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Liu R, Yu Y, Wang Q, Zhao Q, Yao Y, Sun M, Zhuang J, Sun C, Qi Y. Interactions between hedgehog signaling pathway and the complex tumor microenvironment in breast cancer: current knowledge and therapeutic promises. Cell Commun Signal 2024; 22:432. [PMID: 39252010 PMCID: PMC11382420 DOI: 10.1186/s12964-024-01812-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/31/2024] [Indexed: 09/11/2024] Open
Abstract
Breast cancer ranks as one of the most common malignancies among women, with its prognosis and therapeutic efficacy heavily influenced by factors associated with the tumor cell biology, particularly the tumor microenvironment (TME). The diverse elements of the TME are engaged in dynamic bidirectional signaling interactions with various pathways, which together dictate the growth, invasiveness, and metastatic potential of breast cancer. The Hedgehog (Hh) signaling pathway, first identified in Drosophila, has been established as playing a critical role in human development and disease. Notably, the dysregulation of the Hh pathway is recognized as a major driver in the initiation, progression, and metastasis of breast cancer. Consequently, elucidating the mechanisms by which the Hh pathway interacts with the distinct components of the breast cancer TME is essential for comprehensively evaluating the link between Hh pathway activation and breast cancer risk. This understanding is also imperative for devising novel targeted therapeutic strategies and preventive measures against breast cancer. In this review, we delineate the current understanding of the impact of Hh pathway perturbations on the breast cancer TME, including the intricate and complex network of intersecting signaling cascades. Additionally, we focus on the therapeutic promise and clinical challenges of Hh pathway inhibitors that target the TME, providing insights into their potential clinical utility and the obstacles that must be overcome to harness their full therapeutic potential.
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Affiliation(s)
- Ruijuan Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, 261000, China
| | - Yang Yu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, 999078, China
| | - Qingyang Wang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Qianxiang Zhao
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Yan Yao
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, 261000, China
| | - Mengxuan Sun
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Jing Zhuang
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, 261000, China.
| | - Changgang Sun
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, 261000, China.
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, 261000, China.
| | - Yuanfu Qi
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
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Ilg MM, Harding S, Lapthorn AR, Kirvell S, Ralph DJ, Bustin SA, Ball G, Cellek S. Temporal gene signature of myofibroblast transformation in Peyronie's disease: first insights into the molecular mechanisms of irreversibility. J Sex Med 2024; 21:278-287. [PMID: 38383071 DOI: 10.1093/jsxmed/qdae006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/09/2023] [Accepted: 11/27/2023] [Indexed: 02/23/2024]
Abstract
BACKGROUND Transformation of resident fibroblasts to profibrotic myofibroblasts in the tunica albuginea is a critical step in the pathophysiology of Peyronie's disease (PD). We have previously shown that myofibroblasts do not revert to the fibroblast phenotype and we suggested that there is a point of no return at 36 hours after induction of the transformation. However, the molecular mechanisms that drive this proposed irreversibility are not known. AIM Identify molecular pathways that drive the irreversibility of myofibroblast transformation by analyzing the expression of the genes involved in the process in a temporal fashion. METHODS Human primary fibroblasts obtained from tunica albuginea of patients with Peyronie's disease were transformed to myofibroblasts using transforming growth factor beta 1 (TGF-β1). The mRNA of the cells was collected at 0, 24, 36, 48, and 72 hours after stimulation with TGF-β1 and then analyzed using a Nanostring nCounter Fibrosis panel. The gene expression results were analyzed using Reactome pathway analysis database and ANNi, a deep learning-based inference algorithm based on a swarm approach. OUTCOMES The study outcome was the time course of changes in gene expression during transformation of PD-derived fibroblasts to myofibroblasts. RESULTS The temporal analysis of the gene expression revealed that the majority of the changes at the gene expression level happened within the first 24 hours and remained so throughout the 72-hour period. At 36 hours, significant changes were observed in genes involved in MAPK-Hedgehog signaling pathways. CLINICAL TRANSLATION This study highlights the importance of early intervention in clinical management of PD and the future potential of new drugs targeting the point of no return. STRENGTHS AND LIMITATIONS The use of human primary cells and confirmation of results with further RNA analysis are the strengths of this study. The study was limited to 760 genes rather than the whole transcriptome. CONCLUSION This study is to our knowledge the first analysis of temporal gene expression associated with the regulation of the transformation of resident fibroblasts to profibrotic myofibroblasts in PD. Further research is warranted to investigate the role of the MAPK-Hedgehog signaling pathways in reversibility of PD.
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Affiliation(s)
- Marcus M Ilg
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, CM1 1SQ, United Kingdom
| | - Sophie Harding
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, CM1 1SQ, United Kingdom
| | - Alice R Lapthorn
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, CM1 1SQ, United Kingdom
| | - Sara Kirvell
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, CM1 1SQ, United Kingdom
| | - David J Ralph
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, CM1 1SQ, United Kingdom
- Urology Department, University College London, London, W1G 8PH, United Kingdom
| | - Stephen A Bustin
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, CM1 1SQ, United Kingdom
| | - Graham Ball
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, CM1 1SQ, United Kingdom
| | - Selim Cellek
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, CM1 1SQ, United Kingdom
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Liao Y, Gui Y, Li Q, An J, Wang D. The signaling pathways and targets of natural products from traditional Chinese medicine treating gastric cancer provide new candidate therapeutic strategies. Biochim Biophys Acta Rev Cancer 2023; 1878:188998. [PMID: 37858623 DOI: 10.1016/j.bbcan.2023.188998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/26/2023] [Accepted: 10/08/2023] [Indexed: 10/21/2023]
Abstract
Gastric cancer (GC) is one of the severe malignancies with high incidence and mortality, especially in Eastern Asian countries. Significant advancements have been made in diagnosing and treating GC over the past few decades, resulting in tremendous improvements in patient survival. In recent years, traditional Chinese medicine (TCM) has garnered considerable attention as an alternative therapeutic approach for GC due to its multicomponent and multitarget characteristics. Consequently, natural products found in TCM have attracted researchers' attention, as growing evidence suggests that these natural products can impede GC progression by regulating various biological processes. Nevertheless, their molecular mechanisms are not systematically uncovered. Here, we review the major signaling pathways involved in GC development. Additionally, clinical GC samples were analyzed. Moreover, the anti-GC effects of natural products, their underlying mechanisms and potential targets were summarized. These summaries are intended to facilitate further relevant research, and accelerate the clinical applications of natural products in GC treatment.
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Affiliation(s)
- Yile Liao
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yu Gui
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Qingzhou Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jun An
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Dong Wang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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4
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Wang Y, Ali M, Zhang Q, Sun Q, Ren J, Wang W, Tang D, Wang D. ATF4 Transcriptionally Activates SHH to Promote Proliferation, Invasion, and Migration of Gastric Cancer Cells. Cancers (Basel) 2023; 15:1429. [PMID: 36900220 PMCID: PMC10000907 DOI: 10.3390/cancers15051429] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/18/2023] [Accepted: 02/20/2023] [Indexed: 03/06/2023] Open
Abstract
Activating transcription factor 4 (ATF4) is a DNA-binding protein widely generated in mammals, which has two biological characteristics that bind the cAMP response element (CRE). The mechanism of ATF4 as a transcription factor in gastric cancer affecting the Hedgehog pathway remains unclear. Here, we observed that ATF4 was markedly upregulated in gastric cancer (GC) using immunohistochemistry and Western blotting assays in 80 paraffin-embedded GC samples and 4 fresh samples and para-cancerous tissues. ATF4 knockdown using lentiviral vectors strongly inhibited the proliferation and invasion of GC cells. ATF4 upregulation using lentiviral vectors promoted the proliferation and invasion of GC cells. We predicted that the transcription factor ATF4 is bound to the SHH promoter via the JASPA database. Transcription factor ATF4 is bound to the promoter region of SHH to activate the Sonic Hedgehog pathway. Mechanistically, rescue assays showed that ATF4 regulated gastric cancer cells' proliferation and invasive ability through SHH. Similarly, ATF4 enhanced the tumor formation of GC cells in a xenograft model.
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Affiliation(s)
- Yang Wang
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225009, China
- Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou 225001, China
- General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225009, China
- Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou 225001, China
| | - Muhammad Ali
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225009, China
- Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou 225001, China
- General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225009, China
- Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou 225001, China
| | - Qi Zhang
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225009, China
| | - Qiannan Sun
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225009, China
| | - Jun Ren
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225009, China
| | - Wei Wang
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225009, China
| | - Dong Tang
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225009, China
- Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou 225001, China
- General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225009, China
- Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou 225001, China
| | - Daorong Wang
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225009, China
- Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou 225001, China
- General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225009, China
- Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou 225001, China
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Li X, Wang F, Zhang X, Sun Q, Kuang E. Suppression of KSHV lytic replication and primary effusion lymphoma by selective RNF5 inhibition. PLoS Pathog 2023; 19:e1011103. [PMID: 36656913 PMCID: PMC9888681 DOI: 10.1371/journal.ppat.1011103] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/31/2023] [Accepted: 01/06/2023] [Indexed: 01/20/2023] Open
Abstract
Primary effusion lymphoma (PEL), a rare aggressive B-cell lymphoma in immunosuppressed patients, is etiologically associated with oncogenic γ-herpesvirus infection. Chemotherapy is commonly used to treat PEL but usually results in poor prognosis and survival; thus, novel therapies and drug development are urgently needed for PEL treatment. Here, we demonstrated that inhibition of Ring finger protein 5 (RNF5), an ER-localized E3 ligase, suppresses multiple cellular pathways and lytic replication of Kaposi sarcoma-associated herpesvirus (KSHV) in PEL cells. RNF5 interacts with and induces Ephrin receptors A3 (EphA3) and EphA4 ubiquitination and degradation. RNF5 inhibition increases the levels of EphA3 and EphA4, thereby reducing ERK and Akt activation and KSHV lytic replication. RNF5 inhibition decreased PEL xenograft tumor growth and downregulated viral gene expression, cell cycle gene expression, and hedgehog signaling in xenograft tumors. Our study suggests that RNF5 plays the critical roles in KSHV lytic infection and tumorigenesis of primary effusion lymphoma.
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Affiliation(s)
- Xiaojuan Li
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
- College of Clinical Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Fan Wang
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Xiaolin Zhang
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Qinqin Sun
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Ersheng Kuang
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
- * E-mail:
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6
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 145] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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Matissek SJ, Karbalivand M, Han W, Boutilier A, Yzar-Garcia E, Kehoe LL, Gardner DS, Hage A, Fleck K, Jeffers V, Rajsbaum R, Elsawa SF. A novel mechanism of regulation of the oncogenic transcription factor GLI3 by toll-like receptor signaling. Oncotarget 2022; 13:944-959. [PMID: 35937499 PMCID: PMC9348707 DOI: 10.18632/oncotarget.28261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 07/25/2022] [Indexed: 01/05/2023] Open
Abstract
The transcription factor GLI3 is a member of the GLI family and has been shown to be regulated by canonical hedgehog (HH) signaling through smoothened (SMO). Little is known about SMO-independent regulation of GLI3. Here, we identify TLR signaling as a novel pathway regulating GLI3 expression. We show that GLI3 expression is induced by LPS/TLR4 in human monocyte cell lines and peripheral blood CD14+ cells. Further analysis identified TRIF, but not MyD88, signaling as the adapter used by TLR4 to regulate GLI3. Using pharmacological and genetic tools, we identified IRF3 as the transcription factor regulating GLI3 downstream of TRIF. Furthermore, using additional TLR ligands that signal through TRIF such as the TLR4 ligand, MPLA and the TLR3 ligand, Poly(I:C), we confirm the role of TRIF-IRF3 in the regulation of GLI3. We found that IRF3 directly binds to the GLI3 promoter region and this binding was increased upon stimulation of TRIF-IRF3 with Poly(I:C). Furthermore, using Irf3 -/- MEFs, we found that Poly(I:C) stimulation no longer induced GLI3 expression. Finally, using macrophages from mice lacking Gli3 expression in myeloid cells (M-Gli3-/- ), we found that in the absence of Gli3, LPS stimulated macrophages secrete less CCL2 and TNF-α compared with macrophages from wild-type (WT) mice. Taken together, these results identify a novel TLR-TRIF-IRF3 pathway that regulates the expression of GLI3 that regulates inflammatory cytokines and expands our understanding of the non-canonical signaling pathways involved in the regulation of GLI transcription factors.
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Affiliation(s)
- Stephan J. Matissek
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
| | - Mona Karbalivand
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
| | - Weiguo Han
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
| | - Ava Boutilier
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
| | - Estefania Yzar-Garcia
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
| | - Laura L. Kehoe
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
| | - Devin Storm Gardner
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
| | - Adam Hage
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Krista Fleck
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
| | - Vicki Jeffers
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
| | - Ricardo Rajsbaum
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
- Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA
| | - Sherine F. Elsawa
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
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El-Kishky AHM, Moussa N, Helmy MW, Haroun M. GANT61/BI-847325 combination: a new hope in lung cancer treatment. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:144. [PMID: 35834029 PMCID: PMC9283175 DOI: 10.1007/s12032-022-01738-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 04/22/2022] [Indexed: 12/24/2022]
Abstract
Despite the huge efforts employed to implement novel chemotherapeutic paradigms for lung cancer, the disease still remains a major concern worldwide. Targeting molecular pathways as Hedgehog (Hh) and Mitogen-activated protein kinase (MAPK) represent a new hope in lung cancer treatment. This work was undertaken to evaluate the antitumor effects of GANT61 (5 μM), BI-847325(30 μM), and GANT61 (5 μM)/BI-847325(30 μM) combination on A549 adenocarcinoma lung cancer cell line. The growth inhibition 50 (GI50) for both drugs was performed using MTT. The protein levels of Caspase-3, Bcl-2-associated X protein (Bax), Myeloid cell leukemia sequence 1 (MCL-1), cyclin D1, vascular endothelial growth factor (VEGF), extracellular signal-regulated kinases (ERK), p-Akt, and phosphohistone H3 (pHH3) were measured using ELISA. Glioma-associated oncogene homolog 1(Gli1) gene expression was assessed by quantitative real-time PCR. The GI50 for GANT61 and BI-8473255 were 5 µM and 30 µM, respectively. Caspase-3 and Bax protein levels were significantly elevated while MCL-1, cyclin D1, VEGF, ERK 1/2, p-Akt, and pHH3 levels were significantly reduced by both drugs and their combination relative to the control group. Gli1 gene expression was down-regulated in all groups relative to the control group. GANT61, BI-847325 and their combination inhibited proliferation and angiogenesis but activated the apoptotic pathway. Both drugs conferred a profound negative impact on the crosstalk between each of Hh and MAPK pathways and Phosphoinositide 3 -kinases (PI3K)/Akt/Mammalian target of Rapamycin (mTOR). To the best of our knowledge, the antitumor effects of BI-847325/GANT61 combination have not been tested before. Further in-vitro and in-vivo studies are warranted to support the findings.
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Affiliation(s)
- Abdel Halim M El-Kishky
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt
| | - Nermine Moussa
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt.
| | - Maged W Helmy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhur University, Damanhur, Egypt
| | - Medhat Haroun
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt
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Nguyen NM, Cho J. Hedgehog Pathway Inhibitors as Targeted Cancer Therapy and Strategies to Overcome Drug Resistance. Int J Mol Sci 2022; 23:ijms23031733. [PMID: 35163655 PMCID: PMC8835893 DOI: 10.3390/ijms23031733] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 01/27/2023] Open
Abstract
Hedgehog (Hh) signaling is a highly conserved pathway that plays a vital role during embryonic development. Recently, uncontrolled activation of this pathway has been demonstrated in various types of cancer. Therefore, Hh pathway inhibitors have emerged as an important class of anti-cancer agents. Unfortunately, however, their reputation has been tarnished by the emergence of resistance during therapy, necessitating clarification of mechanisms underlying the drug resistance. In this review, we briefly overview canonical and non-canonical Hh pathways and their inhibitors as targeted cancer therapy. In addition, we summarize the mechanisms of resistance to Smoothened (SMO) inhibitors, including point mutations of the drug binding pocket or downstream molecules of SMO, and non-canonical mechanisms to reinforce Hh pathway output. A distinct mechanism involving loss of primary cilia is also described to maintain GLI activity in resistant tumors. Finally, we address the main strategies to circumvent the drug resistance. These strategies include the development of novel and potent inhibitors targeting different components of the canonical Hh pathway or signaling molecules of the non-canonical pathway. Further studies are necessary to avoid emerging resistance to Hh inhibitors and establish an optimal customized regimen with improved therapeutic efficacy to treat various types of cancer, including basal cell carcinoma.
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10
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Zhao H, Gao XY, Wu XJ, Zhang YB, Wang XF. The Shh/Gli1 signaling pathway regulates regeneration via transcription factor Olig1 expression after focal cerebral ischemia in rats. Neurol Res 2021; 44:318-330. [PMID: 34592910 DOI: 10.1080/01616412.2021.1981106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE Ischemic stroke is a major cause of death in the global population, with a high disability and mortality rate. Lack of regenerative ability is considered to be the fundamental cause. This study aims to determine the effect of Shh pathway, which mediates regenerative signaling in response to CNS injury, on myelin repair and Olig1 expression in focal ischemic lesions in the rat. METHODS A model of middle cerebral artery occlusion (MCAO) was established using the intraluminal suture method where the middle cerebral artery (MCA) was restricted for 120 min. Cyclopamine, a specific inhibitor of Shh, or saline was administered 12 h after MCAO surgery and lasted for 7 days. After MCA occlusion, male Sprague-Dawley rats were randomly allocated to cyclopamine- or saline-treated groups. A group of no-injection animals after MCAO were used as controls. The Shh signaling pathway, myelinogenesis-related factor MBP and Olig1 were testedby immunohistochemistry and RT-PCR assay. RESULTS The levels of Shh and its component Gli1 were elevated from 1 d up to 14 d following ischemia, indicating that the Shh-Gli1 axis was broadly reactivated. Treatment with cyclopamine can partially block the Shh signaling pathway, prevent myelin repair, and decrease the Olig1 expression following ischemic stroke. CONCLUSION That blockade of Shh signaling concurrently with the creation of a lesion aggravated ischemic myelin damage, probably via its downstream effects on Olig1 transcription. Shh plays a contributory role during regeneration in the CNS, thereby providing promising new therapeutic strategies to assist in recovery from ischemic stroke.
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Affiliation(s)
- Hong Zhao
- Department of Neurology, Dalian Municipal Central Hospital, Dalian
| | - Xiao-Yu Gao
- Department of Neurology, Yuhuangding Hospital, Yantai
| | - Xiao-Jun Wu
- Department of Neurology, Anshan Hospital, the First Affiliated Hospital of China Medical University, Anshan
| | - Yong-Bo Zhang
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing
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11
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Liang Y, Yang L, Xie J. The Role of the Hedgehog Pathway in Chemoresistance of Gastrointestinal Cancers. Cells 2021; 10:cells10082030. [PMID: 34440799 PMCID: PMC8391142 DOI: 10.3390/cells10082030] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/24/2021] [Accepted: 08/06/2021] [Indexed: 12/13/2022] Open
Abstract
The hedgehog pathway, which plays a significant role in embryonic development and stem cell regulation, is activated in gastrointestinal cancers. Chemotherapy is widely used in cancer treatment. However, chemoresistance becomes a substantial obstacle in cancer therapy. This review focuses on the recent advances in the hedgehog pathway's roles in drug resistance of gastrointestinal cancers and the novel drugs and strategies targeting hedgehog signaling.
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Affiliation(s)
- Yabing Liang
- Inner Mongolia Key Laboratory of Medical Cell Biology, Clinical Medical Research Center of the Affiliated Hospital, Inner Mongolia Medical University, Hohhot 010050, China;
| | - Ling Yang
- Inner Mongolia Key Laboratory of Medical Cell Biology, Clinical Medical Research Center of the Affiliated Hospital, Inner Mongolia Medical University, Hohhot 010050, China;
- Correspondence: (L.Y.); (J.X.)
| | - Jingwu Xie
- Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Correspondence: (L.Y.); (J.X.)
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12
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Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease. Cancers (Basel) 2021; 13:cancers13143410. [PMID: 34298625 PMCID: PMC8304605 DOI: 10.3390/cancers13143410] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The Hedgehog/GLI (Hh/GLI) pathway plays a major role during development and it is commonly dysregulated in many diseases, including cancer. This highly concerted series of ligands, receptors, cytoplasmic signaling molecules, transcription factors, and co-regulators is involved in regulating the biological functions controlled by this pathway. Activation of Hh/GLI in cancer is most often through a non-canonical method of activation, independent of ligand binding. This review is intended to summarize our current understanding of the Hh/GLI signaling, non-canonical mechanisms of pathway activation, its implication in disease, and the current therapeutic strategies targeting this cascade. Abstract The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3β, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3β) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer.
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Kotulak-Chrząszcz A, Kmieć Z, Wierzbicki PM. Sonic Hedgehog signaling pathway in gynecological and genitourinary cancer (Review). Int J Mol Med 2021; 47:106. [PMID: 33907821 PMCID: PMC8057295 DOI: 10.3892/ijmm.2021.4939] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 03/10/2021] [Indexed: 01/07/2023] Open
Abstract
Cancers of the urinary tract, as well as those of the female and male reproductive systems, account for a large percentage of malignancies worldwide. Mortality is frequently affected by late diagnosis or therapeutic difficulties. The Sonic Hedgehog (SHH) pathway is an evolutionary conserved molecular cascade, which is mainly associated with the development of the central nervous system in fetal life. The present review aimed to provide an in‑depth summary of the SHH signaling pathway, including the characterization of its major components, the mechanism of its upstream regulation and non‑canonical activation, as well as its interactions with other cellular pathways. In addition, the three possible mechanisms of the cellular SHH cascade in cancer tissue are discussed. The aim of the present review was to summarize significant findings with regards to the expression of the SHH pathway components in kidney, bladder, ovarian, cervical and prostate cancer. Reports associated with common deficits and de‑regulations of the SHH pathway were summarized, despite the differences in molecular and histological patterns among these malignancies. However, currently, neither are SHH pathway elements included in panels of prognostic/therapeutic molecular patterns in any of the discussed cancers, nor have the drugs targeting SMO or GLIs been approved for therapy. The findings of the present review may support future studies on the treatment of and/or molecular targets for gynecological and genitourinary cancers.
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Affiliation(s)
| | | | - Piotr M. Wierzbicki
- Correspondence to: Dr Piotr M. Wierzbicki, Department of Histology, Faculty of Medicine, Medical University of Gdansk, ul. Debinki 1, 80211 Gdansk, Poland, E-mail:
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Avery JT, Zhang R, Boohaker RJ. GLI1: A Therapeutic Target for Cancer. Front Oncol 2021; 11:673154. [PMID: 34113570 PMCID: PMC8186314 DOI: 10.3389/fonc.2021.673154] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/30/2021] [Indexed: 12/11/2022] Open
Abstract
GLI1 is a transcriptional effector at the terminal end of the Hedgehog signaling (Hh) pathway and is tightly regulated during embryonic development and tissue patterning/differentiation. GLI1 has low-level expression in differentiated tissues, however, in certain cancers, aberrant activation of GLI1 has been linked to the promotion of numerous hallmarks of cancer, such as proliferation, survival, angiogenesis, metastasis, metabolic rewiring, and chemotherapeutic resistance. All of these are driven, in part, by GLI1’s role in regulating cell cycle, DNA replication and DNA damage repair processes. The consequences of GLI1 oncogenic activity, specifically the activity surrounding DNA damage repair proteins, such as NBS1, and cell cycle proteins, such as CDK1, can be linked to tumorigenesis and chemoresistance. Therefore, understanding the underlying mechanisms driving GLI1 dysregulation can provide prognostic and diagnostic biomarkers to identify a patient population that would derive therapeutic benefit from either direct inhibition of GLI1 or targeted therapy towards proteins downstream of GLI1 regulation.
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Affiliation(s)
- Justin T Avery
- Oncology Department, Drug Discovery Division, Southern Research, Birmingham, AL, United States
| | - Ruowen Zhang
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Rebecca J Boohaker
- Oncology Department, Drug Discovery Division, Southern Research, Birmingham, AL, United States
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15
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Iriana S, Asha K, Repak M, Sharma-Walia N. Hedgehog Signaling: Implications in Cancers and Viral Infections. Int J Mol Sci 2021; 22:1042. [PMID: 33494284 PMCID: PMC7864517 DOI: 10.3390/ijms22031042] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022] Open
Abstract
The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.
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16
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Sonic Hedgehog Signature in Pediatric Primary Bone Tumors: Effects of the GLI Antagonist GANT61 on Ewing's Sarcoma Tumor Growth. Cancers (Basel) 2020; 12:cancers12113438. [PMID: 33228057 PMCID: PMC7699338 DOI: 10.3390/cancers12113438] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/16/2020] [Accepted: 11/17/2020] [Indexed: 01/07/2023] Open
Abstract
Simple Summary The poor clinical outcomes for Osteosarcoma (OS) and Ewing’s sarcoma (ES) patients underscore the urgency of developing novel therapeutic strategies for these pathologies. In this context, the emerging role of Sonic hedgehog (SHH) signaling in cancer has been critically evaluated, focusing on the potential for targeting SHH signaling as an anticancer strategy. The aims of this work were (1) to highlight and to compare a possible SHH/Gli signature between OS and ES, (2) to strengthen our knowledge concerning the role of EWS-FLI1 in the SHH signature in ES and (3) to evaluate the effect of the specific Gli inhibitor GANT61 in vivo on the growth of ES tumors using an orthotopic mice model. Our work identifies Gli1 as a promising therapeutic target in ES and demonstrates that GANT61, through inhibition of Gli1 transcriptional activity, may be a promising therapeutic strategy hindering ES tumor progression, and specifically primary tumor growth. Abstract Osteosarcoma (OS) and Ewing’s sarcoma (ES) are the most common malignant bone tumors in children and adolescents. In many cases, the prognosis remains very poor. The Sonic hedgehog (SHH) signaling pathway, strongly involved in the development of many cancers, regulate transcription via the transcriptional factors Gli1-3. In this context, RNAseq analysis of OS and ES cell lines reveals an increase of some major compounds of the SHH signaling cascade in ES cells, such as the transcriptional factor Gli1. This increase leads to an augmentation of the transcriptional response of Gli1 in ES cell lines, demonstrating a dysregulation of Gli1 signaling in ES cells and thus the rationale for targeting Gli1 in ES. The use of a preclinical model of ES demonstrates that GANT61, an inhibitor of the transcriptional factor Gli1, reduces ES primary tumor growth. In vitro experiments show that GANT61 decreases the viability of ES cell, mainly through its ability to induce caspase-3/7-dependent cell apoptosis. Taken together, these results demonstrates that GANT61 may be a promising therapeutic strategy for inhibiting the progression of primary ES tumors.
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Dusek CO, Hadden MK. Targeting the GLI family of transcription factors for the development of anti-cancer drugs. Expert Opin Drug Discov 2020; 16:289-302. [PMID: 33006903 DOI: 10.1080/17460441.2021.1832078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION GLI1 is a transcription factor that has been identified as a downstream effector for multiple tumorigenic signaling pathways. These include the Hedgehog, RAS-RAF-MEK-ERK, and PI3K-AKT-mTOR pathways, which have all been separately validated as individual anti-cancer drug targets. The identification of GLI1 as a key transcriptional regulator for each of these pathways highlights its promise as a therapeutic target. Small molecule GLI1 inhibitors are potentially efficacious against human malignancies arising from multiple oncogenic mechanisms. AREAS COVERED This review provides an overview of the key oncogenic cellular pathways that regulate GLI1 transcriptional activity. It also provides a detailed account of small molecule GLI1 inhibitors that are currently under development as potential anti-cancer chemotherapeutics. EXPERT OPINION Interest in developing inhibitors of GLI1-mediated transcription has significantly increased as its role in multiple oncogenic signaling pathways has been elucidated. To date, it has proven difficult to directly target GLI1 with small molecules, and the majority of compounds that inhibit GLI1 activity function through indirect mechanisms. To date, no direct-acting GLI1 inhibitor has entered clinical trials. The identification and development of new scaffolds that can bind and directly inhibit GLI1 are essential to further advance this class of chemotherapeutics.
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Affiliation(s)
- Christopher O Dusek
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
| | - M Kyle Hadden
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
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18
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Scheidt T, Alka O, Gonczarowska-Jorge H, Gruber W, Rathje F, Dell’Aica M, Rurik M, Kohlbacher O, Zahedi RP, Aberger F, Huber CG. Phosphoproteomics of short-term hedgehog signaling in human medulloblastoma cells. Cell Commun Signal 2020; 18:99. [PMID: 32576205 PMCID: PMC7310537 DOI: 10.1186/s12964-020-00591-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 05/05/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Aberrant hedgehog (HH) signaling is implicated in the development of various cancer entities such as medulloblastoma. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Increased phosphorylation of essential effectors such as Smoothened (SMO) and GLI proteins by kinases including Protein Kinase A, Casein Kinase 1, and Glycogen Synthase Kinase 3 β controls effector activity, stability and processing. However, a deeper and more comprehensive understanding of phosphorylation in the signal transduction remains unclear, particularly during early response processes involved in SMO activation and preceding GLI target gene regulation. METHODS We applied temporal quantitative phosphoproteomics to reveal phosphorylation dynamics underlying the short-term chemical activation and inhibition of early hedgehog signaling in HH responsive human medulloblastoma cells. Medulloblastoma cells were treated for 5.0 and 15 min with Smoothened Agonist (SAG) to induce and with vismodegib to inhibit the HH pathway. RESULTS Our phosphoproteomic profiling resulted in the quantification of 7700 and 10,000 phosphosites after 5.0 and 15 min treatment, respectively. The data suggest a central role of phosphorylation in the regulation of ciliary assembly, trafficking, and signal transduction already after 5.0 min treatment. ERK/MAPK signaling, besides Protein Kinase A signaling and mTOR signaling, were differentially regulated after short-term treatment. Activation of Polo-like Kinase 1 and inhibition of Casein Kinase 2A1 were characteristic for vismodegib treatment, while SAG treatment induced Aurora Kinase A activity. Distinctive phosphorylation of central players of HH signaling such as SMO, SUFU, GLI2 and GLI3 was observed only after 15 min treatment. CONCLUSIONS This study provides evidence that phosphorylation triggered in response to SMO modulation dictates the localization of hedgehog pathway components within the primary cilium and affects the regulation of the SMO-SUFU-GLI axis. The data are relevant for the development of targeted therapies of HH-associated cancers including sonic HH-type medulloblastoma. A deeper understanding of the mechanisms of action of SMO inhibitors such as vismodegib may lead to the development of compounds causing fewer adverse effects and lower frequencies of drug resistance. Video Abstract.
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Affiliation(s)
- Tamara Scheidt
- Department of Biosciences, Bioanalytical Research Laboratories and Molecular Cancer Research and Tumor Immunology, Cancer Cluster Salzburg, University of Salzburg, Hellbrunner Straße 34, 5020 Salzburg, Austria
| | - Oliver Alka
- Institute for Bioinformatics and Medical Informatics, University of Tübingen, Sand 14, 72076 Tübingen, Germany
| | - Humberto Gonczarowska-Jorge
- Leibniz-Institute of Analytical Sciences- ISAS - e.V, Dortmund, Germany
- Present address: CAPES Foundation, Ministry of Education of Brazil, Brasília, DF 70040-020 Brazil
| | - Wolfgang Gruber
- Department of Biosciences, Bioanalytical Research Laboratories and Molecular Cancer Research and Tumor Immunology, Cancer Cluster Salzburg, University of Salzburg, Hellbrunner Straße 34, 5020 Salzburg, Austria
- Present address: EVER Valinject GmbH, 4866 Unterach am Attersee, Austria
| | - Florian Rathje
- Department of Biosciences, Bioanalytical Research Laboratories and Molecular Cancer Research and Tumor Immunology, Cancer Cluster Salzburg, University of Salzburg, Hellbrunner Straße 34, 5020 Salzburg, Austria
| | | | - Marc Rurik
- Institute for Bioinformatics and Medical Informatics, University of Tübingen, Sand 14, 72076 Tübingen, Germany
| | - Oliver Kohlbacher
- Institute for Bioinformatics and Medical Informatics, University of Tübingen, Sand 14, 72076 Tübingen, Germany
- Biomolecular Interactions, Max Planck Institute for Developmental Biology, Max-Planck-Ring 5, 72076 Tübingen, Germany
- Institute for Translational Bioinformatics, University Hospital Tübingen, Hoppe-Seyler-Str. 9, 72076 Tübingen, Germany
- Applied Bioinformatics, Center for Bioinformatics, University of Tübingen, Sand 14, 72076 Tübingen, Germany
| | - René P. Zahedi
- Leibniz-Institute of Analytical Sciences- ISAS - e.V, Dortmund, Germany
- Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, Canada
- Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada
| | - Fritz Aberger
- Department of Biosciences, Bioanalytical Research Laboratories and Molecular Cancer Research and Tumor Immunology, Cancer Cluster Salzburg, University of Salzburg, Hellbrunner Straße 34, 5020 Salzburg, Austria
| | - Christian G. Huber
- Department of Biosciences, Bioanalytical Research Laboratories and Molecular Cancer Research and Tumor Immunology, Cancer Cluster Salzburg, University of Salzburg, Hellbrunner Straße 34, 5020 Salzburg, Austria
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Matissek SJ, Elsawa SF. GLI3: a mediator of genetic diseases, development and cancer. Cell Commun Signal 2020; 18:54. [PMID: 32245491 PMCID: PMC7119169 DOI: 10.1186/s12964-020-00540-x] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
The transcription factor GLI3 is a member of the Hedgehog (Hh/HH) signaling pathway that can exist as a full length (Gli3-FL/GLI3-FL) or repressor (Gli3-R/GLI3-R) form. In response to HH activation, GLI3-FL regulates HH genes by targeting the GLI1 promoter. In the absence of HH signaling, GLI3 is phosphorylated leading to its partial degradation and the generation of GLI3-R which represses HH functions. GLI3 is also involved in tissue development, immune cell development and cancer. The absence of Gli3 in mice impaired brain and lung development and GLI3 mutations in humans are the cause of Greig cephalopolysyndactyly (GCPS) and Pallister Hall syndromes (PHS). In the immune system GLI3 regulates B, T and NK-cells and may be involved in LPS-TLR4 signaling. In addition, GLI3 was found to be upregulated in multiple cancers and was found to positively regulate cancerous behavior such as anchorage-independent growth, angiogenesis, proliferation and migration with the exception in acute myeloid leukemia (AML) and medulloblastoma where GLI plays an anti-cancerous role. Finally, GLI3 is a target of microRNA. Here, we will review the biological significance of GLI3 and discuss gaps in our understanding of this molecule. Video Abstract.
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Affiliation(s)
- Stephan J. Matissek
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, 46 College Rd Rudman 291, Durham, NH 03824 USA
| | - Sherine F. Elsawa
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, 46 College Rd Rudman 291, Durham, NH 03824 USA
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Lézot F, Corre I, Morice S, Rédini F, Verrecchia F. SHH Signaling Pathway Drives Pediatric Bone Sarcoma Progression. Cells 2020; 9:cells9030536. [PMID: 32110934 PMCID: PMC7140443 DOI: 10.3390/cells9030536] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/19/2020] [Accepted: 02/23/2020] [Indexed: 02/07/2023] Open
Abstract
Primary bone tumors can be divided into two classes, benign and malignant. Among the latter group, osteosarcoma and Ewing sarcoma are the most prevalent malignant primary bone tumors in children and adolescents. Despite intensive efforts to improve treatments, almost 40% of patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma or Ewing sarcoma remains poor; less than 30% of patients who present metastases will survive 5 years after initial diagnosis. One common and specific point of these bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Over the past years, considerable interest in the Sonic Hedgehog (SHH) pathway has taken place within the cancer research community. The activation of this SHH cascade can be done through different ways and, schematically, two pathways can be described, the canonical and the non-canonical. This review discusses the current knowledge about the involvement of the SHH signaling pathway in skeletal development, pediatric bone sarcoma progression and the related therapeutic options that may be possible for these tumors.
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Pietrobono S, Gagliardi S, Stecca B. Non-canonical Hedgehog Signaling Pathway in Cancer: Activation of GLI Transcription Factors Beyond Smoothened. Front Genet 2019; 10:556. [PMID: 31244888 PMCID: PMC6581679 DOI: 10.3389/fgene.2019.00556] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 05/24/2019] [Indexed: 12/16/2022] Open
Abstract
The Hedgehog-GLI (HH-GLI) pathway is a highly conserved signaling that plays a critical role in controlling cell specification, cell–cell interaction and tissue patterning during embryonic development. Canonical activation of HH-GLI signaling occurs through binding of HH ligands to the twelve-pass transmembrane receptor Patched 1 (PTCH1), which derepresses the seven-pass transmembrane G protein-coupled receptor Smoothened (SMO). Thus, active SMO initiates a complex intracellular cascade that leads to the activation of the three GLI transcription factors, the final effectors of the HH-GLI pathway. Aberrant activation of this signaling has been implicated in a wide variety of tumors, such as those of the brain, skin, breast, gastrointestinal, lung, pancreas, prostate and ovary. In several of these cases, activation of HH-GLI signaling is mediated by overproduction of HH ligands (e.g., prostate cancer), loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO, which occur in the majority of basal cell carcinoma (BCC), SHH-subtype medulloblastoma and rhabdomyosarcoma. Besides the classical canonical ligand-PTCH1-SMO route, mounting evidence points toward additional, non-canonical ways of GLI activation in cancer. By non-canonical we refer to all those mechanisms of activation of the GLI transcription factors occurring independently of SMO. Often, in a given cancer type canonical and non-canonical activation of HH-GLI signaling co-exist, and in some cancer types, more than one mechanism of non-canonical activation may occur. Tumors harboring non-canonical HH-GLI signaling are less sensitive to SMO inhibition, posing a threat for therapeutic efficacy of these antagonists. Here we will review the most recent findings on the involvement of alternative signaling pathways in inducing GLI activity in cancer and stem cells. We will also discuss the rationale of targeting these oncogenic pathways in combination with HH-GLI inhibitors as a promising anti-cancer therapies.
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Affiliation(s)
- Silvia Pietrobono
- Tumor Cell Biology Unit - Core Research Laboratory, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
| | - Sinforosa Gagliardi
- Tumor Cell Biology Unit - Core Research Laboratory, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
| | - Barbara Stecca
- Tumor Cell Biology Unit - Core Research Laboratory, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
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Role of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics. Cells 2019; 8:cells8040375. [PMID: 31027259 PMCID: PMC6523618 DOI: 10.3390/cells8040375] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 04/22/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
Breast cancer (BC) is the leading cause of cancer-related mortality in women, only followed by lung cancer. Given the importance of BC in public health, it is essential to identify biomarkers to predict prognosis, predetermine drug resistance and provide treatment guidelines that include personalized targeted therapies. The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, tissue regeneration, and stem cell renewal. Several lines of evidence endorse the important role of canonical and non-canonical Hh signaling in BC. In this comprehensive review we discuss the role of Hh signaling in breast development and homeostasis and its contribution to tumorigenesis and progression of different subtypes of BC. We also examine the efficacy of agents targeting different components of the Hh pathway both in preclinical models and in clinical trials. The contribution of the Hh pathway in BC tumorigenesis and progression, its prognostic role, and its value as a therapeutic target vary according to the molecular, clinical, and histopathological characteristics of the BC patients. The evidence presented here highlights the relevance of the Hh signaling in BC, and suggest that this pathway is key for BC progression and metastasis.
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Park SH, Jo MJ, Kim BR, Jeong YA, Na YJ, Kim JL, Jeong S, Yun HK, Kim DY, Kim BG, Kang SH, Oh SC, Lee DH. Sonic hedgehog pathway activation is associated with cetuximab resistance and EPHB3 receptor induction in colorectal cancer. Am J Cancer Res 2019; 9:2235-2251. [PMID: 31149041 PMCID: PMC6531304 DOI: 10.7150/thno.30678] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 02/17/2019] [Indexed: 02/06/2023] Open
Abstract
A major problem of colorectal cancer (CRC) targeted therapies is relapse caused by drug resistance. In most cases of CRC, patients develop resistance to anticancer drugs. Cetuximab does not show many of the side effects of other anticancer drugs and improves the survival of patients with metastatic CRC. However, the molecular mechanism of cetuximab resistance is not fully understood. Methods: EPHB3-mediated cetuximab resistance was confirmed by in vitro western blotting, colony-forming assays, WST-1 colorimetric assay, and in vivo xenograft models (n = 7 per group). RNA-seq analysis and receptor tyrosine kinase assays were performed to identify the cetuximab resistance mechanism of EPHB3. All statistical tests were two-sided. Results: The expression of EFNB3, which upregulates the EPHB3 receptor, was shown to be increased via microarray analysis. When resistance to cetuximab was acquired, EPHB3 protein levels increased. Hedgehog signaling, cancer stemness, and epithelial-mesenchymal transition signaling proteins were also increased in the cetuximab-resistant human colon cancer cell line SW48R. Despite cells acquiring resistance to cetuximab, STAT3 was still responsive to EGF and cetuximab treatment. Moreover, inhibition of EPHB3 was associated with decreased STAT3 activity. Co-immunoprecipitation confirmed that EGFR and EPHB3 bind to each other and this binding increases upon resistance acquisition, suggesting that STAT3 is activated by the binding between EGFR and EPHB3. Protein levels of GLI-1, SOX2, and Vimentin, which are affected by STAT3, also increased. Similar results were obtained in samples from patients with CRC. Conclusion: EPHB3 expression is associated with anticancer drug resistance.
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Lau BW, Huh K, Madero-Marroquin R, De Marchi F, Lim Y, Wang Q, Lobo F, Marchionni L, Smith DB, DeZern A, Levis MJ, Aplan PD, Matsui W, Gondek LP. Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity. Oncogene 2019; 38:687-698. [PMID: 30171262 PMCID: PMC6358463 DOI: 10.1038/s41388-018-0431-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 06/08/2018] [Accepted: 07/09/2018] [Indexed: 12/31/2022]
Abstract
Myelodysplastic syndromes (MDSs) are stem cell disorders with risk of transformation to acute myeloid leukemia (AML). Gene expression profiling reveals transcriptional expression of GLI1, of Hedgehog (Hh) signaling, in poor-risk MDS/AML. Using a murine model of MDS we demonstrated that constitutive Hh/Gli1 activation accelerated leukemic transformation and decreased overall survival. Hh/Gli1 activation resulted in clonal expansion of phenotypically defined granulocyte macrophage progenitors (GMPs) and acquisition of self-renewal potential in a non-self-renewing progenitor compartment. Transcriptome analysis of GMPs revealed enrichment in gene signatures of self-renewal pathways, operating via direct Gli1 activation. Using human cell lines we demonstrated that in addition to canonical Hh signaling, GLI1 is activated in a Smoothened-independent manner. GLI1 knockdown or inhibition with GANT61 resulted in decreased proliferation and clonogenic potential. Our data suggest that GLI1 activation is frequent in MDS during disease progression and inhibition of GLI1 is an attractive therapeutic target for a subset of patients.
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MESH Headings
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Proliferation/genetics
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Granulocyte-Macrophage Progenitor Cells/metabolism
- Granulocyte-Macrophage Progenitor Cells/pathology
- Hedgehog Proteins/genetics
- Hedgehog Proteins/metabolism
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Myelodysplastic Syndromes/genetics
- Myelodysplastic Syndromes/metabolism
- Myelodysplastic Syndromes/pathology
- Pyridines/pharmacology
- Pyrimidines/pharmacology
- Zinc Finger Protein GLI1/genetics
- Zinc Finger Protein GLI1/metabolism
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Affiliation(s)
- Bonnie W Lau
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Kyounghee Huh
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Rafael Madero-Marroquin
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Federico De Marchi
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Yiting Lim
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
| | - Qiuju Wang
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Francisco Lobo
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Departamento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Luigi Marchionni
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Douglas B Smith
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Amy DeZern
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Mark J Levis
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Peter D Aplan
- Genetics Branch National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - William Matsui
- LIVESTRONG Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712USA, USA.
| | - Lukasz P Gondek
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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25
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Bariwal J, Kumar V, Dong Y, Mahato RI. Design of Hedgehog pathway inhibitors for cancer treatment. Med Res Rev 2018; 39:1137-1204. [PMID: 30484872 DOI: 10.1002/med.21555] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 10/18/2018] [Accepted: 10/19/2018] [Indexed: 12/11/2022]
Abstract
Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases. While the majority of Hh pathway inhibitors target the transmembrane protein Smoothened (SMO), some small molecules that target the signaling cascade downstream of SMO are of particular interest. Substantial efforts are being made to develop new molecules targeting various components of the Hh signaling pathway. Here, we have discussed the discovery of small molecules as Hh inhibitors from the diverse chemical background. Also, some of the recently identified natural products have been included as a separate section. Extensive structure-activity relationship (SAR) of each chemical class is the focus of this review. Also, clinically advanced molecules are discussed from the last 5 to 7 years. Nanomedicine-based delivery approaches for Hh pathway inhibitors are also discussed concisely.
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Affiliation(s)
- Jitender Bariwal
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
| | - Virender Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
| | - Yuxiang Dong
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
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26
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Del Giovane A, Ragnini-Wilson A. Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies. Int J Mol Sci 2018; 19:E3677. [PMID: 30463396 PMCID: PMC6274747 DOI: 10.3390/ijms19113677] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/09/2018] [Accepted: 11/14/2018] [Indexed: 12/20/2022] Open
Abstract
Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance.
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Affiliation(s)
- Alice Del Giovane
- Department of Biology University of Rome Tor Vergata, Viale Della Ricerca Scientifica, 00133 Rome, Italy.
| | - Antonella Ragnini-Wilson
- Department of Biology University of Rome Tor Vergata, Viale Della Ricerca Scientifica, 00133 Rome, Italy.
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27
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Giroux-Leprieur E, Costantini A, Ding VW, He B. Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance. Int J Mol Sci 2018; 19:E2835. [PMID: 30235830 PMCID: PMC6165231 DOI: 10.3390/ijms19092835] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 09/11/2018] [Accepted: 09/17/2018] [Indexed: 12/14/2022] Open
Abstract
Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research.
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Affiliation(s)
- Etienne Giroux-Leprieur
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France.
- EA 4340, UVSQ, Université Paris-Saclay, 92100 Boulogne-Billancourt, France.
| | - Adrien Costantini
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France.
- EA 4340, UVSQ, Université Paris-Saclay, 92100 Boulogne-Billancourt, France.
| | - Vivianne W Ding
- Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
| | - Biao He
- Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
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28
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Amarante MK, Vitiello GAF, Rosa MH, Mancilla IA, Watanabe MAE. Potential use of CXCL12/CXCR4 and sonic hedgehog pathways as therapeutic targets in medulloblastoma. Acta Oncol 2018; 57:1134-1142. [PMID: 29771176 DOI: 10.1080/0284186x.2018.1473635] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Medulloblastoma (MB) is the most common malignant brain tumor occurring in children, and although high long-term survival rates have been reached with current therapeutic protocols, several neurological injuries are still observed among survivors. It has been shown that the development of MB is highly dependent on the microenvironment surrounding it and that the CXCL12 chemokine and its receptor, CXCR4 and the Sonic Hedgehog (SHH) pathway are crucial for cerebellar development, coordinating proliferation and migration of embryonic cells and malfunctions in these axes can lead to MB development. Indeed, the concomitant overactivation of these axes was suggested to define a new MB molecular subgroup. New molecules are being studied, aiming to inhibit either CXCR4 or the SHH pathways and have been tested in preclinical settings for the treatment of cancers. The use of these molecules could improve MB treatment and save patients from aggressive surgery, chemotherapy and radiotherapy regimens, which are responsible for severe neurological consequences. This review aims to summarize current data about the experimental inhibition of CXCR4 and SHH pathways in MB and its potential implications in treatment of this cancer.
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Affiliation(s)
| | | | - Marcos Henrique Rosa
- Department of Pathological Sciences, Londrina State University, Londrina, Brazil
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29
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Antitumor Efficacy of Dual Blockade of EGFR Signaling by Osimertinib in Combination With Selumetinib or Cetuximab in Activated EGFR Human NCLC Tumor Models. J Thorac Oncol 2018. [DOI: 10.1016/j.jtho.2018.02.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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30
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Goruppi S, Procopio MG, Jo S, Clocchiatti A, Neel V, Dotto GP. The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI. Cell Rep 2018; 20:2468-2479. [PMID: 28877478 DOI: 10.1016/j.celrep.2017.08.048] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 06/15/2017] [Accepted: 08/15/2017] [Indexed: 12/11/2022] Open
Abstract
The connection between signaling pathways activating cancer-associated fibroblasts (CAFs) remains to be determined. Metabolic alterations linked to autophagy have also been implicated in CAF activation. CSL/RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses the gene expression program(s), leading to stromal senescence and CAF activation. Deregulated GLI signaling can also contribute to CAF conversion. Here, we report that compromised CSL function depends on GLI activation for conversion of human dermal fibroblasts into CAFs, separately from cellular senescence. Decreased CSL upregulates the expression of the ULK3 kinase, which binds and activates GLI2. Increased ULK3 also induces autophagy, which is unlinked from GLI and CAF activation. ULK3 upregulation occurs in the CAFs of several tumor types, and ULK3 silencing suppresses the tumor-enhancing properties of these cells. Thus, ULK3 links two key signaling pathways involved in CAF conversion and is an attractive target for stroma-focused anti-cancer intervention.
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Affiliation(s)
- Sandro Goruppi
- Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Bldg., 13th St. Charlestown, MA 02129, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02125, USA
| | - Maria-Giuseppina Procopio
- Department of Biochemistry, University of Lausanne, 155 Chemin des Boveresses, Epalinges 1066, Switzerland
| | - Seunghee Jo
- Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Bldg., 13th St. Charlestown, MA 02129, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02125, USA
| | - Andrea Clocchiatti
- Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Bldg., 13th St. Charlestown, MA 02129, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02125, USA
| | - Victor Neel
- Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - G Paolo Dotto
- Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Bldg., 13th St. Charlestown, MA 02129, USA; Department of Biochemistry, University of Lausanne, 155 Chemin des Boveresses, Epalinges 1066, Switzerland.
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31
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Zhang R, Huang SY, Ka-Wai Li K, Li YH, Hsu WH, Zhang GJ, Chang CJ, Yang JY. Dual degradation signals destruct GLI1: AMPK inhibits GLI1 through β-TrCP-mediated proteasome degradation. Oncotarget 2018; 8:49869-49881. [PMID: 28562331 PMCID: PMC5564814 DOI: 10.18632/oncotarget.17769] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 04/05/2017] [Indexed: 12/11/2022] Open
Abstract
Overexpression of the GLI1 gene has frequently been found in various cancer types, particularly in brain tumors, in which aberrant GLI1 induction promotes cancer cell growth. Therefore, identifying the molecular players controlling GLI1 expression is of clinical importance. Previously, we reported that AMPK directly phosphorylated and destabilized GLI1, resulting in the suppression of the Hedgehog signaling pathway. The current study not only demonstrates that AMPK inhibits GLI1 nuclear localization, but further reveals that β-TrCP plays an essential role in AMPK-induced GLI1 degradation. We found that activation of AMPK promotes the interaction between β-TrCP and GLI1, and induces β-TrCP-mediated GLI1-ubiquitination and degradation. Inhibiting AMPK activity results in the dissociation of the β-TrCP and GLI1 interaction, and diminishes β-TrCP-mediated-GLI1 ubiquitination and degradation. On GLI1, substitution of AMPK phosphorylation sites to aspartic acid (GLI13E) results in stronger binding affinity of GLI1 with β-TrCP, accompanied by enhanced GLI1 ubiquitination and later degradation. In contrast, the GLI1 alanine mutant (GLI13A) shows weaker binding with β-TrCP, which is accompanied by reduced β-TrCP-mediated ubiquitination and degradation. Together, these results demonstrate that AMPK regulates GLI1 interaction with β-TrCP by phosphorylating GLI1 and thus both post-translational modifications by AMPK and β-TrCP ultimately impact GLI1 degradation.
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Affiliation(s)
- Rui Zhang
- Department of Basic Medical Sciences, West Lafayette, Indiana, USA
| | - Sherri Y Huang
- Department of Basic Medical Sciences, West Lafayette, Indiana, USA
| | - Kay Ka-Wai Li
- /F of Cancer Centre, Prince of Wales Hospital, Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Yen-Hsing Li
- Department of Basic Medical Sciences, West Lafayette, Indiana, USA
| | - Wei-Hsuan Hsu
- Department of Basic Medical Sciences, West Lafayette, Indiana, USA
| | - Guang Jun Zhang
- Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.,Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA
| | - Chun-Ju Chang
- Department of Basic Medical Sciences, West Lafayette, Indiana, USA.,Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
| | - Jer-Yen Yang
- Department of Basic Medical Sciences, West Lafayette, Indiana, USA.,Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
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32
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Mastrangelo E, Milani M. Role and inhibition of GLI1 protein in cancer. LUNG CANCER-TARGETS AND THERAPY 2018; 9:35-43. [PMID: 29628779 PMCID: PMC5877502 DOI: 10.2147/lctt.s124483] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
GLI1 is a transcriptional regulator involved in the development of different types of cancer. GLI1 transcriptional activity is regulated within the Hedgehog pathway (canonical activity), but can also be controlled independently (non-canonical activity) in the context of other signaling pathways. Experimental evidences show GLI1 involvement in both small- and non–small-cell lung cancers. Direct inhibition of the protein, in combination with other chemotherapeutic agents, represents a promising strategy for the treatment of different malignancies.
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Affiliation(s)
- Eloise Mastrangelo
- CNR - Biophysics Institute, c/o Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Mario Milani
- CNR - Biophysics Institute, c/o Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
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33
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Silva LM, Jacobs DT, Allard BA, Fields TA, Sharma M, Wallace DP, Tran PV. Inhibition of Hedgehog signaling suppresses proliferation and microcyst formation of human Autosomal Dominant Polycystic Kidney Disease cells. Sci Rep 2018; 8:4985. [PMID: 29563577 PMCID: PMC5862907 DOI: 10.1038/s41598-018-23341-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 03/09/2018] [Indexed: 12/13/2022] Open
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutation of PKD1 or PKD2, which encode polycystin 1 and 2, respectively. The polycystins localize to primary cilia and the functional loss of the polycystin complex leads to the formation and progressive growth of fluid-filled cysts in the kidney. The pathogenesis of ADPKD is complex and molecular mechanisms connecting ciliary dysfunction to renal cystogenesis are unclear. Primary cilia mediate Hedgehog signaling, which modulates cell proliferation and differentiation in a tissue-dependent manner. Previously, we showed that Hedgehog signaling was increased in cystic kidneys of several PKD mouse models and that Hedgehog inhibition prevented cyst formation in embryonic PKD mouse kidneys treated with cAMP. Here, we show that in human ADPKD tissue, Hedgehog target and activator, Glioma 1, was elevated and localized to cyst-lining epithelial cells and to interstitial cells, suggesting increased autocrine and paracrine Hedgehog signaling in ADPKD, respectively. Further, Hedgehog inhibitors reduced basal and cAMP-induced proliferation of ADPKD cells and cyst formation in vitro. These data suggest that Hedgehog signaling is increased in human ADPKD and that suppression of Hedgehog signaling can counter cellular processes that promote cyst growth in vitro.
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Affiliation(s)
- Luciane M Silva
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.,Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Damon T Jacobs
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.,Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Bailey A Allard
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.,Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Timothy A Fields
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.,Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Madhulika Sharma
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.,Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Darren P Wallace
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.,Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.,Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Pamela V Tran
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA. .,Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA.
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34
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Carballo GB, Honorato JR, de Lopes GPF, Spohr TCLDSE. A highlight on Sonic hedgehog pathway. Cell Commun Signal 2018; 16:11. [PMID: 29558958 PMCID: PMC5861627 DOI: 10.1186/s12964-018-0220-7] [Citation(s) in RCA: 312] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 02/16/2018] [Indexed: 12/25/2022] Open
Abstract
Hedgehog (Hh) signaling pathway plays an essential role during vertebrate embryonic development and tumorigenesis. It is already known that Sonic hedgehog (Shh) pathway is important for the evolution of radio and chemo-resistance of several types of tumors. Most of the brain tumors are resistant to chemotherapeutic drugs, consequently, they have a poor prognosis. So, a better knowledge of the Shh pathway opens an opportunity for targeted therapies against brain tumors considering a multi-factorial molecular overview. Therefore, emerging studies are being conducted in order to find new inhibitors for Shh signaling pathway, which could be safely used in clinical trials. Shh can signal through a canonical and non-canonical way, and it also has important points of interaction with other pathways during brain tumorigenesis. So, a better knowledge of Shh signaling pathway opens an avenue of possibilities for the treatment of not only for brain tumors but also for other types of cancers. In this review, we will also highlight some clinical trials that use the Shh pathway as a target for treating brain cancer.
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Affiliation(s)
- Gabriela Basile Carballo
- Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230-024, Brazil.,Programa de Pós-Gradução em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jéssica Ribeiro Honorato
- Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230-024, Brazil.,Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), RJ, Brazil.,Programa de Pós-Gradução em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Giselle Pinto Farias de Lopes
- Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), RJ, Brazil
| | - Tania Cristina Leite de Sampaio E Spohr
- Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230-024, Brazil.
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35
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NOX4-driven ROS formation regulates proliferation and apoptosis of gastric cancer cells through the GLI1 pathway. Cell Signal 2018; 46:52-63. [PMID: 29496628 DOI: 10.1016/j.cellsig.2018.02.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Revised: 02/13/2018] [Accepted: 02/15/2018] [Indexed: 12/21/2022]
Abstract
NADPH Oxidase 4 (NOX4), a member of the NOX family, has emerged as a significant source of reactive oxygen species, playing an important role in tumor cell proliferation, apoptosis, and other physiological processes. However, the potential function of NOX4 in gastric cancer (GC) cell proliferation is yet unknown. The aim of this study was to illustrate whether NOX4 plays a role in regulating gastric cancer cell growth. First, the clinical information from 90 patients was utilized to explore the clinical value of NOX4 as a predictive tool for tumor size and prognosis. Results showed that NOX4 expression was correlated with tumor size and prognosis. In vitro assays confirmed that knockdown of NOX4 expression blocked cell proliferation and the expression of Cyclin D1, BAX, and so on. Interestingly, NOX4 promoted cell proliferation via activation of the GLI1 pathway. GLI1, a well-known transcription factor in the Hedgehog signaling pathway, was overexpressed to test whether NOX4 activates downstream signaling via GLI1. Overexpression of GLI1 reversed the inhibition of proliferation induced by NOX4 knockdown. In addition, overexpression of NOX4 increased GLI1 expression, and depletion of GLI1 expression decreased the effects induced by NOX4 overexpression. Further, ROS generated by NOX4 was required for GLI1 expression, as shown by use of the ROS inhibitor, diphenylene iodonium (DPI). In summary, the findings indicate that NOX4 plays an important role in gastric cancer cell growth and apoptosis through the generation of ROS and subsequent activation of GLI1 signaling. Hence, the targeting of NOX4 may be an attractive therapeutic strategy for blocking gastric cancer cell proliferation.
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36
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Pellegrini C, Maturo MG, Di Nardo L, Ciciarelli V, Gutiérrez García-Rodrigo C, Fargnoli MC. Understanding the Molecular Genetics of Basal Cell Carcinoma. Int J Mol Sci 2017; 18:ijms18112485. [PMID: 29165358 PMCID: PMC5713451 DOI: 10.3390/ijms18112485] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 11/12/2017] [Accepted: 11/21/2017] [Indexed: 12/20/2022] Open
Abstract
Basal cell carcinoma (BCC) is the most common human cancer and represents a growing public health care problem. Several tumor suppressor genes and proto-oncogenes have been implicated in BCC pathogenesis, including the key components of the Hedgehog pathway, PTCH1 and SMO, the TP53 tumor suppressor, and members of the RAS proto-oncogene family. Aberrant activation of the Hedgehog pathway represents the molecular driver in basal cell carcinoma pathogenesis, with the majority of BCCs carrying somatic point mutations, mainly ultraviolet (UV)-induced, and/or copy-loss of heterozygosis in the PTCH1 gene. Recent advances in sequencing technology allowed genome-scale approaches to mutation discovery, identifying new genes and pathways potentially involved in BCC carcinogenesis. Mutational and functional analysis suggested PTPN14 and LATS1, both effectors of the Hippo–YAP pathway, and MYCN as new BCC-associated genes. In addition, emerging reports identified frequent non-coding mutations within the regulatory promoter sequences of the TERT and DPH3-OXNAD1 genes. Thus, it is clear that a more complex genetic network of cancer-associated genes than previously hypothesized is involved in BCC carcinogenesis, with a potential impact on the development of new molecular targeted therapies. This article reviews established knowledge and new hypotheses regarding the molecular genetics of BCC pathogenesis.
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Affiliation(s)
- Cristina Pellegrini
- Department of Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Maria Giovanna Maturo
- Department of Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Lucia Di Nardo
- Department of Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Valeria Ciciarelli
- Department of Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Carlota Gutiérrez García-Rodrigo
- Department of Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Maria Concetta Fargnoli
- Department of Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
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Kasiri S, Shao C, Chen B, Wilson AN, Yenerall P, Timmons BC, Girard L, Tian H, Behrens C, Wistuba II, Gazdar AF, Kim J. GLI1 Blockade Potentiates the Antitumor Activity of PI3K Antagonists in Lung Squamous Cell Carcinoma. Cancer Res 2017; 77:4448-4459. [PMID: 28652248 DOI: 10.1158/0008-5472.can-16-3315] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/13/2017] [Accepted: 06/13/2017] [Indexed: 01/05/2023]
Abstract
Lung squamous cell carcinoma (SCC), strongly associated with smoking, is treated primarily with traditional cytotoxic chemotherapy due to a lack of FDA-approved targeted agents available. Here, we identify the Hedgehog pathway transcription factor GLI1 as a critical driver of lung SCC. Analysis of human lung cancer datasets showed that GLI1 mRNA was highly expressed in human lung SCC and portended a poor prognosis. Inhibition of GLI1 in human lung SCC cell lines suppressed tumor cell clonogenicity and proliferation in culture and in vivo Addition of SHH ligand, SMO antagonists, or other Hedgehog pathway agonists did not affect GLI1 expression in lung SCC cells. However, GLI1 expression was modulated by either inhibition or activation of the PI3K and MAPK pathways. Furthermore, in vivo growth of SCC harboring amplifications of the PI3K gene PIK3CA was attenuated by antagonizing GLI1 and PI3K. Thus, a combinatorial therapeutic strategy that targets the PI3K-mTOR pathway and GLI1 may lead to effective outcomes for PI3K pathway-dependent cancers, in contrast to recent results of human trials with single-agent PI3K antagonists. Cancer Res; 77(16); 4448-59. ©2017 AACR.
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Affiliation(s)
- Sahba Kasiri
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Chunli Shao
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Baozhi Chen
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Alexandra N Wilson
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Paul Yenerall
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Brenda C Timmons
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Luc Girard
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Hui Tian
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Carmen Behrens
- Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Ignacio I Wistuba
- Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Adi F Gazdar
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - James Kim
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. .,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma. Oncogene 2017; 36:4641-4652. [PMID: 28368412 PMCID: PMC5558095 DOI: 10.1038/onc.2017.91] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 02/04/2017] [Accepted: 02/26/2017] [Indexed: 02/07/2023]
Abstract
Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs.
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Dixit R, Pandey M, Tripathi SK, Dwivedi AND, Shukla VK. Comparative Analysis of Mutational Profile of Sonic hedgehog Gene in Gallbladder Cancer. Dig Dis Sci 2017; 62:708-714. [PMID: 28058596 DOI: 10.1007/s10620-016-4438-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 12/28/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Gallbladder cancer has high incidence in northeastern India; mortality too is high as the disease is often diagnosed late. Numerous studies have shown the role of sonic hedgehog (shh) in different cancers, an important ligand of the hedgehog signaling pathway. AIM This study was carried out to evaluate the shh gene mutations in gallbladder cancer patients. METHODS PCR-SSCP was performed for shh gene in 50 samples each of gallbladder cancer, cholelithiasis, and control. The samples showing aberration in banding pattern were sequenced. RESULTS Variation in banding pattern was observed in 20% gallbladder cancer cases, 10% in cholelithiasis, and none of the control (χ 2 = 11.111; p < 0.05). Sequencing results revealed seven novel point mutations in GBC cases. These novel mutations were found to be associated with histopathology (p < 0.05) and stage (p < 0.05) of gallbladder cancer. CONCLUSION This study reveals several novel individual and repetitive mutations of shh gene in GBC and cholelithiasis samples that may be used as diagnostic markers for gallbladder carcinogenesis.
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Affiliation(s)
- Ruhi Dixit
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Manoj Pandey
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Sunil Kumar Tripathi
- Department of Forensic Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Amit Nandan Dhar Dwivedi
- Department of Radio Diagnosis, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Vijay Kumar Shukla
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India.
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Enzenhofer E, Parzefall T, Haymerle G, Schneider S, Kadletz L, Heiduschka G, Pammer J, Oberndorfer F, Wrba F, Loader B, Grasl MC, Perisanidis C, Erovic BM. Impact of Sonic Hedgehog Pathway Expression on Outcome in HPV Negative Head and Neck Carcinoma Patients after Surgery and Adjuvant Radiotherapy. PLoS One 2016; 11:e0167665. [PMID: 27918595 PMCID: PMC5137890 DOI: 10.1371/journal.pone.0167665] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Accepted: 11/17/2016] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION HPV positive patients suffering from head and neck cancer benefit from intensified radiotherapy when applied as a primary as well as an adjuvant treatment strategy. However, HPV negative patients treated with surgery and adjuvant radiotherapy lack validated prognostic biomarkers. It is therefore important to define prognostic biomarkers in this particular patient population. Especially, ´high-risk groups´ need to be defined in order to adapt treatment protocols. Since dysregulation of the sonic hedgehog pathway plays an important role in carcinogenesis, we aimed to assess whether members of the sonic hedgehog-signaling pathway may act as prognostic factors in patients with HPV negative head and neck squamous cell carcinoma. MATERIALS AND METHODS In this prospective study, pretreatment tumor biopsies of patients with head and neck squamous cell carcinoma were taken during panendoscopy (2005 to 2008). All patients were treated with surgery and postoperative radiotherapy. After assessment of HPV and p16 status, protein expression profiles of the Sonic hedgehog-signaling pathway were determined by immunohistochemistry and tissue microarray analyses in 36 HPV negative tumor biopsies. Expression profiles of Sonic hedgehog, Indian hedgehog, Patched, Smoothened, Gli-1, Gli-2 and Gli-3 were correlated with patients´ clinical data, local-control rate, disease-free as well as overall survival. Data from The Cancer Genome Atlas databank were used for external validation of our results. RESULTS Gli-1 (p = 0.04) and Gli-2 (p = 0.02) overexpression was significantly linked to improved overall survival of HPV negative patients. Gli-2 (p = 0.04) overexpression correlated significantly with prolonged disease-free survival. Cox-multivariate analysis showed that overexpression of Gli-2 correlated independently (HR 0.40, 95% CI 0.16-0.95, p = 0.03) with increased overall survival. DISCUSSION Gli-1 and Gli-2 overexpression represents a substantial prognostic factor for overall and disease-free survival in patients with locally advanced HPV negative head and neck cancer undergoing surgery and postoperative radiotherapy.
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Affiliation(s)
- Elisabeth Enzenhofer
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Thomas Parzefall
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Georg Haymerle
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Sven Schneider
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Lorenz Kadletz
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Gregor Heiduschka
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Johannes Pammer
- Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Fritz Wrba
- Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | - Benjamin Loader
- Department of Otorhinolaryngology, Head and Neck Surgery, Rudolfstiftung, Vienna, Austria
| | - Matthäus Christoph Grasl
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Christos Perisanidis
- Department of Oral and Maxillofacial Surgery, Medical University of Vienna, Vienna, Austria
| | - Boban M. Erovic
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
- * E-mail:
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Lucas C, Ferreira C, Cazzanelli G, Franco-Duarte R, Tulha J, Roelink H, Conway SJ. Yeast Gup1(2) Proteins Are Homologues of the Hedgehog Morphogens Acyltransferases HHAT(L): Facts and Implications. J Dev Biol 2016; 4:E33. [PMID: 29615596 PMCID: PMC5831804 DOI: 10.3390/jdb4040033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 10/25/2016] [Accepted: 10/27/2016] [Indexed: 12/16/2022] Open
Abstract
In multiple tissues, the Hedgehog secreted morphogen activates in the receiving cells a pathway involved in cell fate, proliferation and differentiation in the receiving cells. This pathway is particularly important during embryogenesis. The protein HHAT (Hedgehog O-acyltransferase) modifies Hh morphogens prior to their secretion, while HHATL (Hh O-acyltransferase-like) negatively regulates the pathway. HHAT and HHATL are homologous to Saccharomyces cerevisiae Gup2 and Gup1, respectively. In yeast, Gup1 is associated with a high number and diversity of biological functions, namely polarity establishment, secretory/endocytic pathway functionality, vacuole morphology and wall and membrane composition, structure and maintenance. Phenotypes underlying death, morphogenesis and differentiation are also included. Paracrine signalling, like the one promoted by the Hh pathway, has not been shown to occur in microbial communities, despite the fact that large aggregates of cells like biofilms or colonies behave as proto-tissues. Instead, these have been suggested to sense the population density through the secretion of quorum-sensing chemicals. This review focuses on Gup1/HHATL and Gup2/HHAT proteins. We review the functions and physiology associated with these proteins in yeasts and higher eukaryotes. We suggest standardisation of the presently chaotic Gup-related nomenclature, which includes KIAA117, c3orf3, RASP, Skinny, Sightless and Central Missing, in order to avoid the disclosure of otherwise unnoticed information.
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Affiliation(s)
- Cândida Lucas
- CBMA—Centre of Molecular and Environmental Biology, University of Minho, Campus de Gualtar, 4710-054 Braga, Portugal; (G.C.); (R.F.-D.); (J.T.)
| | - Célia Ferreira
- CBMA—Centre of Molecular and Environmental Biology, University of Minho, Campus de Gualtar, 4710-054 Braga, Portugal; (G.C.); (R.F.-D.); (J.T.)
- School of Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK;
| | - Giulia Cazzanelli
- CBMA—Centre of Molecular and Environmental Biology, University of Minho, Campus de Gualtar, 4710-054 Braga, Portugal; (G.C.); (R.F.-D.); (J.T.)
| | - Ricardo Franco-Duarte
- CBMA—Centre of Molecular and Environmental Biology, University of Minho, Campus de Gualtar, 4710-054 Braga, Portugal; (G.C.); (R.F.-D.); (J.T.)
| | - Joana Tulha
- CBMA—Centre of Molecular and Environmental Biology, University of Minho, Campus de Gualtar, 4710-054 Braga, Portugal; (G.C.); (R.F.-D.); (J.T.)
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Avan A, Narayan R, Giovannetti E, Peters GJ. Role of Akt signaling in resistance to DNA-targeted therapy. World J Clin Oncol 2016; 7:352-369. [PMID: 27777878 PMCID: PMC5056327 DOI: 10.5306/wjco.v7.i5.352] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/25/2016] [Accepted: 07/29/2016] [Indexed: 02/06/2023] Open
Abstract
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
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Wang LC, Almazan G. Role of Sonic Hedgehog Signaling in Oligodendrocyte Differentiation. Neurochem Res 2016; 41:3289-3299. [PMID: 27639396 DOI: 10.1007/s11064-016-2061-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/26/2016] [Accepted: 09/08/2016] [Indexed: 11/28/2022]
Abstract
During development, the secreted molecule Sonic Hedgehog (Shh) is required for lineage specification and proliferation of oligodendrocyte progenitors (OLPs), which are the glia cells responsible for the myelination of axons in the central nervous system (CNS). Shh signaling has been implicated in controlling both the generation of oligodendrocytes (OLGs) during embryonic development and their production in adulthood. Although, some evidence points to a role of Shh signaling in OLG development, its involvement in OLG differentiation remains to be fully determined. The objective of this study was to assess whether Shh signaling is involved in OLG differentiation after neural stem cell commitment to the OLG lineage. To address these questions, we manipulated Shh signaling using cyclopamine, a potent inhibitor of Shh signaling activator Smoothened (Smo), alone or combined with the agonist SAG in OLG primary cultures and assessed expression of myelin-specific markers. We found that inactivation of Shh signaling caused a dose-dependent decrease in myelin basic protein (MBP) and myelin associated glycoprotein (MAG) in differentiating OLGs. Co-treatment of the cells with SAG reversed the inhibitory effect of cyclopamine on both myelin-specific protein levels and morphological changes associated with it. Further experiments are required to elucidate the molecular mechanism by which Shh signaling regulates OLG differentiation.
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Affiliation(s)
- Li-Chun Wang
- Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
| | - Guillermina Almazan
- Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.
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Habib JG, O'Shaughnessy JA. The hedgehog pathway in triple-negative breast cancer. Cancer Med 2016; 5:2989-3006. [PMID: 27539549 PMCID: PMC5083752 DOI: 10.1002/cam4.833] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 05/26/2016] [Accepted: 06/30/2016] [Indexed: 12/11/2022] Open
Abstract
Treatment of triple‐negative breast cancer (TNBC) remains challenging due to the underlying heterogeneity of this disease coupled with the lack of predictive biomarkers and effective targeted therapies. Intratumoral heterogeneity, particularly enrichment for breast cancer stem cell‐like subpopulations, has emerged as a leading hypothesis for systemic therapy resistance and clinically aggressive course of poor prognosis TNBC. A growing body of literature supports the role of the stem cell renewal Hedgehog (Hh) pathway in breast cancer. Emerging preclinical data also implicate Hh signaling in TNBC pathogenesis. Herein, we review the evidence for a pathophysiologic role of Hh signaling in TNBC and explore mechanisms of crosstalk between the Hh pathway and other key signaling networks as well as their potential implications for Hh‐targeted interventions in TNBC.
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Affiliation(s)
- Joyce G Habib
- Baylor Charles A. Sammons Cancer Center, Dallas, Texas
| | - Joyce A O'Shaughnessy
- Baylor Charles A. Sammons Cancer Center, Dallas, Texas.
- Texas Oncology, Dallas, Texas.
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Meister MT, Boedicker C, Graab U, Hugle M, Hahn H, Klingebiel T, Fulda S. Arsenic trioxide induces Noxa-dependent apoptosis in rhabdomyosarcoma cells and synergizes with antimicrotubule drugs. Cancer Lett 2016; 381:287-95. [PMID: 27521572 DOI: 10.1016/j.canlet.2016.07.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 07/06/2016] [Accepted: 07/11/2016] [Indexed: 12/23/2022]
Abstract
The prognosis of metastatic or relapsed rhabdomyosarcoma (RMS) is poor, highlighting the need of new treatment options. In the present study, we evaluated the in vitro efficacy of arsenic trioxide (ATO) in RMS, a FDA-approved drug used in pediatric leukemia. Here, we report that ATO exerts antitumor activity against RMS cells both as single agent and in combination with microtubule-targeting drugs. Monotherapy with ATO reduces cell viability, triggers apoptosis and suppresses clonogenic survival of RMS cells, at least in part, by transcriptional induction of the proapoptotic BH3-only protein Noxa. siRNA-mediated knockdown of Noxa significantly rescues ATO-mediated cell death, demonstrating that Noxa is required for cell death. Also, ATO suppresses endogenous Hedgehog (Hh) signaling, as it significantly reduces Gli1 transcriptional activity and expression levels of several Hh target genes. Furthermore, we identify synergistic induction of apoptosis by ATO together with several antimicrotubule agents including vincristine (VCR), vinblastine and eribulin. The addition of the broad-range caspase inhibitor zVAD.fmk or overexpression of the antiapoptotic protein Bcl-2 significantly reduce ATO/VCR-induced cell death, indicating that the ATO/VCR combination triggers caspase-dependent apoptosis via the mitochondrial pathway. In summary, ATO exerts antitumor activity against RMS, especially in combination with antimicrotubule drugs. These findings have important implications for the development of novel therapeutic strategies for RMS.
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Affiliation(s)
- Michael Torsten Meister
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Cathinka Boedicker
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ulrike Graab
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany
| | - Manuela Hugle
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany
| | - Heidi Hahn
- Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany
| | - Thomas Klingebiel
- German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Simone Fulda
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Riquelme I, Saavedra K, Espinoza JA, Weber H, García P, Nervi B, Garrido M, Corvalán AH, Roa JC, Bizama C. Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy. Oncotarget 2016; 6:24750-79. [PMID: 26267324 PMCID: PMC4694793 DOI: 10.18632/oncotarget.4990] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 07/17/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer mortality worldwide. Although surgical resection is a potentially curative approach for localized cases of GC, most cases of GC are diagnosed in an advanced, non-curable stage and the response to traditional chemotherapy is limited. Fortunately, recent advances in our understanding of the molecular mechanisms that mediate GC hold great promise for the development of more effective treatment strategies. In this review, an overview of the morphological classification, current treatment approaches, and molecular alterations that have been characterized for GC are provided. In particular, the most recent molecular classification of GC and alterations identified in relevant signaling pathways, including ErbB, VEGF, PI3K/AKT/mTOR, and HGF/MET signaling pathways, are described, as well as inhibitors of these pathways. An overview of the completed and active clinical trials related to these signaling pathways are also summarized. Finally, insights regarding emerging stem cell pathways are described, and may provide additional novel markers for the development of therapeutic agents against GC. The development of more effective agents and the identification of biomarkers that can be used for the diagnosis, prognosis, and individualized therapy for GC patients, have the potential to improve the efficacy, safety, and cost-effectiveness for GC treatments.
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Affiliation(s)
- Ismael Riquelme
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Kathleen Saavedra
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Jaime A Espinoza
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bruno Nervi
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo Garrido
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro H Corvalán
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
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47
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Psyrri A, Seiwert TY, Jimeno A. Molecular pathways in head and neck cancer: EGFR, PI3K, and more. Am Soc Clin Oncol Educ Book 2016:246-55. [PMID: 23714515 DOI: 10.14694/edbook_am.2013.33.246] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The treatment of head and neck squamous cell carcinoma (HNSCC) is set to undergo rapid changes, as novel treatment targets informed by genomic profiling and novel molecularly targeted therapies continue to make strides. In this review we provide an overview of the latest developments regarding (1) EGFR targeting for HNSCC, (2) PI3K as a novel treatment target, and (3) newly described key genetic events in HNSCC such as NOTCH1 mutations and emerging candidate targets including ALK1 and hedgehog. The first molecular targeting strategy to demonstrate a survival advantage for patients with HNSCC has emerged in the context of EGFR biology. Cetuximab remains the only U.S. Food and Drug Administration (FDA)-approved targeted therapy available for HNSCC, but EGFR as a target has not been individualized in this disease. The PI3K-AKT pathway is downstream of EGFR and is emerging as potentially one of the most important pathways in HNSCC. PIK3CA is the most frequently mutated oncogene for HNSCC (approximately 20%) and may play a role for both HPV-negative and HPV-positive tumors. Multiple therapeutic strategies targeting PI3K are being explored, and multiple agents either alone or in combination are in development. NOTCH1 is a key tumor suppressor gene and its genetic alterations lead to abnormal pathway activation. ALK1 is a novel target involved in angiogenesis, and efficacy in patients with HNSCC was documented in an early inhibitor trial. The hedgehog pathway modulates EGFR dependence and epithelial to mesenchymal transition (EMT), a key invasion and drug-resistance mechanism in HNSCC.
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Affiliation(s)
- Amanda Psyrri
- From the Department of Medicine, Section of Medical Oncology, Attikon University Hospital, Athens, Greece; Department of Medicine, University of Chicago School of Medicine and Biological Sciences, Chicago, IL; Division of Medical Oncology, University of Colorado School of Medicine, Denver, CO
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48
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Gu D, Schlotman KE, Xie J. Deciphering the role of hedgehog signaling in pancreatic cancer. J Biomed Res 2016; 30:353-360. [PMID: 27346466 PMCID: PMC5044707 DOI: 10.7555/jbr.30.20150107] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Revised: 12/11/2015] [Accepted: 12/25/2015] [Indexed: 12/30/2022] Open
Abstract
Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is a leading cause of cancer-related death in the US, with a dismal median survival of 6 months. Thus, there is an urgent unmet need to identify ways to diagnose and to treat this deadly cancer. Although a number of genetic changes have been identified in pancreatic cancer, their mechanisms of action in tumor development, progression and metastasis are not completely understood. Hedgehog signaling, which plays a major role in embryonic development and stem cell regulation, is known to be activated in pancreatic cancer; however, specific inhibitors targeting the smoothened molecule failed to improve the condition of pancreatic cancer patients in clinical trials. Furthermore, results regarding the role of Hh signaling in pancreatic cancer are controversial with some reporting tumor promoting activities whereas others tumor suppressive actions. In this review, we will summarize what we know about hedgehog signaling in pancreatic cancer, and try to explain the contradicting roles of hedgehog signaling as well as the reason(s) behind the failed clinical trials. In addition to the canonical hedgehog signaling, we will also discuss several non-canonical hedgehog signaling mechanisms.
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Affiliation(s)
- Dongsheng Gu
- Wells Center for Pediatric Research, Division of Hematology and Oncology, Department of Pediatrics, Indiana University Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
| | - Kelly E Schlotman
- Wells Center for Pediatric Research, Division of Hematology and Oncology, Department of Pediatrics, Indiana University Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
| | - Jingwu Xie
- Wells Center for Pediatric Research, Division of Hematology and Oncology, Department of Pediatrics, Indiana University Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA;
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49
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Sakakini N, Turchi L, Bergon A, Holota H, Rekima S, Lopez F, Paquis P, Almairac F, Fontaine D, Baeza-Kallee N, Van Obberghen-Schilling E, Junier MP, Chneiweiss H, Figarella-Branger D, Burel-Vandenbos F, Imbert J, Virolle T. A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells. J Biol Chem 2016; 291:10684-99. [PMID: 27002148 DOI: 10.1074/jbc.m116.720698] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Indexed: 01/06/2023] Open
Abstract
Glioblastomas are the most common primary brain tumors, highly vascularized, infiltrating, and resistant to current therapies. This cancer leads to a fatal outcome in less than 18 months. The aggressive behavior of glioblastomas, including resistance to current treatments and tumor recurrence, has been attributed to glioma stemlike/progenitor cells. The transcription factor EGR1 (early growth response 1), a member of a zinc finger transcription factor family, has been described as tumor suppressor in gliomas when ectopically overexpressed. Although EGR1 expression in human glioblastomas has been associated with patient survival, its precise location in tumor territories as well as its contribution to glioblastoma progression remain elusive. In the present study, we show that EGR1-expressing cells are more frequent in high grade gliomas where the nuclear expression of EGR1 is restricted to proliferating/progenitor cells. We show in primary cultures of glioma stemlike cells that EGR1 contributes to stemness marker expression and proliferation by orchestrating a PDGFA-dependent growth-stimulatory loop. In addition, we demonstrate that EGR1 acts as a positive regulator of several important genes, including SHH, GLI1, GLI2, and PDGFA, previously linked to the maintenance and proliferation of glioma stemlike cells.
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Affiliation(s)
- Nathalie Sakakini
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France
| | - Laurent Turchi
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France
| | - Aurélie Bergon
- INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France
| | - Hélène Holota
- INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France
| | - Samah Rekima
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France
| | - Fabrice Lopez
- INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France
| | - Philipe Paquis
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, the Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, Nice 06107, France
| | - Fabien Almairac
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, the Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, Nice 06107, France
| | - Denys Fontaine
- the Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, Nice 06107, France
| | - Nathalie Baeza-Kallee
- Aix Marseille Université, Faculté de Médecine de la Timone, 13284 Marseille, France, CRO2, INSERM UMR 911, 13284 Marseille Cedex, France
| | | | - Marie-Pierre Junier
- CNRS UMR8246 Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, INSERM U1130, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, and University Pierre and Marie Curie UMCR18, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France
| | - Hervé Chneiweiss
- CNRS UMR8246 Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, INSERM U1130, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, and University Pierre and Marie Curie UMCR18, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France
| | - Dominique Figarella-Branger
- Aix Marseille Université, Faculté de Médecine de la Timone, 13284 Marseille, France, CRO2, INSERM UMR 911, 13284 Marseille Cedex, France, the Departement de Pathology, CHU de la Timone, 13385 Marseille Cedex 5, France
| | - Fanny Burel-Vandenbos
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, the Service d'Anatomopathologie, Hôpital Pasteur, CHU de Nice, Nice 06107, France
| | - Jean Imbert
- INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France,
| | - Thierry Virolle
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France,
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50
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Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors. Cancers (Basel) 2016; 8:cancers8020022. [PMID: 26891329 PMCID: PMC4773745 DOI: 10.3390/cancers8020022] [Citation(s) in RCA: 435] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 01/25/2016] [Accepted: 02/05/2016] [Indexed: 12/25/2022] Open
Abstract
The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.
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Affiliation(s)
- Tadas K Rimkus
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
| | - Richard L Carpenter
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
| | - Shadi Qasem
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
| | - Michael Chan
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
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