with conventional chemotherapy to reduce the adverse side effects and drug resistance.
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Affiliation(s)
- Mohamad Khalil
- Laboratory Rammal Rammal (ATAC), Faculty of Sciences, Lebanese University, Beirut, Lebanon.,Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Genova, Italy
| | - Hala Khalifeh
- Laboratory Rammal Rammal (ATAC), Faculty of Sciences, Lebanese University, Beirut, Lebanon
| | - Francesca Baldini
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Genova, Italy
| | - Nadia Serale
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Genova, Italy
| | - Alessia Parodi
- Centre of Excellence for Biomedical Research (CEBR), University of Genova, Genova, Italy
| | - Adriana Voci
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Genova, Italy
| | - Laura Vergani
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Genova, Italy
| | - Ahmad Daher
- Laboratory Rammal Rammal (ATAC), Faculty of Sciences, Lebanese University, Beirut, Lebanon
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8
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Gharibi T, Babaloo Z, Hosseini A, Abdollahpour-alitappeh M, Hashemi V, Marofi F, Nejati K, Baradaran B. Targeting STAT3 in cancer and autoimmune diseases. Eur J Pharmacol 2020; 878:173107. [DOI: 10.1016/j.ejphar.2020.173107] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 04/05/2020] [Accepted: 04/06/2020] [Indexed: 02/08/2023]
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Arshad S, Naveed M, Ullia M, Javed K, Butt A, Khawar M, Amjad F. Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges. Genet Mol Biol 2020; 43:e20180160. [PMID: 32167126 PMCID: PMC7198026 DOI: 10.1590/1678-4685-gmb-2018-0160] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 10/20/2018] [Indexed: 12/25/2022] Open
Abstract
Signal transducers and activators of transcription 3 (STAT-3) is a transcription
factor that regulates the gene expression of several target genes. These factors
are activated by the binding of cytokines and growth factors with STAT-3
specific receptors on cell membrane. Few years ago, STAT-3 was considered an
acute phase response element having several cellular functions such as
inflammation, cell survival, invasion, metastasis and proliferation, genetic
alteration, and angiogenesis. STAT-3 is activated by several types of
inflammatory cytokines, carcinogens, viruses, growth factors, and oncogenes.
Thus, the STAT3 pathway is a potential target for cancer therapeutics. Abnormal
STAT-3 activity in tumor development and cellular transformation can be targeted
by several genomic and pharmacological methodologies. An extensive review of the
literature has been conducted to emphasize the role of STAT-3 as a unique cancer
drug target. This review article discusses in detail the wide range of STAT-3
inhibitors that show antitumor effects both in vitro and
in vivo. Thus, targeting constitutive STAT-3 signaling is a
remarkable therapeutic methodology for tumor progression. Finally, current
limitations, trials and future perspectives of STAT-3 inhibitors are also
critically discussed.
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Affiliation(s)
- Sundas Arshad
- University of Lahore, Department of Allied Health Sciences, Gujrat Campus, Pakistan
| | - Muhammad Naveed
- University of Central Punjab, Faculty of life sciences, Department of Biotechnology, Lahore, Pakistan
| | - Mahad Ullia
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
| | - Khadija Javed
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
| | - Ayesha Butt
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
| | - Masooma Khawar
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
| | - Fazeeha Amjad
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
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10
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Cui B, Chen J, Luo M, Wang L, Chen H, Kang Y, Wang J, Zhou X, Feng Y, Zhang P. Protein kinase D3 regulates the expression of the immunosuppressive protein, PD‑L1, through STAT1/STAT3 signaling. Int J Oncol 2020; 56:909-920. [PMID: 32319563 PMCID: PMC7050980 DOI: 10.3892/ijo.2020.4974] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 12/17/2019] [Indexed: 12/20/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is capable of constructing a favorable immune escape environment through interactions of cells with cells and of cells with the environment. Programmed death ligand-1 (PD-L1) is a well-recognized inhibitor of anti-tumor immunity that plays an important role in tumor immune escape. However, the molecular mechanisms regulating PD-L1 expression are not yet fully understood. In this study, to investigate the role of protein kinase D3 (PKD3) in the regulation of PD-L1 expression, the expression and correlation of PKD3 and PD-L1 were first analyzed by the immunostaining of human OSCC tissue sections, cell experiments and TCGA gene expression databases. The expression levels of PKD3 and PD-L1 were found to be significantly higher in OSCC cells than in normal tissues or cells. In addition, the expression levels of PKD3 and PD-L1 were found to be significantly positively correlated. Subsequently, it was found that the levsel of PD-L1 expression decreased following the silencing of PKD3 and that the ability of interferon (IFN)-γ to induce PD-L1 expression was also decreased in OSCC. The opposite phenomenon occurred following the overexpression of PKD3. It was also found that the phosphorylation of signal transducer and activator of transcription (STAT)1/STAT3 was reduced by the knockdown of PKD3 in OSCC. Moreover, the expression level of PD-L1 was decreased after the use of siRNA to knockdown STAT1 or STAT3. On the whole, the findings of this study confirm that PKD3 regulates the expression of PD-L1 induced by IFN-γ by regulating the phosphorylation of STAT1/STAT3. These findings broaden the understanding of the biological function of PKD3, suggesting that PKD is a potential therapeutic target for OSCC.
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Affiliation(s)
- Bomiao Cui
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jiao Chen
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Min Luo
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Liwei Wang
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hongli Chen
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yingzhu Kang
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jingnan Wang
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yun Feng
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ping Zhang
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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11
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Swiatek-Machado K, Kaminska B. STAT Signaling in Glioma Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1202:203-222. [PMID: 32034715 DOI: 10.1007/978-3-030-30651-9_10] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.
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Affiliation(s)
- Karolina Swiatek-Machado
- Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St, PL 02-093, Warsaw, Poland.
| | - Bozena Kaminska
- Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St, PL 02-093, Warsaw, Poland
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Ashrafizadeh M, Ahmadi Z, Kotla NG, Afshar EG, Samarghandian S, Mandegary A, Pardakhty A, Mohammadinejad R, Sethi G. Nanoparticles Targeting STATs in Cancer Therapy. Cells 2019; 8:E1158. [PMID: 31569687 PMCID: PMC6829305 DOI: 10.3390/cells8101158] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 12/12/2022] Open
Abstract
Over the past decades, an increase in the incidence rate of cancer has been witnessed. Although many efforts have been made to manage and treat this life threatening condition, it is still one of the leading causes of death worldwide. Therefore, scientists have attempted to target molecular signaling pathways involved in cancer initiation and metastasis. It has been shown that signal transducers and activator of transcription (STAT) contributes to the progression of cancer cells. This important signaling pathway is associated with a number of biological processes including cell cycle, differentiation, proliferation and apoptosis. It appears that dysregulation of the STAT signaling pathway promotes the migration, viability and malignancy of various tumor cells. Hence, there have been many attempts to target the STAT signaling pathway. However, it seems that currently applied therapeutics may not be able to effectively modulate the STAT signaling pathway and suffer from a variety of drawbacks such as low bioavailability and lack of specific tumor targeting. In the present review, we demonstrate how nanocarriers can be successfully applied for encapsulation of STAT modulators in cancer therapy.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 5166616471, Iran.
| | - Zahra Ahmadi
- Department of Basic Science, Shoushtar Branch, Islamic Azad University, Shoushtar 6451741117, Iran.
| | - Niranjan G Kotla
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Newcastle, Galway H91 W2TY, Ireland.
| | - Elham Ghasemipour Afshar
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7619813159, Iran.
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur 9318614139, Iran.
| | - Ali Mandegary
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7619813159, Iran.
| | - Abbas Pardakhty
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7619813159, Iran.
| | - Reza Mohammadinejad
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7616911319, Iran.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
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Megalencephalic Leukoencephalopathy with Subcortical Cysts Protein-1 (MLC1) Counteracts Astrocyte Activation in Response to Inflammatory Signals. Mol Neurobiol 2019; 56:8237-8254. [DOI: 10.1007/s12035-019-01657-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/20/2019] [Indexed: 01/08/2023]
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14
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Kalo D, Vitorino Carvalho A, Archilla C, Duranthon V, Moroldo M, Levin Y, Kupervaser M, Smith Y, Roth Z. Mono(2-ethylhexyl) phthalate (MEHP) induces transcriptomic alterations in oocytes and their derived blastocysts. Toxicology 2019; 421:59-73. [DOI: 10.1016/j.tox.2019.04.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/27/2019] [Accepted: 04/29/2019] [Indexed: 12/16/2022]
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15
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Sharma J, Larkin J. Therapeutic Implication of SOCS1 Modulation in the Treatment of Autoimmunity and Cancer. Front Pharmacol 2019; 10:324. [PMID: 31105556 PMCID: PMC6499178 DOI: 10.3389/fphar.2019.00324] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 03/18/2019] [Indexed: 12/14/2022] Open
Abstract
The suppressor of cytokine signaling (SOCS) family of intracellular proteins has a vital role in the regulation of the immune system and resolution of inflammatory cascades. SOCS1, also called STAT-induced STAT inhibitor (SSI) or JAK-binding protein (JAB), is a member of the SOCS family with actions ranging from immune modulation to cell cycle regulation. Knockout of SOCS1 leads to perinatal lethality in mice and increased vulnerability to cancer, while several SNPs associated with the SOCS1 gene have been implicated in human inflammation-mediated diseases. In this review, we describe the mechanism of action of SOCS1 and its potential therapeutic role in the prevention and treatment of autoimmunity and cancer. We also provide a brief outline of the other JAK inhibitors, both FDA-approved and under investigation.
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Affiliation(s)
- Jatin Sharma
- Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, United States
| | - Joseph Larkin
- Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, United States
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16
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Loh CY, Arya A, Naema AF, Wong WF, Sethi G, Looi CY. Signal Transducer and Activator of Transcription (STATs) Proteins in Cancer and Inflammation: Functions and Therapeutic Implication. Front Oncol 2019; 9:48. [PMID: 30847297 PMCID: PMC6393348 DOI: 10.3389/fonc.2019.00048] [Citation(s) in RCA: 243] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 01/17/2019] [Indexed: 01/10/2023] Open
Abstract
Signal Transducer and Activator of Transcription (STAT) pathway is connected upstream with Janus kinases (JAK) family protein and capable of integrating inputs from different signaling pathways. Each family member plays unique functions in signal transduction and crucial in mediating cellular responses to different kind of cytokines. STAT family members notably STAT3 and STAT5 have been involved in cancer progression whereas STAT1 plays opposite role by suppressing tumor growth. Persistent STAT3/5 activation is known to promote chronic inflammation, which increases susceptibility of healthy cells to carcinogenesis. Here, we review the role of STATs in cancers and inflammation while discussing current therapeutic implications in different cancers and test models, especially the delivery of STAT3/5 targeting siRNA using nanoparticulate delivery system.
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Affiliation(s)
- Chin-Yap Loh
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Aditya Arya
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Ahmed Fadhil Naema
- Center of Biotechnology Researches, University of Al-Nahrain, Baghdad, Iraq
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
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17
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Zhao X, Cheng Z, Wang J. Long Noncoding RNA FEZF1-AS1 Promotes Proliferation and Inhibits Apoptosis in Ovarian Cancer by Activation of JAK-STAT3 Pathway. Med Sci Monit 2018; 24:8088-8095. [PMID: 30416194 PMCID: PMC6243867 DOI: 10.12659/msm.911194] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) have been acknowledged as important regulators in human cancers, including ovarian cancer. Several reports identified lncRNA FEZF1-AS1 as an oncogene in gastric cancer, colorectal carcinoma, and non-small cell lung cancer (NSCLC). However, the function of FEZF1-AS1 in ovarian cancer remains largely unknown. This study was aimed to investigate the role of FEZF1-AS1 in ovarian cancer. MATERIAL AND METHODS FEZF1-AS1 expression levels in pairs of ovarian cancer tissues and adjacent normal tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier curve analysis was used to determine the correlation between FEZF1-AS1 expression and prognosis in ovarian cancer patients. The effects of FEZF1-AS1 knockdown on ovarian cancer cell proliferation, cell-cycle, and apoptosis were analyzed by Cell Counting Kit-8 (CCK8) and Fluorescence activated Cell Sorting (FACS) assays. Western blot was utilized to assess the effect of FEZF1-AS1 on the activation of JAK-STAT3 pathway. RESULTS FEZF1-AS1 was overexpressed in ovarian cancer tissues compared to adjacent normal tissues. Consistently, FEZF1-AS1 expression was also upregulated in ovarian cancer cell lines compared with normal cell line. Furthermore, higher expression of FEZF1-AS1 in ovarian cancer patients contributed to poorer prognosis. FEZF1-AS1 knockdown significantly suppressed the proliferation and promoted apoptosis in ovarian cancer cells. In mechanism, FEZF1-AS1 regulated activation of JAK-STAT3 signaling pathway by modulating STAT3 phosphorylation. Knockdown of FEZF1-AS1 significantly impaired the phosphorylation of STAT3. CONCLUSIONS Our study demonstrated that FEZF1-AS1 exerted an oncogenic role in ovarian cancer via modulating JAK-STAT3 pathway.
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Affiliation(s)
- Xia Zhao
- Department of Obstetrics and Gynecology, The People's Hospital of Zhangqiu District, Jinan, Shandong, China (mainland)
| | - Zhaofang Cheng
- Department of Obstetrics and Gynecology, The People's Hospital of Zhangqiu District, Jinan, Shandong, China (mainland)
| | - Jian Wang
- Department of Obstetrics and Gynaecology, Zaozhuang Municipal Hospital, Zaozhuang, Shandong, China (mainland)
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Sun X, Wang J, Huang M, Chen T, Chen J, Zhang F, Zeng H, Xu Z, Ke Y. STAT3 promotes tumour progression in glioma by inducing FOXP1 transcription. J Cell Mol Med 2018; 22:5629-5638. [PMID: 30134017 PMCID: PMC6201216 DOI: 10.1111/jcmm.13837] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 06/21/2018] [Indexed: 01/25/2023] Open
Abstract
Objective This paper investigated the effects of STAT3 through promoting FOXP1 transcription on proliferation, apoptosis and invasion in glioma cells. Methods Quantitative real‐time PCR (qRT‐PCR) and Western blot assay were administered to assess the mRNA and protein expression levels of STAT3 and FOXP1 in glioma tissues and cells, respectively. Luciferase reporter and Chromatin Immunoprecipitation (ChIP) assays were implemented to determine the correlation between STAT3 and FOXP1. MTT and colony formation assays were conducted to identify cell growth. Flow cytometry was run to detect the cell apoptosis rate of glioma cells. Transwell assays were conducted to reveal cell invasion ability. Results The mRNA and protein expression levels of STAT3 were highly expressed in glioma tissues and cells. After cells transfected with siRNA of STAT3, both STAT3 and FOXP1 were simultaneously downregulated. STAT3 directly regulated FOXP1 transcription. STAT3 promoted cell proliferation, inhibited cell apoptosis and enhanced cell invasion through promoting FOXP1 transcription in glioma cells. Conclusion In summary, STAT3 gene was a transcriptional regulator of FOXP1. Depleted STAT3 restrained cell proliferation and invasion, promoted cell apoptosis in glioma cells. This molecular mechanism between STAT3 and FOXP1 can serve as a therapeutic target for glioma treatment.
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Affiliation(s)
- Xinlin Sun
- National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jihui Wang
- National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Min Huang
- National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Taoliang Chen
- National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jiansheng Chen
- National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fabing Zhang
- National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Huijun Zeng
- National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhimin Xu
- Affiliated Bayi Brain Hospital, PLA General Army Hospital, Beijing, China
| | - Yiquan Ke
- National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Kim M, Baek M, Kim DJ. Protein Tyrosine Signaling and its Potential Therapeutic Implications in Carcinogenesis. Curr Pharm Des 2018. [PMID: 28625132 DOI: 10.2174/1381612823666170616082125] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Protein tyrosine phosphorylation is a crucial signaling mechanism that plays a role in epithelial carcinogenesis. Protein tyrosine kinases (PTKs) control various cellular processes including growth, differentiation, metabolism, and motility by activating major signaling pathways including STAT3, AKT, and MAPK. Genetic mutation of PTKs and/or prolonged activation of PTKs and their downstream pathways can lead to the development of epithelial cancer. Therefore, PTKs became an attractive target for cancer prevention. PTK inhibitors are continuously being developed, and they are currently used for the treatment of cancers that show a high expression of PTKs. Protein tyrosine phosphatases (PTPs), the homeostatic counterpart of PTKs, negatively regulate the rate and duration of phosphotyrosine signaling. PTPs initially were considered to be only housekeeping enzymes with low specificity. However, recent studies have demonstrated that PTPs can function as either tumor suppressors or tumor promoters, depending on their target substrates. Together, both PTK and PTP signal transduction pathways are potential therapeutic targets for cancer prevention and treatment.
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Affiliation(s)
- Mihwa Kim
- Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Minwoo Baek
- Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Dae Joon Kim
- Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
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20
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KIAA0247 suppresses the proliferation, angiogenesis and promote apoptosis of human glioma through inactivation of the AKT and Stat3 signaling pathway. Oncotarget 2018; 7:87100-87113. [PMID: 27893430 PMCID: PMC5349974 DOI: 10.18632/oncotarget.13527] [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] [Received: 08/19/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023] Open
Abstract
Gliomas are the most common and aggressive type of primary adult brain tumors. Although KIAA0247 previously is a speculated target of the tumor suppressor gene, little is known about the association between KIAA0247 and glioma. In this study, we clearly demonstrate that KIAA0247 expression is decreased in glioma and was negatively correlated with the histologic grade. Overexpression of KIAA0247 in glioma cells inhibits proliferation, angiogenesis and promoted apoptosis of human glioma cells in vitro. In contrast, knockdown of KIAA0247 increases the proliferation, angiogenesis and decreases apoptosis of these cells. In a tumor xenograft model, overexpression of KIAA0247 suppresses tumor growth of glioma cells in vivo, while KIAA0247 knockdown promotes the tumor growth. Mechanistically, overexpression of KIAA0247 is able to inhibit phosphorylation of AKT and Stat3 in glioma cells, resulting in inactivation of the AKT and Stat3 signaling pathways, this ultimately decreases the expression of PCNA, CyclinD1, Bcl2 and VEGF. Collectively, these data indicate that KIAA0247 may work as a tumor suppressor gene in glioma and a promising therapeutic target for gliomas.
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21
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Wu D, Cheng J, Sun G, Wu S, Li M, Gao Z, Zhai S, Li P, Su D, Wang X. p70S6K promotes IL-6-induced epithelial-mesenchymal transition and metastasis of head and neck squamous cell carcinoma. Oncotarget 2017; 7:36539-36550. [PMID: 27174914 PMCID: PMC5095019 DOI: 10.18632/oncotarget.9282] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 04/24/2016] [Indexed: 12/14/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide and a common cause of cancer-related death, with a 5-year survival rate of less than 60%. IL-6 has been suggested to play an important role in cancer metastasis, but its mechanism in HNSCC has not been fully clarified. p70S6K has been reported to induce epithelial-mesenchymal transition (EMT) of ovarian cancer, but its role in HNSCC remains unknown. In this study, we found that p70S6K and IL-6 were upregulated in high-metastatic HNSCC cell lines that underwent EMT when compared to paired low-metastatic cell lines. Overexpression of p70S6K promoted EMT and migration of HNSCC cells, while downregulation of p70S6K attenuated IL-6-induced EMT and cell migration. Furthermore, IL-6-induced p70S6K activation was attenuated by inhibitors of the PI3K/Akt/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways, suggesting that it located downstream of these pathways. These findings suggest that p70S6K promotes IL-6-induced EMT and metastasis of HNSCC. Targeting p70S6K for HNSCC therapy may benefit patients through the inhibition of tumor growth, as well as metastasis.
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Affiliation(s)
- Dandan Wu
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.,Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang, Jiangsu Province 222000, China
| | - Jie Cheng
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
| | - Geng Sun
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
| | - Shengjie Wu
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
| | - Min Li
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
| | - Zhongyuan Gao
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
| | - Sulan Zhai
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
| | - Ping Li
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
| | - Dongming Su
- Center for Clinical Pathology and Laboratory, Affiliated Hospital of Yifu, Nanjing Medical University, Nanjing, Jiangsu Province 211166, China.,Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
| | - Xuerong Wang
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.,Center for Clinical Pathology and Laboratory, Affiliated Hospital of Yifu, Nanjing Medical University, Nanjing, Jiangsu Province 211166, China.,Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China
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22
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Portillo JAC, Muniz-Feliciano L, Lopez Corcino Y, Lee SJ, Van Grol J, Parsons SJ, Schiemman WP, Subauste CS. Toxoplasma gondii induces FAK-Src-STAT3 signaling during infection of host cells that prevents parasite targeting by autophagy. PLoS Pathog 2017; 13:e1006671. [PMID: 29036202 PMCID: PMC5658194 DOI: 10.1371/journal.ppat.1006671] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 10/26/2017] [Accepted: 09/26/2017] [Indexed: 02/01/2023] Open
Abstract
Targeting of Toxoplasma gondii by autophagy is an effective mechanism by which host cells kill the protozoan. Thus, the parasite must avoid autophagic targeting to survive. Here we show that the mammalian cytoplasmic molecule Focal Adhesion Kinase (FAK) becomes activated during invasion of host cells. Activated FAK appears to accompany the formation of the moving junction (as assessed by expression the parasite protein RON4). FAK activation was inhibited by approaches that impaired β1 and β3 integrin signaling. FAK caused activation of Src that in turn mediated Epidermal Growth Factor Receptor (EGFR) phosphorylation at the unique Y845 residue. Expression of Src-resistant Y845F EGFR mutant markedly inhibited ROP16-independent activation of STAT3 in host cells. Activation of FAK, Y845 EGFR or STAT3 prevented activation of PKR and eIF2α, key stimulators of autophagy. Genetic or pharmacologic inhibition of FAK, Src, EGFR phosphorylation at Y845, or STAT3 caused accumulation of the autophagy protein LC3 and LAMP-1 around the parasite and parasite killing dependent on autophagy proteins (ULK1 and Beclin 1) and lysosomal enzymes. Parasite killing was inhibited by expression of dominant negative PKR. Thus, T. gondii activates a FAK→Src→Y845-EGFR→STAT3 signaling axis within mammalian cells, thereby enabling the parasite to survive by avoiding autophagic targeting through a mechanism likely dependent on preventing activation of PKR and eIF2α.
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Affiliation(s)
- Jose-Andres C. Portillo
- Department of Medicine, Division of Infectious Disease and HIV Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
| | - Luis Muniz-Feliciano
- Department of Medicine, Division of Infectious Disease and HIV Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
| | - Yalitza Lopez Corcino
- Department of Medicine, Division of Infectious Disease and HIV Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
| | - So Jung Lee
- Department of Medicine, Division of Infectious Disease and HIV Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
| | - Jennifer Van Grol
- Department of Medicine, Division of Infectious Disease and HIV Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
| | - Sarah J. Parsons
- Department of Microbiology and Cancer Center, University of Virginia, Charlottesville, VA, United States of America
| | - William P. Schiemman
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States of America
| | - Carlos S. Subauste
- Department of Medicine, Division of Infectious Disease and HIV Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America
- * E-mail:
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Chang N, Ahn SH, Kong DS, Lee HW, Nam DH. The role of STAT3 in glioblastoma progression through dual influences on tumor cells and the immune microenvironment. Mol Cell Endocrinol 2017; 451:53-65. [PMID: 28089821 DOI: 10.1016/j.mce.2017.01.004] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 01/05/2017] [Indexed: 01/07/2023]
Abstract
Glioblastoma multiforme (GBM) is the most aggressive form of cancer that begins within the brain; generally, the patient has a dismal prognosis and limited therapeutic options. Signal transducer and activator of transcription 3 (STAT3) is a critical mediator of tumorigenesis, tumor progression, and suppression of anti-tumor immunity in GBM. In a high percentage of GBM cells and tumor microenvironments, persistent activation of STAT3 induces cell proliferation, anti-apoptosis, glioma stem cell maintenance, tumor invasion, angiogenesis, and immune evasion. This makes STAT3 an attractive therapeutic target and a prognostic indicator in GBM. Targeting STAT3 affords an opportunity to disrupt multiple pro-oncogenic pathways at a single molecular hub. Unfortunately, there are no successful STAT3 inhibitors currently in clinical trials. However, strong clinical evidence implicating STAT3 as a major factor in GBM justifies the identification of safe and effective strategies for inhibiting STAT3.
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Affiliation(s)
- Nakho Chang
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, South Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, South Korea
| | - Sun Hee Ahn
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, South Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, South Korea
| | - Doo-Sik Kong
- Departments of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
| | - Hye Won Lee
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, South Korea; Institute for Future Medicine, Samsung Medical Center, Seoul 06351, South Korea.
| | - Do-Hyun Nam
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, South Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, South Korea; Departments of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.
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24
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Sen M, Johnston PA, Pollock NI, DeGrave K, Joyce SC, Freilino ML, Hua Y, Camarco DP, Close DA, Huryn DM, Wipf P, Grandis JR. Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines. J Chem Biol 2017; 10:129-141. [PMID: 28684999 DOI: 10.1007/s12154-017-0169-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 04/06/2017] [Indexed: 12/13/2022] Open
Abstract
Studies indicate that elevated interleukin-6 (IL-6) levels engage IL6Rα-gp130 receptor complexes to activate signal transducer and activator of transcription 3 (STAT3) that is hyperactivated in many cancers including head and neck squamous cell carcinoma (HNSCC). Our previous HCS campaign identified several hits that selectively blocked IL-6-induced STAT3 activation. This study describes our investigation of the mechanism(s) of action of three of the four chemical series that progressed to lead activities: a triazolothiadiazine (864669), amino alcohol (856350), and an oxazole-piperazine (4248543). We demonstrated that all three blocked IL-6-induced upregulation of the cyclin D1 and Bcl-XL STAT3 target genes. None of the compounds exhibited direct binding interactions with STAT3 in surface plasmon resonance (SPR) binding assays; neither did they inhibit the recruitment and binding of a phospho-tyrosine-gp130 peptide to STAT3 in a fluorescence polarization assay. Furthermore, they exhibited little or no inhibition in a panel of 83 cancer-associated in vitro kinase profiling assays, including lack of inhibition of IL-6-induced Janus kinase (JAK 1, 2, and 3) activation. Further, 864669 and 4248543 selectively inhibited IL-6-induced STAT3 activation but not that induced by oncostatin M (OSM). The compounds 864669 and 4248543 abrogated IL-6-induced phosphorylation of the gp130 signaling subunit (phospho-gp130Y905) of the IL-6-receptor complex in HNSCC cell lines which generate docking sites for the SH2 domains of STAT3. Our data indicate that 864669 and 4248543 block IL-6-induced STAT activation by interfering with the recruitment, assembly, or activation of the hexamer-activated IL-6/IL-6Rα/gp130 signaling complex that occurs after IL-6 binding to IL-6Rα subunits.
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Affiliation(s)
- Malabika Sen
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Paul A Johnston
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Netanya I Pollock
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Kara DeGrave
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Sonali C Joyce
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Maria L Freilino
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Yun Hua
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Daniel P Camarco
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - David A Close
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Donna M Huryn
- University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260 USA
| | - Peter Wipf
- University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260 USA
| | - Jennifer R Grandis
- Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94118 USA.,Clinical and Translational Science Institute, University of California, San Francisco, Box 0558, 550 16th Street, San Francisco, CA 94143 USA
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25
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Mathupala SP, Guthikonda M, Sloan AE. RNAi Based Approaches to the Treatment of Malignant Glioma. Technol Cancer Res Treat 2016; 5:261-9. [PMID: 16700622 DOI: 10.1177/153303460600500313] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
RNA interference (RNAi) is a recently discovered, powerful molecular mechanism that can be harnessed to engineer gene-specific silencing in mammalian tissues. A mechanism, where short double-stranded RNA (dsRNA) molecules, when introduced into cells elicit specific “knock-down” of gene expression via degradation of targeted messenger RNA, has lately become the technique of choice for analysis of gene function in oncology research. Thus, RNAi is currently being extensively evaluated as a potential therapeutic strategy against malignant gliomas, since surgical, radiological, and chemotherapeutic interventions during the past few decades have done little to improve the poor prognosis rate for patients with these dreaded tumors. This review summarizes the pre-clinical studies that are currently underway to test the validity of RNAi as a potential therapeutic strategy against malignant gliomas, and discusses the potential technical Hurdles that remain to be overcome before the technique can become a promising clinical therapy to combat this frequently lethal disease.
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Affiliation(s)
- Saroj P Mathupala
- Department of Neurological Surgery, Karmanos Cancer Institute, Wayne State University School of Medicine, 808 HWCRC, 4100 John R. Road, Detroit, MI 48201, USA.
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26
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Bharadwaj U, Kasembeli MM, Tweardy DJ. STAT3 Inhibitors in Cancer: A Comprehensive Update. ACTA ACUST UNITED AC 2016. [DOI: 10.1007/978-3-319-42949-6_5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Ouédraogo ZG, Biau J, Kemeny JL, Morel L, Verrelle P, Chautard E. Role of STAT3 in Genesis and Progression of Human Malignant Gliomas. Mol Neurobiol 2016; 54:5780-5797. [PMID: 27660268 DOI: 10.1007/s12035-016-0103-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 09/06/2016] [Indexed: 12/23/2022]
Abstract
Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in glioblastoma and has been identified as a relevant therapeutic target in this disease and many other human cancers. After two decades of intensive research, there is not yet any approved STAT3-based glioma therapy. In addition to the canonical activation by tyrosine 705 phosphorylation, concordant reports described a potential therapeutic relevance of other post-translational modifications including mainly serine 727 phosphorylation. Such reports reinforce the need to refine the strategy of targeting STAT3 in each concerned disease. This review focuses on the role of serine 727 and tyrosine 705 phosphorylation of STAT3 in glioma. It explores their contribution to glial cell transformation and to the mechanisms that make glioma escape to both immune control and standard treatment.
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Affiliation(s)
- Zangbéwendé Guy Ouédraogo
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, Clermont-Ferrand, France.,Département de Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, Centre Jean Perrin, EA7283 CREaT - Université d'Auvergne, 58 rue Montalembert, F-63000-63011, Clermont Ferrand, France.,Laboratoire de Pharmacologie, de Toxicologie et de Chimie Thérapeutique, Université de Ouagadougou, 03, Ouagadougou, BP 7021, Burkina Faso
| | - Julian Biau
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, Clermont-Ferrand, France.,Département de Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, Centre Jean Perrin, EA7283 CREaT - Université d'Auvergne, 58 rue Montalembert, F-63000-63011, Clermont Ferrand, France.,Département de Radiothérapie, Institut Curie, 91405, Orsay, France
| | - Jean-Louis Kemeny
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, Clermont-Ferrand, France.,CHU Clermont-Ferrand, Service d'Anatomopathologie, F-63003, Clermont-Ferrand, France
| | - Laurent Morel
- Clermont Université, Université Blaise-Pascal, GReD, UMR CNRS 6293, INSERM U1103, 24 Avenue des Landais BP80026, 63171, Aubière, France
| | - Pierre Verrelle
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, Clermont-Ferrand, France.,Département de Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, Centre Jean Perrin, EA7283 CREaT - Université d'Auvergne, 58 rue Montalembert, F-63000-63011, Clermont Ferrand, France.,Département de Radiothérapie, Institut Curie, 91405, Orsay, France
| | - Emmanuel Chautard
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, Clermont-Ferrand, France. .,Département de Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, Centre Jean Perrin, EA7283 CREaT - Université d'Auvergne, 58 rue Montalembert, F-63000-63011, Clermont Ferrand, France.
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28
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Baburajeev CP, Mohan CD, Patil GS, Rangappa S, Pandey V, Sebastian A, Fuchs JE, Bender A, Lobie PE, Basappa B, Rangappa KS. Nano-cuprous oxide catalyzed one-pot synthesis of a carbazole-based STAT3 inhibitor: a facile approach via intramolecular C–N bond formation reactions. RSC Adv 2016. [DOI: 10.1039/c6ra01906d] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
In this study, we report the one-pot synthesis of substituted carbazole derivatives using nano cuprous oxide as a catalyst and demonstrated the STAT3 inhibitory activity of new compounds.
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Affiliation(s)
- C. P. Baburajeev
- Laboratory of Chemical Biology
- Department of Chemistry
- Bangalore University
- Bangalore 560001
- India
| | | | | | - Shobith Rangappa
- Frontier Research Center for Post-Genome Science and Technology
- Hokkaido University
- Sapporo 060-0808
- Japan
| | - Vijay Pandey
- Cancer Science Institute of Singapore
- National University of Singapore
- Singapore 117599
| | - Anusha Sebastian
- Laboratory of Chemical Biology
- Department of Chemistry
- Bangalore University
- Bangalore 560001
- India
| | - Julian E. Fuchs
- Centre for Molecular Informatics
- Department of Chemistry
- University of Cambridge
- Cambridge
- UK
| | - Andreas Bender
- Centre for Molecular Informatics
- Department of Chemistry
- University of Cambridge
- Cambridge
- UK
| | - Peter E. Lobie
- Cancer Science Institute of Singapore
- National University of Singapore
- Singapore 117599
| | - Basappa Basappa
- Laboratory of Chemical Biology
- Department of Chemistry
- Bangalore University
- Bangalore 560001
- India
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29
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E804 induces growth arrest, differentiation and apoptosis of glioblastoma cells by blocking Stat3 signaling. J Neurooncol 2015; 125:265-75. [DOI: 10.1007/s11060-015-1917-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 08/31/2015] [Indexed: 12/31/2022]
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Ouédraogo ZG, Müller-Barthélémy M, Kemeny JL, Dedieu V, Biau J, Khalil T, Raoelfils LI, Granzotto A, Pereira B, Beaudoin C, Guissou IP, Berger M, Morel L, Chautard E, Verrelle P. STAT3 Serine 727 Phosphorylation: A Relevant Target to Radiosensitize Human Glioblastoma. Brain Pathol 2015; 26:18-30. [PMID: 25736961 DOI: 10.1111/bpa.12254] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 02/03/2015] [Indexed: 01/23/2023] Open
Abstract
Radiotherapy is an essential component of glioma standard treatment. Glioblastomas (GBM), however, display an important radioresistance leading to tumor recurrence. To improve patient prognosis, there is a need to radiosensitize GBM cells and to circumvent the mechanisms of resistance caused by interactions between tumor cells and their microenvironment. STAT3 has been identified as a therapeutic target in glioma because of its involvement in mechanisms sustaining tumor escape to both standard treatment and immune control. Here, we studied the role of STAT3 activation on tyrosine 705 (Y705) and serine 727 (S727) in glioma radioresistance. This study explored STAT3 phosphorylation on Y705 (pSTAT3-Y705) and S727 (pSTAT3-S727) in glioma cell lines and in clinical samples. Radiosensitizing effect of STAT3 activation down-modulation by Gö6976 was explored. In a panel of 15 human glioma cell lines, we found that the level of pSTAT3-S727 was correlated to intrinsic radioresistance. Moreover, treating GBM cells with Gö6976 resulted in a highly significant radiosensitization associated to a concomitant pSTAT3-S727 down-modulation only in GBM cell lines that exhibited no or weak pSTAT3-Y705. We report the constitutive activation of STAT3-S727 in all GBM clinical samples. Targeting pSTAT3-S727 mainly in pSTAT3-Y705-negative GBM could be a relevant approach to improve radiation therapy.
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Affiliation(s)
- Zangbéwendé Guy Ouédraogo
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.,Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France.,Laboratoire de Pharmacologie, de Toxicologie et de Chimie Thérapeutique, Université de Ouagadougou, 03 BP 7021, OUAGADOUGOU 03, BURKINA FASO
| | - Mélanie Müller-Barthélémy
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.,Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France
| | - Jean-Louis Kemeny
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.,CHU Clermont-Ferrand, Service d'Anatomopathologie, F-63003, CLERMONT-FERRAND, France
| | - Véronique Dedieu
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.,Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France
| | - Julian Biau
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.,Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France.,Institut Curie, CNRS UMR3347, INSERM U2021, 91405, Orsay, France
| | - Toufic Khalil
- CHU Clermont-Ferrand, Service de Neurochirurgie, F-63003, CLERMONT-FERRAND, France.,Clermont Université, Université d'Auvergne, EA 7282, IGCNC, BP 10448, F-63000, CLERMONT-FERRAND, France
| | - Lala Ines Raoelfils
- Centre Jean Perrin, Service D'anatomopathologie, F-63000, CLERMONT-FERRAND, France
| | | | - Bruno Pereira
- CHU Clermont-Ferrand, Biostatistics unit, DRCI, F-63003, CLERMONT-FERRAND, France
| | - Claude Beaudoin
- Clermont Université, Université Blaise-Pascal, GReD, UMR CNRS 6293, INSERM U1103, 24 Avenue des Landais BP80026, 63171 Aubière 63177, AUBIERE, France
| | - Innocent Pierre Guissou
- Laboratoire de Pharmacologie, de Toxicologie et de Chimie Thérapeutique, Université de Ouagadougou, 03 BP 7021, OUAGADOUGOU 03, BURKINA FASO
| | - Marc Berger
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.,CHU Clermont-Ferrand, Service d'Hématologie Biologique/Immunologie, F-63003, CLERMONT-FERRAND, France
| | - Laurent Morel
- Clermont Université, Université Blaise-Pascal, GReD, UMR CNRS 6293, INSERM U1103, 24 Avenue des Landais BP80026, 63171 Aubière 63177, AUBIERE, France
| | - Emmanuel Chautard
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.,Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France
| | - Pierre Verrelle
- Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.,Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France
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Koppaka V, Lakshman N, Petroll WM. Effect of HDAC Inhibitors on Corneal Keratocyte Mechanical Phenotypes in 3-D Collagen Matrices. Mol Vis 2015; 21:502-14. [PMID: 25999677 PMCID: PMC4415596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 04/27/2015] [Indexed: 11/24/2022] Open
Abstract
PURPOSE Histone deacetylase inhibitors (HDAC) have been shown to inhibit the TGFβ-induced myofibroblast transformation of corneal fibroblasts in 2-D culture. However, the effect of HDAC inhibitors on keratocyte spreading, contraction, and matrix remodeling in 3-D culture has not been directly assessed. The goal of this study was to investigate the effects of the HDAC inhibitors Trichostatin A (TSA) and Vorinostat (SAHA) on corneal keratocyte mechanical phenotypes in 3-D culture using defined serum-free culture conditions. METHODS Rabbit corneal keratocytes were plated within standard rat tail type I collagen matrices (2.5 mg/ml) or compressed collagen matrices (~100 mg/ml) and cultured for up to 4 days in serum-free media, PDGF BB, TGFβ1, and either 50 nM TSA, 10 μM SAHA, or vehicle (DMSO). F-actin, α-SM-actin, and collagen fibrils were imaged using confocal microscopy. Cell morphology and global matrix contraction were quantified digitally. The expression of α-SM-actin was assessed using western blotting. RESULTS Corneal keratocytes in 3-D matrices had a quiescent mechanical phenotype, as indicated by a dendritic morphology, a lack of stress fibers, and minimal cell-induced matrix remodeling. This phenotype was generally maintained following the addition of TSA or SAHA. TGFβ1 induced a contractile phenotype, as indicated by a loss of dendritic cell processes, the development of stress fibers, and significant matrix compaction. In contrast, cells cultured in TGFβ1 plus TSA or SAHA remained dendritic and did not form stress fibers or induce ECM compaction. Western blotting showed that the expression of α-SM actin after treatment with TGFβ1 was inhibited by TSA and SAHA. PDGF BB stimulated the elongation of keratocytes and the extension of dendritic processes within 3-D matrices without inducing stress fiber formation or collagen reorganization. This spreading response was maintained in the presence of TSA or SAHA. CONCLUSIONS Overall, HDAC inhibitors appear to mitigate the effects of TGFβ1 on the transformation of corneal keratocytes to a contractile, myofibroblast phenotype in both compliant and rigid 3-D matrices while preserving normal cell spreading and their ability to respond to the pro-migratory growth factor PDGF.
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Affiliation(s)
- Vindhya Koppaka
- Department of Ophthalmology, University of Texas Southwestern Medical Center,
Dallas, TX
| | - Neema Lakshman
- Department of Ophthalmology, University of Texas Southwestern Medical Center,
Dallas, TX
| | - W Matthew Petroll
- Department of Ophthalmology, University of Texas Southwestern Medical Center,
Dallas, TX
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32
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Seehase M, Jennekens W, Zwanenburg A, Andriessen P, Collins JJ, Kuypers E, Zimmermann LJ, Vles JS, Gavilanes AW, Kramer BW. Propofol administration to the maternal-fetal unit improved fetal EEG and influenced cerebral apoptotic pathway in preterm lambs suffering from severe asphyxia. Mol Cell Pediatr 2015; 2:4. [PMID: 26542294 PMCID: PMC4530565 DOI: 10.1186/s40348-015-0016-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 02/24/2015] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Term and near-term infants are at high risk of developing brain injury and life-long disability if they have suffered from severe perinatal asphyxia. We hypothesized that propofol administration to the maternal-fetal unit can diminish cerebral injury in term and near-term infant fetuses in states of progressive severe asphyxia. METHODS Forty-four late preterm lambs underwent total umbilical cord occlusion (UCO) or sham treatment in utero. UCO resulted in global asphyxia and cardiac arrest. After emergency cesarean section under either maternal propofol or isoflurane anesthesia, the fetuses were resuscitated and subsequently anesthetized the same way as their mothers. RESULTS Asphyctic lambs receiving isoflurane showed a significant increase of total and low-frequency spectral power in bursts indicating seizure activity and more burst-suppression with a marked increase of interburst interval length during UCO. Asphyctic lambs receiving propofol showed less EEG changes. Propofol increased levels of anti-apoptotic B-cell lymphoma-extra large (Bcl-xL) and phosphorylated STAT-3 and reduced the release of cytochrome c from the mitochondria and the protein levels of activated cysteinyl aspartate-specific protease (caspase)-3, -9, and N-methyl-d-aspartate (NMDA) receptor. CONCLUSIONS Improvement of fetal EEG during and after severe asphyxia could be achieved by propofol treatment of the ovine maternal-fetal unit. The underlying mechanism is probably the reduction of glutamate-induced cytotoxicity by down-regulation of NMDA receptors and an inhibition of the mitochondrial apoptotic pathway.
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Affiliation(s)
- Matthias Seehase
- Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. .,School of Mental Health and Neuroscience; School of Oncology and Developmental Biology, Maastricht University, and European Graduate School of Neuroscience (EURON), P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. .,Department of Pediatric Cardiology and Intensive Care Medicine with Neonatology, University Hospital, Georg-August-University, Robert-Koch-Str. 40, D 37099, Göttingen, Germany.
| | - Ward Jennekens
- Department of Clinical Physics, Maasstad Hospital, Postbus 9100, 3007 AC, Rotterdam, The Netherlands.
| | - Alex Zwanenburg
- Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. .,Department of Biomedical Technology, Maastricht University, Faculty of Health, Medicine and Life Sciences, School of Cardiovascular Diseases, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands.
| | - Peter Andriessen
- Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. .,Department of Paediatrics, Máxima Medical Center, De Run 4600, 5504 DB, Veldhoven, The Netherlands.
| | - Jennifer Jp Collins
- Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. .,School of Mental Health and Neuroscience; School of Oncology and Developmental Biology, Maastricht University, and European Graduate School of Neuroscience (EURON), P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. .,Regenerative Medicine Program, Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute, 725 Parkdale Ave, Ottawa ON K1Y 4E9, Ontario, Canada.
| | - Elke Kuypers
- Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. .,School of Mental Health and Neuroscience; School of Oncology and Developmental Biology, Maastricht University, and European Graduate School of Neuroscience (EURON), P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands.
| | - Luc J Zimmermann
- Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands.
| | - Johan Sh Vles
- Department of Neurology, Maastricht University Medical Center, Faculty of Health, Medicine and Life Sciences, School of Mental Health and Neuroscience, Maastricht University, and European Graduate School of Neuroscience (EURON), P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands.
| | - Antonio Wd Gavilanes
- Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands.
| | - Boris W Kramer
- Department of Paediatrics, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands. .,School of Mental Health and Neuroscience; School of Oncology and Developmental Biology, Maastricht University, and European Graduate School of Neuroscience (EURON), P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands.
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Di Maggio FM, Minafra L, Forte GI, Cammarata FP, Lio D, Messa C, Gilardi MC, Bravatà V. Portrait of inflammatory response to ionizing radiation treatment. J Inflamm (Lond) 2015; 12:14. [PMID: 25705130 PMCID: PMC4336767 DOI: 10.1186/s12950-015-0058-3] [Citation(s) in RCA: 194] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 01/29/2015] [Indexed: 01/05/2023] Open
Abstract
Ionizing radiation (IR) activates both pro-and anti-proliferative signal pathways producing an imbalance in cell fate decision. IR is able to regulate several genes and factors involved in cell-cycle progression, survival and/or cell death, DNA repair and inflammation modulating an intracellular radiation-dependent response. Radiation therapy can modulate anti-tumour immune responses, modifying tumour and its microenvironment. In this review, we report how IR could stimulate inflammatory factors to affect cell fate via multiple pathways, describing their roles on gene expression regulation, fibrosis and invasive processes. Understanding the complex relationship between IR, inflammation and immune responses in cancer, opens up new avenues for radiation research and therapy in order to optimize and personalize radiation therapy treatment for each patient.
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Affiliation(s)
- Federica Maria Di Maggio
- />Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy
- />IBFM CNR – LATO, Contrada Pietrapollastra Pisciotto, Cefalù, PA Italy
| | - Luigi Minafra
- />IBFM CNR – LATO, Contrada Pietrapollastra Pisciotto, Cefalù, PA Italy
| | - Giusi Irma Forte
- />IBFM CNR – LATO, Contrada Pietrapollastra Pisciotto, Cefalù, PA Italy
| | | | - Domenico Lio
- />Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy
| | - Cristina Messa
- />IBFM CNR – LATO, Contrada Pietrapollastra Pisciotto, Cefalù, PA Italy
- />Department of Health Sciences, Tecnomed Foundation, University of Milano-Bicocca, Milan, Italy
- />Nuclear Medicine Center, San Gerardo Hospital, Monza, Italy
| | - Maria Carla Gilardi
- />IBFM CNR – LATO, Contrada Pietrapollastra Pisciotto, Cefalù, PA Italy
- />Department of Health Sciences, Tecnomed Foundation, University of Milano-Bicocca, Milan, Italy
- />Nuclear Medicine, San Raffaele Scientific Institute, Milan, Italy
| | - Valentina Bravatà
- />IBFM CNR – LATO, Contrada Pietrapollastra Pisciotto, Cefalù, PA Italy
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Abstract
RNA interference or post-transcriptional gene silencing is one of the latest, innovative, highly specific, and efficient technologies for gene therapy application in molecular oncology. It is already a well-established research tool for analyses of molecular mechanisms for various diseases including cancer as it efficiently silences the expression of genes of interest. However, for its proper therapeutic use, an efficient tumor-specific in-vivo delivery mechanism is essential. Many scientific groups and companies are involved in the development of efficient in-vivo delivery mechanisms for small interfering RNA, but are still struggling. The present article suggests utilization of albumin as a delivery module for small interfering RNA as it is an endogenous natural nanoparticle known for its binding properties to various endogenous metabolites, drugs, and metal ions.
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Affiliation(s)
- Anshoo Malhotra
- Department of Biophysics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Swiatek-Machado K, Mieczkowski J, Ellert-Miklaszewska A, Swierk P, Fokt I, Szymanski S, Skora S, Szeja W, Grynkiewicz G, Lesyng B, Priebe W, Kaminska B. Novel small molecular inhibitors disrupt the JAK/STAT3 and FAK signaling pathways and exhibit a potent antitumor activity in glioma cells. Cancer Biol Ther 2014; 13:657-70. [DOI: 10.4161/cbt.20083] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Chowdhari S, Saini N. hsa-miR-4516 mediated downregulation of STAT3/CDK6/UBE2N plays a role in PUVA induced apoptosis in keratinocytes. J Cell Physiol 2014; 229:1630-8. [PMID: 24610393 DOI: 10.1002/jcp.24608] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Accepted: 03/05/2014] [Indexed: 12/13/2022]
Abstract
Psoriasis is a chronic inflammatory skin disorder mediated by cross-talk occurring between epidermal keratinocytes, dermal vascular cells and immunocytes. Literature reveals that Signal transducer and activator of transcription 3 (STAT3), a protein involved in transmitting extracellular signals to the nucleus, is a possible important link between keratinocytes and immunocytes and is crucial to the development of psoriasis. Although photochemotherapy using UV in combination with 8 methoxypsoralen is one of the most effective therapy for moderate to severe plaque psoriasis, its mechanism of action is largely unknown. Herein, we studied the change in miRNA profiles of cultured human keratinocytes (HaCaT cells) before and after in vitro PUVA treatment by 8 methoxypsoralen and found significant up regulation of hsa-miR-4516. We for the first time demonstrate that ectopic expression of hsa-miR-4516 directly targets STAT3 protein by binding to its 3'UTR in HaCaT cells as confirmed by Luciferase reporter assays and Western blot analysis. We further show that overexpression of hsa-miR-4516 downregulates STAT3, p-STAT3, CDK6, and UBE2N proteins that are consistently upregulated in psoriasis and induces apoptosis in HaCaT cells. We also observed that anti-miR-4516 treatment was able to partially inhibit PUVA-induced apoptosis, suggesting that miR-4516 is involved in PUVA-induced apoptosis. Taken together, these results not only indicate the mechanistic involvement of hsa-miR-4516 in PUVA mediated effects by down-regulating STAT3 in HaCaT keratinocytes, but also highlight the potential of hsa-miR-4516 in development of novel therapeutic strategies. J. Cell. Physiol. 229: 1630-1638, 2014. © 2014 Wiley Periodicals, Inc.
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Affiliation(s)
- Shruti Chowdhari
- Functional Genomics Unit, CSIR, Institute of Genomics and Integrative Biology, Delhi, India
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Allegra A, Alonci A, Penna G, Innao V, Gerace D, Rotondo F, Musolino C. The cancer stem cell hypothesis: a guide to potential molecular targets. Cancer Invest 2014; 32:470-95. [PMID: 25254602 DOI: 10.3109/07357907.2014.958231] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Common cancer theories hold that tumor is an uncontrolled somatic cell proliferation caused by the progressive addition of random mutations in critical genes that control cell growth. Nevertheless, various contradictions related to the mutation theory have been reported previously. These events may be elucidated by the persistence of residual tumor cells, called Cancer Stem Cells (CSCs) responsible for tumorigenesis, tumor maintenance, tumor spread, and tumor relapse. Herein, we summarize the current understanding of CSCs, with a focus on the possibility to identify specific markers of CSCs, and discuss the clinical application of targeting CSCs for cancer treatment.
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Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening. Methods 2014; 71:38-43. [PMID: 25160651 DOI: 10.1016/j.ymeth.2014.07.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 07/19/2014] [Accepted: 07/21/2014] [Indexed: 12/16/2022] Open
Abstract
STAT3 modulates the transcription of a wide variety of regulatory genes involved in cell proliferation, differentiation, migration, apoptosis, and other critical cellular functions. Constitutive activation of STAT3 has been detected in a wide spectrum of human malignancies. A pharmacophore model constructed from a training set of STAT3 inhibitors binding to the SH2 domain was used to screen an in-house database of compounds, from which azepine 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with comparable potency to the well-known STAT3 inhibitor S3I-201. A fluorescence polarization assay revealed that compound 1 targeted the SH2 domain of STAT3. Furthermore, compound 1 inhibited STAT3 phosphorylation in cells without affecting the total expression of STAT3. This study also validates the use of pharmacophore modeling to identify inhibitors of protein-protein interactions.
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Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1839:1341-50. [PMID: 25111868 DOI: 10.1016/j.bbagrm.2014.07.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 06/18/2014] [Accepted: 07/14/2014] [Indexed: 01/04/2023]
Abstract
BACKGROUND Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune regulation. Only a small fraction of those genes has been proven to be direct STAT3 targets. In gliomas, STAT3 can play tumor suppressive or oncogenic roles depending on the tumor genetic background with target genes being largely unknown. RESULTS We used chromatin immunoprecipitation, promoter microarrays and deep sequencing to assess the genome-wide occupancy of phospho (p)-Stat3 and epigenetic modifications of H3K4me3 and H3ac in C6 glioma cells. This combined assessment identified a list of 1200 genes whose promoters have both Stat3 binding sites and epigenetic marks characteristic for actively transcribed genes. The Stat3 and histone markings data were also intersected with a set of microarray data from C6 glioma cells after inhibition of Jak2/Stat3 signaling. Subsequently, we found 284 genes characterized by p-Stat3 occupancy, activating histone marks and transcriptional changes. Novel genes were screened for their potential involvement in oncogenesis, and the most interesting hits were verified by ChIP-PCR and STAT3 knockdown in human glioma cells. CONCLUSIONS Non-random association between silent genes, histone marks and p-Stat3 binding near transcription start sites was observed, consistent with its repressive role in transcriptional regulation of target genes in glioma cells with specific genetic background.
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Knockdown of PKCε Expression Inhibits Growth, Induces Apoptosis and Decreases Invasiveness of Human Glioma Cells Partially Through Stat3. J Mol Neurosci 2014; 55:21-31. [DOI: 10.1007/s12031-014-0341-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Accepted: 05/22/2014] [Indexed: 12/21/2022]
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The Multifaceted Roles of STAT3 Signaling in the Progression of Prostate Cancer. Cancers (Basel) 2014; 6:829-59. [PMID: 24722453 PMCID: PMC4074806 DOI: 10.3390/cancers6020829] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 03/11/2014] [Accepted: 03/17/2014] [Indexed: 01/09/2023] Open
Abstract
The signal transducer and activator of transcription (STAT)3 governs essential functions of epithelial and hematopoietic cells that are often dysregulated in cancer. While the role for STAT3 in promoting the progression of many solid and hematopoietic malignancies is well established, this review will focus on the importance of STAT3 in prostate cancer progression to the incurable metastatic castration-resistant prostate cancer (mCRPC). Indeed, STAT3 integrates different signaling pathways involved in the reactivation of androgen receptor pathway, stem like cells and the epithelial to mesenchymal transition that drive progression to mCRPC. As equally important, STAT3 regulates interactions between tumor cells and the microenvironment as well as immune cell activation. This makes it a major factor in facilitating prostate cancer escape from detection of the immune response, promoting an immunosuppressive environment that allows growth and metastasis. Based on the multifaceted nature of STAT3 signaling in the progression to mCRPC, the promise of STAT3 as a therapeutic target to prevent prostate cancer progression and the variety of STAT3 inhibitors used in cancer therapies is discussed.
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Assessment of drug delivery and anticancer potentials of nanoparticles-loaded siRNA targeting STAT3 in lung cancer, in vitro and in vivo. Toxicol Lett 2014; 225:454-66. [PMID: 24440344 DOI: 10.1016/j.toxlet.2014.01.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 12/31/2013] [Accepted: 01/07/2014] [Indexed: 01/01/2023]
Abstract
Activation of signal transducer and activator of transcription3 (STAT3) is a hallmark of several types of cancer. Failure to inhibit STAT3 expression by injection of siRNA for STAT3 directly to Balb/c mice led us to adopt alternative means. We formulated nanoparticle-based encapsulation of siRNA (NsiRNA) with polyethylenimine (PEI) and poly(lactide-co-glycolide) (PLGA) and characterized them. The siRNA treated and NsiRNA-treated cells were subjected separately to different assay systems. We also checked if NsiRNA could cross the blood brain barrier (BBB). Cell viability reduced dramatically in A549 cells after NsiRNA administration (23.89% at 24 h), thereby implicating considerable silencing of STAT3 by NsiRNA, but not after siRNA administration. Compared to controls, a significant decrease in expression of IL-6 and the angiogenic factor (VEGF) and increase in Caspase 3 activity was observed with corresponding regression in tumor growth in mice treated with NsiRNA. NsiRNA induced apoptosis of cells and arrested cells at G1/G0 stage, both in vitro and in vivo. Apoptosis was also verified by Annexin-V-FITC/Propidium-iodide staining. NsiRNA could cross blood brain barrier. Overall results revealed PEI-PLGA to be a promising carrier for delivery of siRNA targeting STAT3 expression, which can be utilized as an effective strategy for cancer therapy.
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Liang Q, Ma C, Zhao Y, Gao G, Ma J. Inhibition of STAT3 reduces astrocytoma cell invasion and constitutive activation of STAT3 predicts poor prognosis in human astrocytoma. PLoS One 2013; 8:e84723. [PMID: 24386409 PMCID: PMC3875539 DOI: 10.1371/journal.pone.0084723] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Accepted: 11/19/2013] [Indexed: 11/18/2022] Open
Abstract
Astrocytoma cells characteristically possess high invasion potentials. Recent studies have revealed that knockdown of signal transducers and activators of transcription 3 (STAT3) expression by RNAi induces apoptosis in astrocytoma cell. Nevertheless, the distinct roles of STAT3 in astrocytoma's invasion and recurrence have not been elucidated. In this study, we silenced STAT3 using Small interfering RNAs in two human glioblastoma multiforme (GBM) cell lines (U251 and U87), and investigated the effect on GBM cell adhesion and invasion. Our results demonstrate that disruption of STAT3 inhibits GBM cell's adhesion and invasion. Knockdown of STAT3 significantly increased E-cadherin but decreased N-cadherin, vascular endothelial growth factor, matrix metalloproteinase 2 and matrix metalloproteinase 9. Additionally, expression of pSTAT3(Tyr705) correlates with astrocytoma WHO classification, Karnofsky performance status scale score, tumor recurrence and survival. Furthermore, pSTAT3(Tyr705) is a significant prognostic factor in astrocytoma. In conclusion, STAT3 may affect astrocytoma invasion, expression of pSTAT3(Tyr705) is a significant prognostic factor in tumor recurrence and overall survival in astrocytoma patients. Therefore, STAT3 may provide a potential target for molecular therapy in human astrocytoma, and pSTAT3(Tyr705)could be an important biomarker for astrocytoma prognosis.
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Affiliation(s)
- Qinchuan Liang
- Department of Pediatric Neurosurgery, Xin-Hua Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, People’s Republic of China
- Department of Neurosurgery, Tang-Du Hospital, Institution for Functional Neurosurgery of P.L.A., Fourth Military Medical University, Xi’an, Shannxi Province, People’s Republic of China
| | - Chenkai Ma
- Department of Pediatric Neurosurgery, Xin-Hua Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, People’s Republic of China
| | - Yang Zhao
- Department of Pediatric Neurosurgery, Xin-Hua Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, People’s Republic of China
| | - Guodong Gao
- Department of Neurosurgery, Tang-Du Hospital, Institution for Functional Neurosurgery of P.L.A., Fourth Military Medical University, Xi’an, Shannxi Province, People’s Republic of China
| | - Jie Ma
- Department of Pediatric Neurosurgery, Xin-Hua Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, People’s Republic of China
- * E-mail:
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Liu M, Wang F, Wen Z, Shi M, Zhang H. Blockage of STAT3 signaling pathway with a decoy oligodeoxynucleotide inhibits growth of human ovarian cancer cells. Cancer Invest 2013; 32:8-12. [PMID: 24328557 DOI: 10.3109/07357907.2013.861471] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Transcription factor decoy oligodeoxynucleotides (ODN) represent a novel tool for targeted inhibition of the STAT3 signaling pathway. To investigate its therapeutic potential in ovarian cancer, a double-stranded decoy ODN mimicking STAT3-specific cis-elements was transfected into two ovarian cancer cell lines OVCAR3 and SKOV3. The STAT3 decoy ODN treatment specifically blocked STAT3 signaling, and inhibited cell proliferation by inducing apoptosis and cell cycle arrest. These results suggest that targeted blockade of the STAT3 signaling pathway with a decoy ODN may represent a potential therapeutic approach in the treatment of ovarian cancer.
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Affiliation(s)
- Ming Liu
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
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Furqan M, Akinleye A, Mukhi N, Mittal V, Chen Y, Liu D. STAT inhibitors for cancer therapy. J Hematol Oncol 2013; 6:90. [PMID: 24308725 PMCID: PMC4029528 DOI: 10.1186/1756-8722-6-90] [Citation(s) in RCA: 155] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Accepted: 12/02/2013] [Indexed: 12/24/2022] Open
Abstract
Signal Transducer and Activator of Transcription (STAT) proteins are a family of cytoplasmic transcription factors consisting of 7 members, STAT1 to STAT6, including STAT5a and STAT5b. STAT proteins are thought to be ideal targets for anti-cancer therapy since cancer cells are more dependent on the STAT activity than their normal counterparts. Inhibitors targeting STAT3 and STAT5 have been developed. These included peptidomimetics, small molecule inhibitors and oligonucleotides. This review summarized advances in preclinical and clinical development of these compounds.
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Affiliation(s)
- Muhammad Furqan
- Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY 10595, USA
| | - Akintunde Akinleye
- Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY 10595, USA
| | - Nikhil Mukhi
- Department of Medicine, SUNY Downstate Medical Center Brooklyn, Brooklyn, NY 11203, USA
| | - Varun Mittal
- Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY 10595, USA
| | - Yamei Chen
- Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY 10595, USA
- Department of Hematology, Xiamen Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Delong Liu
- Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY 10595, USA
- Division of Hematology and Oncology, Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY 10595, USA
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Lee JS, Xiao J, Patel P, Schade J, Wang J, Deneen B, Erdreich-Epstein A, Song HR. A novel tumor-promoting role for nuclear factor IA in glioblastomas is mediated through negative regulation of p53, p21, and PAI1. Neuro Oncol 2013; 16:191-203. [PMID: 24305710 DOI: 10.1093/neuonc/not167] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Background Nuclear factor IA (NFIA), a transcription factor and essential regulator in embryonic glial development, is highly expressed in human glioblastoma (GBM) compared with normal brain, but its contribution to GBM and cancer pathogenesis is unknown. Here we demonstrate a novel role for NFIA in promoting growth and migration of GBM and establish the molecular mechanisms mediating these functions. Methods To determine the role of NFIA in glioma, we examined the effects of NFIA in growth, proliferation, apoptosis, and migration. We used gain-of-function (overexpression) and loss-of-function (shRNA knockdown) of NFIA in primary patient-derived GBM cells and established glioma cell lines in culture and in intracranial xenografts in mouse brains. Results Knockdown of native NFIA blocked tumor growth and induced cell death and apoptosis. Complementing this, NFIA overexpression accelerated growth, proliferation, and migration of GBM in cell culture and in mouse brains. These NFIA tumor-promoting effects were mediated via transcriptional repression of p53, p21, and plasminogen activator inhibitor 1 (PAI1) through specific NFIA-recognition sequences in their promoters. Importantly, the effects of NFIA on proliferation and apoptosis were independent of TP53 mutation status, a finding especially relevant for GBM, in which TP53 is frequently mutated. Conclusion NFIA is a modulator of GBM growth and migration, and functions by distinct regulation of critical oncogenic pathways that govern the malignant behavior of GBM.
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Affiliation(s)
- Jun Sung Lee
- Corresponding author: Hae-Ri Song, MD, New York University School of Medicine, Smilow Research Center 1306, 522 First Avenue, New York, NY 10016.
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Ren F, Su F, Ning H, Wang Y, Geng Y, Feng Y, Wang Y, Zhang Y, Jin Z, Li Y, Jia B, Chang Z. SIPAR negatively regulates STAT3 signaling and inhibits progression of melanoma. Cell Signal 2013; 25:2272-80. [PMID: 23917203 DOI: 10.1016/j.cellsig.2013.07.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 07/08/2013] [Accepted: 07/26/2013] [Indexed: 01/10/2023]
Abstract
Persistently activated STAT3 is important for tumorigenesis in a variety of cancers, including melanoma. Although many co-factors in the regulation of STAT3 activity have been identified, it remains unclear how STAT3 phosphorylation is negatively regulated. Here, we report that SIPAR (STAT3-Interacting Protein As a Repressor) inhibits STAT3 activity by accelerating its dephosphorylation. We observed that SIPAR directly interacted with STAT3 upon IL-6 stimulation. Moreover, over-expression of SIPAR reduced, whereas depletion enhanced, the level of phosphorylated STAT3. We further demonstrated that SIPAR inhibited the growth of melanoma cells by decreasing the level of phosphorylated STAT3 and the expression of its target genes. These results suggest that SIPAR, functioning as a new negative regulator, inhibits STAT3 activity by enhancing its dephosphorylation and represses melanoma progression.
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Affiliation(s)
- Fangli Ren
- State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, Tsinghua University, Beijing 100084, China
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Kang Y, Park MA, Heo SW, Park SY, Kang KW, Park PH, Kim JA. The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells. Biochim Biophys Acta Gen Subj 2013; 1830:2638-48. [PMID: 23246576 DOI: 10.1016/j.bbagen.2012.12.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Revised: 11/20/2012] [Accepted: 12/06/2012] [Indexed: 11/27/2022]
Abstract
BACKGROUND Chemotherapeutic drug resistance remains a clinical obstacle in cancer management. Drug-resistant cancer cells usually exhibit cross-resistance to ionizing radiation, which has devastating consequences for patients. With a better understanding of the molecular mechanisms, it will be possible to develop strategies to overcome this cross-resistance and to increase therapeutic sensitivity. METHODS Natural and synthetic flavonoid compounds including xanthohumol, the principal flavonoid in hops, were investigated for its radio-sensitizing activity on human breast cancer MCF-7 and adriamycin-resistant MCF-7 (MCF-7/ADR) cells. Chemo-sensitizing or radio-sensitizing effect was analyzed by tetrazolium-based colorimetric assay and flow cytometry. Western blot analysis, confocal microscopy, gene silencing with siRNA transfection and luciferase reporter gene assay were performed to examine signaling molecule activation. RESULTS Among the tested flavonoid compounds, pretreatment of the cells with xanthohumol significantly sensitized MCF-7/ADR cells to the radiation treatment by inducing apoptosis. In MCF-7/ADR cells, treatment with xanthohumol alone or with gamma-rays significantly decreased levels of anti-apoptotic proteins. Multi-drug resistance 1 (MDR1), epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) expression levels in MCF-7/ADR cells were suppressed by xanthohumol treatment. In addition, xanthohumol treatment increased death receptor (DR)-4 and DR5 expression. The xanthohumol-induced changes of these resistance-related molecules in MCF-7/ADR cells were synergistically increased by gamma-ray treatment. CONCLUSIONS Xanthohumol restored sensitivity of MCF-7/ADR cells to doxorubicin and radiation therapies. GENERAL SIGNIFICANCE Our results suggest that xanthohumol may be a potent chemo- and radio-sensitizer, and its actions are mediated through STAT3 and EGFR inhibition.
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Affiliation(s)
- Youra Kang
- College of Pharmacy, Yeungnam University, Gyeongsang 712-749, South Korea
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Luwor RB, Stylli SS, Kaye AH. The role of Stat3 in glioblastoma multiforme. J Clin Neurosci 2013; 20:907-11. [PMID: 23688441 DOI: 10.1016/j.jocn.2013.03.006] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 02/28/2013] [Accepted: 03/09/2013] [Indexed: 01/27/2023]
Abstract
Glioblastoma multiforme (GBM) is the most common brain tumor and has the worst prognosis. Several signaling molecules have been clearly implicated in the development, progression, and aggressiveness of GBM. Here we review the role of signal transducer and activator of transcription-3 (Stat3) in GBM. We particularly focus on its expression in clinical GBM samples, its role in brain tumorigenicity in cell lines and animal models, and discuss possible therapeutic strategies targeting Stat3. This review also summarizes the current knowledge regarding the role of Stat3 regulation by upstream activators and repressors in promoting GBM progression in both translational and clinical studies.
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Affiliation(s)
- Rodney B Luwor
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
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Ho Y, Tsao SW, Zeng M, Lui VWY. STAT3 as a therapeutic target for Epstein-Barr virus (EBV) – associated nasopharyngeal carcinoma. Cancer Lett 2013; 330:141-9. [DOI: 10.1016/j.canlet.2012.11.052] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 11/28/2012] [Accepted: 11/28/2012] [Indexed: 12/24/2022]
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