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1
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Zheng L, Rajamanickam V, Wang M, Zhang H, Fang S, Linnebacher M, Abd El-Aty AM, Zhang X, Zhang Y, Wang J, Chen M, Zhao Z, Ji J. Fangchinoline inhibits metastasis and reduces inflammation-induced epithelial-mesenchymal transition by targeting the FOXM1-ADAM17 axis in hepatocellular carcinoma. Cell Signal 2024; 124:111467. [PMID: 39393566 DOI: 10.1016/j.cellsig.2024.111467] [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: 07/08/2024] [Revised: 09/10/2024] [Accepted: 10/08/2024] [Indexed: 10/13/2024]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Efforts have been focused on developing new anti-HCC agents and understanding their pharmacology. However, few agents have been able to effectively combat tumor growth and invasiveness due to the rapid progression of HCC. In this study, we discovered that fangchinoline (FAN), a bisbenzylisoquinoline alkaloid derived from Stephania tetrandra S. Moore, effectively inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells. FAN treatment also led to the suppression of IL6 and IL1β release, as well as the expression of inflammation-related proteins such as COX-2 and iNOS, and the activation of the NF-κB pathway, thereby reducing inflammation-related EMT. Additionally, FAN directly bound to forkhead box protein M1 (FOXM1), resulting in decreased levels of FOXM1 proteins and disruption of the FOXM1-ADAM17 axis. Our in vivo findings confirmed that FAN effectively hindered the growth and lung metastasis of HCCLM3-xenograft tumors. Importantly, the upregulation of FOXM1 in HCC tissue suggested that targeting FOXM1 inhibition with FAN or its inhibitors could be a promising therapeutic approach for HCC. Overall, this study elucidated the anti-tumor effects and potential pharmacological mechanisms of FAN, and proposed that targeting FOXM1 inhibition may be an effective therapeutic strategy for HCC with potential clinical applications.
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Affiliation(s)
- Liyun Zheng
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Vinothkumar Rajamanickam
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Mengyuan Wang
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China
| | - Huajun Zhang
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Shiji Fang
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Michael Linnebacher
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, Rostock 18059, Germany
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211 Giza, Egypt
| | - Xinbin Zhang
- Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Yeyu Zhang
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Jianbo Wang
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Minjiang Chen
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China.
| | - Zhongwei Zhao
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China.
| | - Jiansong Ji
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China.
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2
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Dilmac S, Hamurcu Z, Ozpolat B. Therapeutic Landscape of FOXM1 in Triple-Negative Breast Cancer and Aggressive Solid Cancers. Cancers (Basel) 2024; 16:3823. [PMID: 39594778 PMCID: PMC11593102 DOI: 10.3390/cancers16223823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/11/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer, lacking common treatment targets such as estrogen (ER), progesterone (PR), and HER2 receptors. This subtype is associated with significant heterogeneity, chemoresistance, early recurrence, metastasis, and poor patient survival. FOXM1 is a cancer-promoting transcription factor that plays a critical role in TNBC and other highly aggressive cancers by driving cell proliferation, invasion, metastasis, and drug resistance. In TNBC, mutations in the TP53 gene-detected in approximately 80% of patients-lead to the overexpression of FOXM1, making it a promising therapeutic target. Beyond TNBC, FOXM1 is implicated in other solid cancers, such as brain (glioblastoma), lung, and pancreatic cancers, and is considered an Achilles' heel of aggressive cancers. Despite its potential as a therapeutic target, there are currently no FDA-approved FOXM1 inhibitors, and none have advanced to clinical trials. This review explores the role of FOXM1 in cancer progression and highlights the current status of efforts to develop effective FOXM1 inhibitors.
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Affiliation(s)
- Sayra Dilmac
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA;
| | - Zuhal Hamurcu
- Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri 38030, Turkey;
| | - Bulent Ozpolat
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA;
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3
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Abusharkh KAN, Comert Onder F, Çınar V, Onder A, Sıkık M, Hamurcu Z, Ozpolat B, Ay M. Novel benzothiazole/benzothiazole thiazolidine-2,4-dione derivatives as potential FOXM1 inhibitors: In silico, synthesis, and in vitro studies. Arch Pharm (Weinheim) 2024:e2400504. [PMID: 39318080 DOI: 10.1002/ardp.202400504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 08/25/2024] [Accepted: 08/29/2024] [Indexed: 09/26/2024]
Abstract
The oncogenic transcription factor FOXM1 overexpressed in breast and other solid cancers, is a key driver of tumor growth and progression through complex interactions, making it an attractive molecular target for the development of targeted therapies. Despite the availability of small-molecule inhibitors, their limited specificity, potency, and efficacy hinder clinical translation. To identify effective FOXM1 inhibitors, we synthesized novel benzothiazole derivatives (KC10-KC13) and benzothiazole hybrids with thiazolidine-2,4-dione (KC21-KC36). These compounds were evaluated for FOXM1 inhibition. Molecular docking and molecular dynamics simulation analysis revealed their binding patterns and affinities for the FOXM1-DNA binding domain. The interactions with key amino acids such as Asn283, His287, and Arg286, crucial for FOXM1 inhibition, have been determined with the synthesized compounds. Additionally, the molecular modeling study indicated that KC12, KC21, and KC30 aligned structurally and interacted similarly to the reference compound FDI-6. In vitro studies with the MDA-MB-231 breast cancer cell line demonstrated that KC12, KC21, and KC30 significantly inhibited FOXM1, showing greater potency than FDI-6, with IC50 values of 6.13, 10.77, and 12.86 µM, respectively, versus 20.79 µM for FDI-6. Our findings suggest that KC12, KC21, and KC30 exhibit strong activity as FOXM1 inhibitors and may be suitable for in vivo animal studies.
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Affiliation(s)
- Khaled A N Abusharkh
- Department of Chemistry, School of Graduate Studies, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
- Department of Chemistry, Natural Products and Drug Research Laboratory, Faculty of Science, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
- Department of Chemistry and Chemical Technology, Faculty of Science and Technology, Al-Quds University, East Jerusalem, Palestine
| | - Ferah Comert Onder
- Department of Medical Biology, Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
| | - Venhar Çınar
- Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye
| | - Alper Onder
- Department of Chemistry, Natural Products and Drug Research Laboratory, Faculty of Science, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
| | - Merve Sıkık
- Department of Medical System Biology, School of Graduate Studies, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
| | - Zuhal Hamurcu
- Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye
| | - Bulent Ozpolat
- Department of Nanomedicine, Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, Texas, USA
| | - Mehmet Ay
- Department of Chemistry, Natural Products and Drug Research Laboratory, Faculty of Science, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
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Kociper B, Škorja Milić N, Ogrizek I, Miš K, Pirkmajer S. Inhibition of the ubiquitin-proteasome system reduces the abundance of pyruvate dehydrogenase kinase 1 in cultured myotubes. J Muscle Res Cell Motil 2024; 45:155-169. [PMID: 39080182 DOI: 10.1007/s10974-024-09679-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 07/05/2024] [Indexed: 08/11/2024]
Abstract
Pyruvate dehydrogenase kinase (PDK), which phosphorylates the pyruvate dehydrogenase complex, regulates glucose metabolism in skeletal muscle. PDK1, an isozyme whose expression is controlled by hypoxia-inducible factor-1α (HIF-1α), is thought to play a role in muscle adaptation to hypoxia. While transcriptional upregulation of PDK1 by HIF-1α is well characterised, mechanisms controlling proteolysis of PDK1 in skeletal muscle have not been thoroughly investigated. Proteasome inhibitor MG132 paradoxically reduced the abundance of PDK1 in human cancer cells and rat L6 myotubes, suggesting that MG132 might direct PDK1 towards autophagic degradation. The objectives of our current study were to determine (1) whether MG132 suppresses PDK1 levels in primary human myotubes, (2) whether chloroquine, an inhibitor of autophagy, prevents MG132-induced suppression of PDK1 in L6 myotubes, and (3) whether PYR-41, an inhibitor of ubiquitination, suppresses PDK1 in L6 myotubes. Using qPCR and/or immunoblotting, we found that despite markedly upregulating HIF-1α protein, MG132 did not alter the PDK1 expression in cultured primary human myotubes, while it suppressed both PDK1 mRNA and protein in L6 myotubes. The PDK1 levels in L6 myotubes were suppressed also during co-treatment with chloroquine and MG132. PYR-41 markedly increased the abundance of HIF-1α in primary human and L6 myotubes, while reducing the abundance of PDK1. In L6 myotubes treated with PYR-41, chloroquine increased the abundance of the epidermal growth factor receptor, but did not prevent the suppression of PDK1. Collectively, our results suggest that cultured myotubes degrade PDK1 via a pathway that cannot be inhibited by MG132, PYR-41, and/or chloroquine.
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Affiliation(s)
- Blaž Kociper
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, Ljubljana, 1000, Slovenia
| | - Nives Škorja Milić
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, Ljubljana, 1000, Slovenia
| | - Ivana Ogrizek
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, Ljubljana, 1000, Slovenia
| | - Katarina Miš
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, Ljubljana, 1000, Slovenia
| | - Sergej Pirkmajer
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, Ljubljana, 1000, Slovenia.
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5
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Almilaibary A. Phyto-therapeutics as anti-cancer agents in breast cancer: Pathway targeting and mechanistic elucidation. Saudi J Biol Sci 2024; 31:103935. [PMID: 38327657 PMCID: PMC10847379 DOI: 10.1016/j.sjbs.2024.103935] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/08/2024] [Accepted: 01/19/2024] [Indexed: 02/09/2024] Open
Abstract
Cancer of the breast is the mainly prevalent class of cancer in females diagnosed over the globe. It also happens to be the 2nd most prevalent reason of cancer-related deaths among females worldwide. Some of the most common type's therapies for carcinoma of the breast involve radiation therapy, chemotherapy, and resection. Many studies are being conducted to develop new therapeutic strategies for better diagnosis of breast cancer. An enormous number of anticancer medications have been developed as a result of growing understanding of the molecular pathways behind the advancement of cancer. Over the past few decades, the general survival rate has not greatly increased due to the usage of chemically manufactured medications. Therefore, in order to increase the effectiveness of current cancer treatments, new tactics and cutting-edge chemoprevention drugs are required. Phytochemicals, which are naturally occurring molecules derived from plants, are important sources for both cancer therapy and innovative medication development. These phytochemicals frequently work by controlling molecular pathways linked to the development and spread of cancer. Increasing antioxidant status, inactivating carcinogens, preventing proliferation, causing cell cycle arrest and apoptosis, and immune system control are some of the specific ways. This primary objective of this review is to provide an overview of the active ingredients found in natural goods, including information on their pharmacologic action, molecular targets, and current state of knowledge. We have given a thorough description of a number of natural substances that specifically target the pathways linked to breast carcinoma in this study. We've conducted a great deal of study on a few natural compounds that may help us identify novel targets for the detection of breast carcinoma.
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Affiliation(s)
- Abdullah Almilaibary
- Department of Family and Community Medicine, Faculty of Medicine, Albaha University, Albaha, Saudi Arabia
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6
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Merjaneh N, Hajjar M, Lan YW, Kalinichenko VV, Kalin TV. The Promise of Combination Therapies with FOXM1 Inhibitors for Cancer Treatment. Cancers (Basel) 2024; 16:756. [PMID: 38398147 PMCID: PMC10886945 DOI: 10.3390/cancers16040756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 01/21/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Forkhead box M1 (FOXM1) is a transcription factor in the forkhead (FOX) family, which is required for cellular proliferation in normal and neoplastic cells. FOXM1 is highly expressed in many different cancers, and its expression is associated with a higher tumor stage and worse patient-related outcomes. Abnormally high expression of FOXM1 in cancers compared to normal tissue makes FOXM1 an attractive target for pharmacological inhibition. FOXM1-inhibiting agents and specific FOXM1-targeted small-molecule inhibitors have been developed in the lab and some of them have shown promising efficacy and safety profiles in mouse models. While the future goal is to translate FOXM1 inhibitors to clinical trials, potential synergistic drug combinations can maximize anti-tumor efficacy while minimizing off-target side effects. Hence, we discuss the rationale and efficacy of all previously studied drug combinations with FOXM1 inhibitors for cancer therapies.
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Affiliation(s)
- Nawal Merjaneh
- Center for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
- Department of Child Health, Division of Hematology and Oncology, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA
| | - Mona Hajjar
- The Columbian College of Arts and Sciences, George Washington University, Washington, DC 20052, USA;
| | - Ying-Wei Lan
- Phoenix Children’s Research Institute, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA; (Y.-W.L.)
| | - Vladimir V. Kalinichenko
- Phoenix Children’s Research Institute, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA; (Y.-W.L.)
- Division of Neonatology, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
| | - Tanya V. Kalin
- Center for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
- Department of Child Health, Division of Hematology and Oncology, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA
- Phoenix Children’s Research Institute, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA; (Y.-W.L.)
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7
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Raghuwanshi S, Gartel AL. Small-molecule inhibitors targeting FOXM1: Current challenges and future perspectives in cancer treatments. Biochim Biophys Acta Rev Cancer 2023; 1878:189015. [PMID: 37913940 DOI: 10.1016/j.bbcan.2023.189015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 10/26/2023] [Accepted: 10/27/2023] [Indexed: 11/03/2023]
Abstract
Forkhead box (FOX) protein M1 (FOXM1) is a critical proliferation-associated transcription factor (TF) that is aberrantly overexpressed in the majority of human cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in, cell proliferation, cell migration, invasion, angiogenesis and metastasis. The FOXM1 as a TF directly or indirectly regulates the expression of several target genes whose dysregulation is associated with almost all hallmarks of cancer. Moreover, FOXM1 expression is associated with chemoresistance to different anti-cancer drugs. Several studies have confirmed that suppression of FOXM1 enhanced the drug sensitivity of various types of cancer cells. Current data suggest that small molecule inhibitors targeting FOXM1 in combination with anticancer drugs may represent a novel therapeutic strategy for chemo-resistant cancers. In this review, we discuss the clinical utility of FOXM1, further, we summarize and discuss small-molecule inhibitors targeting FOXM1 and categorize them according to their mechanisms of targeting FOXM1. Despite great progress, small-molecule inhibitors targeting FOXM1 face many challenges, and we present here all small-molecule FOXM1 inhibitors in different stages of development. We discuss the current challenges and provide insights on the future application of FOXM1 inhibition to the clinic.
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Affiliation(s)
- Sanjeev Raghuwanshi
- University of Illinois at Chicago, Department of Medicine, Chicago, IL 60612, USA
| | - Andrei L Gartel
- University of Illinois at Chicago, Department of Medicine, Chicago, IL 60612, USA.
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8
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Tabnak P, Hasanzade Bashkandi A, Ebrahimnezhad M, Soleimani M. Forkhead box transcription factors (FOXOs and FOXM1) in glioma: from molecular mechanisms to therapeutics. Cancer Cell Int 2023; 23:238. [PMID: 37821870 PMCID: PMC10568859 DOI: 10.1186/s12935-023-03090-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/04/2023] [Indexed: 10/13/2023] Open
Abstract
Glioma is the most aggressive and malignant type of primary brain tumor, comprises the majority of central nervous system deaths, and is categorized into different subgroups according to its histological characteristics, including astrocytomas, oligodendrogliomas, glioblastoma multiforme (GBM), and mixed tumors. The forkhead box (FOX) transcription factors comprise a collection of proteins that play various roles in numerous complex molecular cascades and have been discovered to be differentially expressed in distinct glioma subtypes. FOXM1 and FOXOs have been recognized as crucial transcription factors in tumor cells, including glioma cells. Accumulating data indicates that FOXM1 acts as an oncogene in various types of cancers, and a significant part of studies has investigated its function in glioma. Although recent studies considered FOXO subgroups as tumor suppressors, there are pieces of evidence that they may have an oncogenic role. This review will discuss the subtle functions of FOXOs and FOXM1 in gliomas, dissecting their regulatory network with other proteins, microRNAs and their role in glioma progression, including stem cell differentiation and therapy resistance/sensitivity, alongside highlighting recent pharmacological progress for modulating their expression.
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Affiliation(s)
- Peyman Tabnak
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Mohammad Ebrahimnezhad
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdieh Soleimani
- Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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9
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Akhlaghipour I, Fanoodi A, Zangouei AS, Taghehchian N, Khalili-Tanha G, Moghbeli M. MicroRNAs as the Critical Regulators of Forkhead Box Protein Family in Pancreatic, Thyroid, and Liver Cancers. Biochem Genet 2023; 61:1645-1674. [PMID: 36781813 DOI: 10.1007/s10528-023-10346-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 02/02/2023] [Indexed: 02/15/2023]
Abstract
The metabolism of human body is mainly regulated by the pancreas, liver, and thyroid using the hormones or exocrine secretions that affect the metabolic processes from food digestion to intracellular metabolism. Therefore, metabolic organ disorders have wide clinical symptoms that severely affect the quality of patient's life. The pancreatic, liver, and thyroid cancers as the main malignancies of the metabolic system have always been considered as one of the serious health challenges worldwide. Despite the novel therapeutic modalities, there are still significant high mortality and recurrence rates, especially in liver and pancreatic cancer patients which are mainly related to the late diagnosis. Therefore, it is required to assess the molecular bases of tumor progressions to introduce novel early detection and therapeutic markers in these malignancies. Forkhead box (FOX) protein family is a group of transcription factors that have pivotal roles in regulation of cell proliferation, migration, and apoptosis. They function as oncogene or tumor suppressor during tumor progression. MicroRNAs (miRNAs) are also involved in regulation of cellular processes. Therefore, in the present review, we discussed the role of miRNAs during pancreatic, thyroid, and liver tumor progressions through FOX regulation. It has been shown that miRNAs were mainly involved in tumor progression via FOXM and FOXO targeting. This review paves the way for the introduction of miR/FOX axis as an efficient early detection marker and therapeutic target in pancreatic, thyroid, and liver tumors.
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Affiliation(s)
- Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Fanoodi
- Student Research Committee, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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10
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Khan I, Kaempf A, Raghuwanshi S, Chesnokov M, Zhang X, Wang Z, Domling A, Tyner JW, Camacho C, Gartel AL. Favorable outcomes of NPM1 mut AML patients are due to transcriptional inactivation of FOXM1, presenting a new target to overcome chemoresistance. Blood Cancer J 2023; 13:128. [PMID: 37607920 PMCID: PMC10444844 DOI: 10.1038/s41408-023-00898-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 07/21/2023] [Accepted: 08/01/2023] [Indexed: 08/24/2023] Open
Affiliation(s)
- I Khan
- University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - A Kaempf
- OHSU Knight Cancer Institute, School of Medicine, Portland, OR, USA
| | - S Raghuwanshi
- University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA
| | - M Chesnokov
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - X Zhang
- University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA
| | - Z Wang
- The Czech Advanced Technology and Research Institute (CATRIN) of Palacký University, Olomouc, Czech Republic
- University of Groningen, Groningen, Netherlands
| | - A Domling
- The Czech Advanced Technology and Research Institute (CATRIN) of Palacký University, Olomouc, Czech Republic
| | - J W Tyner
- OHSU Knight Cancer Institute, School of Medicine, Portland, OR, USA
| | - C Camacho
- Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - A L Gartel
- University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA.
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11
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Pan F, Chocarro S, Ramos M, Chen Y, Alonso de la Vega A, Somogyi K, Sotillo R. FOXM1 is critical for the fitness recovery of chromosomally unstable cells. Cell Death Dis 2023; 14:430. [PMID: 37452072 PMCID: PMC10349069 DOI: 10.1038/s41419-023-05946-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 06/19/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
Tumor progression and evolution are frequently associated with chromosomal instability (CIN). Tumor cells often express high levels of the mitotic checkpoint protein MAD2, leading to mitotic arrest and cell death. However, some tumor cells are capable of exiting mitosis and consequently increasing CIN. How cells escape the mitotic arrest induced by MAD2 and proliferate with CIN is not well understood. Here, we explored loss-of-function screens and drug sensitivity tests associated with MAD2 levels in aneuploid cells and identified that aneuploid cells with high MAD2 levels are more sensitive to FOXM1 depletion. Inhibition of FOXM1 promotes MAD2-mediated mitotic arrest and exacerbates CIN. Conversely, elevating FOXM1 expression in MAD2-overexpressing human cell lines reverts prolonged mitosis and rescues mitotic errors, cell death and proliferative disadvantages. Mechanistically, we found that FOXM1 facilitates mitotic exit by inhibiting the spindle assembly checkpoint (SAC) and the expression of Cyclin B. Notably, we observed that FOXM1 is upregulated upon aneuploid induction in cells with dysfunctional SAC and error-prone mitosis, and these cells are sensitive to FOXM1 knockdown, indicating a novel vulnerability of aneuploid cells.
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Affiliation(s)
- Fan Pan
- Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Ruprecht Karl University of Heidelberg, Heidelberg, Germany
| | - Sara Chocarro
- Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Ruprecht Karl University of Heidelberg, Heidelberg, Germany
| | - Maria Ramos
- Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Ruprecht Karl University of Heidelberg, Heidelberg, Germany
| | - Yuanyuan Chen
- Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Alicia Alonso de la Vega
- Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Ruprecht Karl University of Heidelberg, Heidelberg, Germany
| | - Kalman Somogyi
- Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Rocio Sotillo
- Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
- German Center for Lung Research (DZL), Translational Lung Research Center Heidelberg (TRLC), Heidelberg, Germany.
- German Consortium for Translational Cancer Research (DKTK), 69120, Heidelberg, Germany.
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12
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Guryanova SV. Immunomodulation, Bioavailability and Safety of Bacteriocins. Life (Basel) 2023; 13:1521. [PMID: 37511896 PMCID: PMC10381439 DOI: 10.3390/life13071521] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/01/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
The rise of antibiotic-resistant bacteria and the emergence of new pathogens have created a need for new strategies to fight against infectious diseases. One promising approach is the use of antimicrobial peptides produced by a certain species of bacteria, known as bacteriocins, which are active against other strains of the same or related species. Bacteriocins can help in the treatment and prevention of infectious diseases. Moreover, bacteriocins can be obtained in prokaryotic organisms, and contribute s to their widespread use. While the use of bacteriocins is currently limited to the food industry (for example, nisin is used as a preservative, E234), a large number of studies on their microbicidal properties suggest that their use in medicine may increase in the foreseeable future. However, for the successful use of bacteriocins in medicine, it is necessary to understand their effect on the immune system, especially in cases where immunity is weakened due to infectious processes, oncological, allergic, or autoimmune diseases. Studies on the immuno-modulatory activity of bacteriocins in animal models and human cells have revealed their ability to induce both pro-inflammatory and anti-inflammatory factors involved in the implementation of innate immunity. The influence of bacteriocins on acquired immunity is revealed by an increase in the number of T-lymphocytes with a simultaneous decrease in B-lymphocyte levels, which makes them attractive substances for reducing inflammation. The widespread use of bacteriocins in the food industry, their low toxicity, and their broad and narrow specificity are reasons for researchers to pay attention to their immunomodulatory properties and explore their medical applications. Inflammation regulation by bacteriocins can be used in the treatment of various pathologies. The aim of the review was to analyze scientific publications on the immunomodulatory activity, bioavailability, and safety of bacteriocins in order to use the data obtained to organize preclinical and clinical studies.
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Affiliation(s)
- Svetlana V Guryanova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
- Medical Institute, Peoples' Friendship University of Russia (RUDN University) of the Ministry of Science and Higher Education of the Russian Federation, 117198 Moscow, Russia
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13
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Sanati M, Afshari AR, Ahmadi SS, Moallem SA, Sahebkar A. Modulation of the ubiquitin-proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors. Biofactors 2023; 49:782-819. [PMID: 37162294 DOI: 10.1002/biof.1958] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/20/2023] [Indexed: 05/11/2023]
Abstract
Regarding the multimechanistic nature of cancers, current chemo- or radiotherapies often fail to eradicate disease pathology, and frequent relapses or resistance to therapies occur. Brain malignancies, particularly glioblastomas, are difficult-to-treat cancers due to their highly malignant and multidimensional biology. Unfortunately, patients suffering from malignant tumors often experience poor prognoses and short survival periods. Thus far, significant efforts have been conducted to discover novel and more effective modalities. To that end, modulation of the ubiquitin-proteasome system (UPS) has attracted tremendous interest since it affects the homeostasis of proteins critically engaged in various cell functions, for example, cell metabolism, survival, proliferation, and differentiation. With their safe and multimodal actions, phytochemicals are among the promising therapeutic tools capable of turning the operation of various UPS elements. The present review, along with an updated outline of the role of UPS dysregulation in multiple cancers, provided a detailed discussion on the impact of phytochemicals on the UPS function in malignancies, especially brain tumors.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
- Experimental and Animal Study Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir R Afshari
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Seyed Sajad Ahmadi
- Department of Ophthalmology, Khatam-Ol-Anbia Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Adel Moallem
- Department of Pharmacology and Toxicology, College of Pharmacy, Al-Zahraa University for Women, Karbala, Iraq
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Alimardan Z, Abbasi M, Hasanzadeh F, Aghaei M, Khodarahmi G, Kashfi K. Heat shock proteins and cancer: The FoxM1 connection. Biochem Pharmacol 2023; 211:115505. [PMID: 36931349 PMCID: PMC10134075 DOI: 10.1016/j.bcp.2023.115505] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023]
Abstract
Heat shock proteins (Hsp) and FoxM1 have significant roles in carcinogenesis. According to their relative molecular weight, Hsps are divided into Hsp110, Hsp90, Hsp70, Hsp60, Hsp40, and small Hsps. Hsp70 can play essential functions in cancer initiation and is overexpressed in several human cancers. Hsp70, in combination with cochaperones HIP and HOP, refolds partially denatured proteins and acts as a cochaperone for Hsp90. Also, Hsp70, in combination with BAG3, regulates the FoxM1 signaling pathway. FoxM1 protein is a transcription factor of the Forkhead family that is overexpressed in most human cancers and is involved in many cancers' development features, including proliferation, migration, invasion, angiogenesis, metastasis, and resistance to apoptosis. This review discusses the Hsp70, Hsp90, and FoxM1 structure and function, the known Hsp70 cochaperones, and Hsp70, Hsp90, and FoxM1 inhibitors.
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Affiliation(s)
- Zahra Alimardan
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Pharmacology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Maryam Abbasi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Farshid Hasanzadeh
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahmud Aghaei
- Department of Biochemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ghadamali Khodarahmi
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA; Graduate Program in Biology, City University of New York Graduate Center, NY, USA.
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15
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Kojasoy V, Tantillo DJ. Importance of Noncovalent Interactions Involving Sulfur Atoms in Thiopeptide Antibiotics─Glycothiohexide α and Nocathiacin I. J Phys Chem A 2023; 127:2081-2090. [PMID: 36855831 DOI: 10.1021/acs.jpca.2c07600] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Noncovalent interactions involving sulfur atoms play essential roles in protein structure and function by significantly contributing to protein stability, folding, and biological activity. Sulfur is a highly polarizable atom that can participate in many types of noncovalent interactions including hydrogen bonding, sulfur-π interactions, and S-lone pair interactions, but the impact of these sulfur-based interactions on molecular recognition and drug design is still often underappreciated. Here, we examine, using quantum chemical calculations, the roles of sulfur-based noncovalent interactions in complex naturally occurring molecules representative of thiopeptide antibiotics: glycothiohexide α and its close structural analogue nocathiacin I. While donor-acceptor orbital interactions make only very small contributions, electrostatic and dispersion contributions are predicted to be significant in many cases. In pursuit of understanding the magnitudes and nature of these noncovalent interactions, we made potential structural modifications that could significantly expand the chemical space of effective thiopeptide antibiotics.
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Affiliation(s)
- Volga Kojasoy
- Department of Chemistry, University of California─Davis, Davis, California 95616, United States
| | - Dean J Tantillo
- Department of Chemistry, University of California─Davis, Davis, California 95616, United States
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16
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Takeshita H, Yoshida R, Inoue J, Ishikawa K, Shinohara K, Hirayama M, Oyama T, Kubo R, Yamana K, Nagao Y, Gohara S, Sakata J, Nakashima H, Matsuoka Y, Nakamoto M, Hirayama M, Kawahara K, Takahashi N, Hirosue A, Kuwahara Y, Fukumoto M, Toya R, Murakami R, Nakayama H. FOXM1-Mediated Regulation of Reactive Oxygen Species and Radioresistance in Oral Squamous Cell Carcinoma Cells. J Transl Med 2023; 103:100060. [PMID: 36801643 DOI: 10.1016/j.labinv.2022.100060] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 12/30/2022] [Indexed: 01/11/2023] Open
Abstract
Radioresistance is a major obstacle to the successful treatment of oral squamous cell carcinoma (OSCC). To help overcome this issue, we have developed clinically relevant radioresistant (CRR) cell lines generated by irradiating parental cells over time, which are useful for OSCC research. In the present study, we conducted gene expression analysis using CRR cells and their parental lines to investigate the regulation of radioresistance in OSCC cells. Based on gene expression changes over time in CRR cells and parental lines subjected to irradiation, forkhead box M1 (FOXM1) was selected for further analysis in terms of its expression in OSCC cell lines, including CRR cell lines and clinical specimens. We suppressed or upregulated the expression of FOXM1 in OSCC cell lines, including CRR cell lines, and examined radiosensitivity, DNA damage, and cell viability under various conditions. The molecular network regulating radiotolerance was also investigated, especially the redox pathway, and the radiosensitizing effect of FOXM1 inhibitors was examined as a potential therapeutic application. We found that FOXM1 was not expressed in normal human keratinocytes but was expressed in several OSCC cell lines. The expression of FOXM1 was upregulated in CRR cells compared with that detected in the parental cell lines. In a xenograft model and clinical specimens, FOXM1 expression was upregulated in cells that survived irradiation. FOXM1-specific small interfering RNA (siRNA) treatment increased radiosensitivity, whereas FOXM1 overexpression decreased radiosensitivity, and DNA damage was altered significantly under both conditions, as well as the levels of redox-related molecules and reactive oxygen species production. Treatment with the FOXM1 inhibitor thiostrepton had a radiosensitizing effect and overcame radiotolerance in CRR cells. According to these results, the FOXM1-mediated regulation of reactive oxygen species could be a novel therapeutic target for the treatment of radioresistant OSCC; thus, treatment strategies targeting this axis might overcome radioresistance in this disease.
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Affiliation(s)
- Hisashi Takeshita
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Ryoji Yoshida
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
| | - Junki Inoue
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kohei Ishikawa
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; Department of Dentistry, Self-Defense Forces Kumamoto Hospital, Kumamoto, Japan
| | - Kosuke Shinohara
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Mayumi Hirayama
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Toru Oyama
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Ryuta Kubo
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Keisuke Yamana
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuka Nagao
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Shunsuke Gohara
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Junki Sakata
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hikaru Nakashima
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | | | - Masafumi Nakamoto
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Masatoshi Hirayama
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kenta Kawahara
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Nozomu Takahashi
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Akiyuki Hirosue
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshikazu Kuwahara
- Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Manabu Fukumoto
- Pathology Informatics Team, RIKEN Center for Advanced Intelligence Project, Chuo-ku, Tokyo, Japan
| | - Ryo Toya
- Department of Radiation Oncology, Kumamoto University Hospital, Kumamoto, Japan
| | - Ryuji Murakami
- Department of Medical Radiation Sciences, Faculty of Life Sciences, Kumamoto, Japan
| | - Hideki Nakayama
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
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FOXM1 Is a Novel Molecular Target of AFP-Positive Hepatocellular Carcinoma Abrogated by Proteasome Inhibition. Int J Mol Sci 2022; 23:ijms23158305. [PMID: 35955438 PMCID: PMC9368809 DOI: 10.3390/ijms23158305] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 11/30/2022] Open
Abstract
Alpha-fetoprotein (AFP) is an oncofetal protein that is elevated in a subset of hepatocellular carcinoma (HCC) with poor prognosis, but the molecular target activated in AFP-positive HCC remains elusive. Here, we demonstrated that the transcription factor forkhead box M1 (FOXM1) is upregulated in AFP-positive HCC. We found that FOXM1 expression was highly elevated in approximately 40% of HCC cases, and FOXM1-high HCC was associated with high serum AFP levels, a high frequency of microscopic portal vein invasion, and poor prognosis. A transcriptome and pathway analysis revealed the activation of the mitotic cell cycle and the inactivation of mature hepatocyte metabolism function in FOXM1-high HCC. The knockdown of FOXM1 reduced AFP expression and induced G2/M cell cycle arrest. We further identified that the proteasome inhibitor carfilzomib attenuated FOXM1 protein expression and suppressed cell proliferation in AFP-positive HCC cells. Carfilzomib in combination with vascular endothelial growth factor receptor 2 (VEGFR2) blockade significantly prolonged survival by suppressing AFP-positive HCC growth in a subcutaneous tumor xenotransplantation model. These data indicated that FOXM1 plays a pivotal role in the proliferation of AFP-positive liver cancer cells. Carfilzomib can effectively inhibit FOXM1 expression to inhibit tumor growth and could be a novel therapeutic option in patients with AFP-positive HCC who receive anti-VEGFR2 antibodies.
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18
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Prolonged proteasome inhibition antagonizes TGFβ1-dependent signalling by promoting the lysosomal-targeting of TGFβ receptors. Cell Signal 2022; 98:110414. [PMID: 35901932 DOI: 10.1016/j.cellsig.2022.110414] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/05/2022] [Accepted: 07/15/2022] [Indexed: 01/18/2023]
Abstract
Impairing autophagy disrupts transforming growth factor beta 1 (TGFβ1) signalling and epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Since autophagy and proteasome-mediated degradation are interdependent, we investigated how prolonged downregulation of proteasomal catalytic activity affected TGFβ1-dependent signalling and EMT. Proteasome-dependent degradation was inhibited in A549 and H1299 NSCLC cells using MG132 and lactacystin, which are reversible and irreversible proteasome inhibitors, respectively. We observed that inhibiting proteasomal activity for 24 h decreased TGFβ-dependent nuclear accumulation of Smad2/3. Time course studies were then carried out to characterize the time frame of this observation. Short-term (< 8 h) proteasome inhibition resulted in increased receptor regulated Smad (R-Smad) phosphorylation and steady-state TGFβ receptor type II (TGFβRII) levels. However, prolonged (8-24 h) proteasome inhibition decreased TGFβ1-dependent R-Smad phosphorylation and steady-state TGFβRI and TGFβRII levels. Furthermore, proteasome inhibition blunted TGFβ-dependent E- to N-Cadherin shift, stress fiber formation, and increased cellular apoptosis via the TAK-1-TRAF6-p38 MAPK pathway. Interestingly, proteasome inhibition also increased autophagic flux, steady-state microtubule-associated protein light chain 3B-II and active uncoordinated 51-like autophagy activating kinase 1 levels, and co-localization of lysosomes with autophagy cargo proteins and autophagy-related proteins. Finally, we observed that proteasome inhibition increased TGFβRII endocytosis and trafficking to lysosomes and we conclude that prolonged proteasome inhibition disrupts TGFβ signalling outcomes through altered TGFβ receptor trafficking.
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Jeong JH, Ryu JH. Urushiol V Suppresses Cell Proliferation and Enhances Antitumor Activity of 5-FU in Human Colon Cancer Cells by Downregulating FoxM1. Biomol Ther (Seoul) 2022; 30:257-264. [PMID: 35264465 PMCID: PMC9047495 DOI: 10.4062/biomolther.2022.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 11/17/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumor. 5-FU is commonly used for the treatment of CRC. However, the development of drug resistance in tumor chemotherapy can seriously reduce therapeutic efficacy of 5-FU. Recent data show that FoxM1 is associated with 5-FU resistance in CRC. FoxM1 plays a critical role in the carcinogenesis and drug resistance of several malignancies. It has been reported that urushiol V isolated from the cortex of Rhus verniciflua Stokes is cytotoxic to several types of cancer cells. However, the underlying molecular mechanisms for its antitumor activity and its potential to attenuate the chemotherapeutic resistance in CRC cells remain unknown. Here, we found that urushiol V could inhibit the cell proliferation and induced S-phase arrest of SW480 colon cancer cells. It inhibited protein expression level of FoxM1 through activation of AMPK. We also investigated the combined effect of urushiol V and 5-FU. The combination treatment reduced FoxM1 expression and consequently reduced cell growth and colony formation in 5-FU resistant colon cancer cells (SW480/5-FUR). Taken together, these result suggest that urushiol V from Rhus verniciflua Stokes can suppress cell proliferation by inhibiting FoxM1 and enhance the antitumor capacity of 5-FU. Therefore, urushiol V may be a potential bioactive compound for CRC therapy.
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Affiliation(s)
- Ji Hye Jeong
- Research Institute of Pharmaceutical Sciences and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Jae-Ha Ryu
- Research Institute of Pharmaceutical Sciences and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea
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20
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Łuczkowska K, Rogińska D, Kulig P, Bielikowicz A, Baumert B, Machaliński B. Bortezomib-Induced Epigenetic Alterations in Nerve Cells: Focus on the Mechanisms Contributing to the Peripheral Neuropathy Development. Int J Mol Sci 2022; 23:ijms23052431. [PMID: 35269574 PMCID: PMC8910765 DOI: 10.3390/ijms23052431] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/18/2022] [Accepted: 02/21/2022] [Indexed: 02/04/2023] Open
Abstract
Bortezomib-induced peripheral neuropathy (BiPN) occurs in approximately 40% of patients with multiple myeloma. The induction of severe neuropathy entails the dose reduction or complete elimination of bortezomib (BTZ). Interestingly, discontinuation of BTZ mostly results in a reduction or complete resolution of peripheral neuropathy (PN) symptoms. Therefore, it is likely that the BiPN mechanisms are based on temporary/reversible changes such as epigenetic alterations. In this study, we examined the effect of treating nerve cells, differentiated from the Lund human mesencephalic (dLUHMES) cell line, with several low-dose BTZ (0.15 nM) applications. We showed a significant decrease in global histone H3 acetylation as well as histone H3 lysine 9 acetylation. Moreover, analysis of the genetic microarray showed changes mainly in epigenetic processes related to chromatin rearrangement, chromatin silencing, and gene silencing. GSEA analysis revealed three interesting signaling pathways (SIRT1, B-WICH and, b-Catenin) that may play a pivotal role in PN development. We also performed an analysis of the miRNA microarray which showed the interactions of miR-6810-5p with the genes MSN, FOXM1, TSPAN9, and SLC1A5, which are directly involved in neuroprotective processes, neuronal differentiation, and signal transduction. The study confirmed the existence of BTZ-induced complex epigenetic alterations in nerve cells. However, further studies are necessary to assess the reversibility of epigenetic changes and their potential impact on the induction/resolution of PN.
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Affiliation(s)
- Karolina Łuczkowska
- Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland; (D.R.); (P.K.); (A.B.)
- Correspondence: (K.Ł.); (B.M.); Tel.: +48-914-661-546 (B.M.); Fax: +48-914-661-548 (B.M.)
| | - Dorota Rogińska
- Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland; (D.R.); (P.K.); (A.B.)
| | - Piotr Kulig
- Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland; (D.R.); (P.K.); (A.B.)
| | - Anna Bielikowicz
- Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland; (D.R.); (P.K.); (A.B.)
| | - Bartłomiej Baumert
- Department of Bone Marrow Transplantation, Pomeranian Medical University, 71-252 Szczecin, Poland;
| | - Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland; (D.R.); (P.K.); (A.B.)
- Department of Bone Marrow Transplantation, Pomeranian Medical University, 71-252 Szczecin, Poland;
- Correspondence: (K.Ł.); (B.M.); Tel.: +48-914-661-546 (B.M.); Fax: +48-914-661-548 (B.M.)
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21
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SOD2, a Potential Transcriptional Target Underpinning CD44-Promoted Breast Cancer Progression. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030811. [PMID: 35164076 PMCID: PMC8839817 DOI: 10.3390/molecules27030811] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 11/17/2022]
Abstract
CD44, a cell-adhesion molecule has a dual role in tumor growth and progression; it acts as a tumor suppressor as well as a tumor promoter. In our previous work, we developed a tetracycline-off regulated expression of CD44's gene in the breast cancer (BC) cell line MCF-7 (B5 clone). Using cDNA oligo gene expression microarray, we identified SOD2 (superoxide dismutase 2) as a potential CD44-downstream transcriptional target involved in BC metastasis. SOD2 gene belongs to the family of iron/manganese superoxide dismutase family and encodes a mitochondrial protein. SOD2 plays a role in cell proliferation and cell invasion via activation of different signaling pathways regulating angiogenic abilities of breast tumor cells. This review will focus on the findings supporting the underlying mechanisms associated with the oncogenic potential of SOD2 in the onset and progression of cancer, especially in BC and the potential clinical relevance of its various inhibitors.
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22
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Bailly C. The bacterial thiopeptide thiostrepton. An update of its mode of action, pharmacological properties and applications. Eur J Pharmacol 2022; 914:174661. [PMID: 34863996 DOI: 10.1016/j.ejphar.2021.174661] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/29/2021] [Indexed: 12/20/2022]
Abstract
The bacterial thiopeptide thiostrepton (TS) is used as a veterinary medicine to treat bacterial infections. TS is a protein translation inhibitor, essentially active against Gram-positive bacteria and some Gram-negative bacteria. In procaryotes, TS abrogates binding of GTPase elongation factors to the 70S ribosome, by altering the structure of rRNA-L11 protein complexes. TS exerts also antimalarial effects by disrupting protein synthesis in the apicoplast genome of Plasmodium falciparum. Interestingly, the drug targets both the infectious pathogen (bacteria or parasite) and host cell, by inducing endoplasmic reticulum stress-mediated autophagy which contributes to enhance the host cell defense. In addition, TS has been characterized as a potent chemical inhibitor of the oncogenic transcription factor FoxM1, frequently overexpressed in cancers or other diseases. The capacity of TS to crosslink FoxM1, and a few other proteins such as peroxiredoxin 3 (PRX3) and the 19S proteasome, contributes to the anticancer effects of the thiopeptide. The anticancer activities of TS evidenced using diverse tumor cell lines, in vivo models and drug combinations are reviewed here, together with the implicated targets and mechanisms. The difficulty to formulate TS is a drag on the pharmaceutical development of the natural product. However, the design of hemisynthetic analogues and the use of micellar drug delivery systems should facilitate a broader utilization of the compound in human and veterinary medicines. This review shed light on the many pharmacological properties of TS, with the objective to promote its use as a pharmacological tool and medicinal product.
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Affiliation(s)
- Christian Bailly
- OncoWitan, Scientific Consulting Office, Lille, Wasquehal, 59290, France.
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23
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Nandi D, Cheema PS, Singal A, Bharti H, Nag A. Artemisinin Mediates Its Tumor-Suppressive Activity in Hepatocellular Carcinoma Through Targeted Inhibition of FoxM1. Front Oncol 2021; 11:751271. [PMID: 34900697 PMCID: PMC8652299 DOI: 10.3389/fonc.2021.751271] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 11/04/2021] [Indexed: 12/28/2022] Open
Abstract
The aberrant up-regulation of the oncogenic transcription factor Forkhead box M1 (FoxM1) is associated with tumor development, progression and metastasis in a myriad of carcinomas, thus establishing it as an attractive target for anticancer drug development. FoxM1 overexpression in hepatocellular carcinoma is reflective of tumor aggressiveness and recurrence, poor prognosis and low survival in patients. In our study, we have identified the antimalarial natural product, Artemisinin, to efficiently curb FoxM1 expression and activity in hepatic cancer cells, thereby exhibiting potential anticancer efficacy. Here, we demonstrated that Artemisinin considerably mitigates FoxM1 transcriptional activity by disrupting its interaction with the promoter region of its downstream targets, thereby suppressing the expression of numerous oncogenic drivers. Augmented level of FoxM1 is implicated in drug resistance of cancer cells, including hepatic tumor cells. Notably, FoxM1 overexpression rendered HCC cells poorly responsive to Artemisinin-mediated cytotoxicity while FoxM1 depletion in resistant liver cancer cells sensitized them to Artemisinin treatment, manifested in lower proliferative and growth index, drop in invasive potential and repressed expression of EMT markers with a concomitantly increased apoptosis. Moreover, Artemisinin, when used in combination with Thiostrepton, an established FoxM1 inhibitor, markedly reduced anchorage-independent growth and displayed more pronounced death in liver cancer cells. We found this effect to be evident even in the resistant HCC cells, thereby putting forth a novel combination therapy for resistant cancer patients. Altogether, our findings provide insight into the pivotal involvement of FoxM1 in the tumor suppressive activities of Artemisinin and shed light on the potential application of Artemisinin for improved therapeutic response, especially in resistant hepatic malignancies. Considering that Artemisinin compounds are in current clinical use with favorable safety profiles, the results from our study will potentiate its utility in juxtaposition with established FoxM1 inhibitors, promoting maximal therapeutic efficacy with minimal adverse effects in liver cancer patients.
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Affiliation(s)
| | | | - Aakriti Singal
- Department of Biochemistry, University of Delhi, New Delhi, India
| | - Hina Bharti
- Department of Biochemistry, University of Delhi, New Delhi, India
| | - Alo Nag
- Department of Biochemistry, University of Delhi, New Delhi, India
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24
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Luo G, Lin X, Vega-Medina A, Xiao M, Li G, Wei H, Velázquez-Martínez CA, Xiang H. Targeting of the FOXM1 Oncoprotein by E3 Ligase-Assisted Degradation. J Med Chem 2021; 64:17098-17114. [PMID: 34812040 DOI: 10.1021/acs.jmedchem.1c01069] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The transcription factor FOXM1 that regulates multiple proliferation-related genes through selective protein-DNA and protein-protein interactions is now considered an attractive oncotarget. There are several small-molecule inhibitors that indirectly suppress the expression of FOXM1 or block its DNA binding domain (FOXM1-DBD). However, insufficient specificity or/and efficacy are two potential drawbacks. Here, we employed in silico modeling of FOXM1-DBD with inhibitors to enable the design of an effective CRBN-recruiting molecule that induced significant FOXM1 protein degradation and exerted promising in vivo antitumor activity against TNBC xenograft models. This study is the first of its kind showcasing the use of an approach described in the literature as protein-targeting chimeras to degrade the elusive FOXM1, providing an alternative strategy to counter the pathological effects resulting from the increased transcriptional activity of FOXM1 observed in cancer cells.
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Affiliation(s)
- Guoshun Luo
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Xin Lin
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Antonio Vega-Medina
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6W1W7, Canada
| | - Maoxu Xiao
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Guolong Li
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Hanlin Wei
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, P. R. China
| | | | - Hua Xiang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, P. R. China
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25
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Kuttikrishnan S, Prabhu KS, Khan AQ, Alali FQ, Ahmad A, Uddin S. Thiostrepton inhibits growth and induces apoptosis by targeting FoxM1/SKP2/MTH1 axis in B-precursor acute lymphoblastic leukemia cells. Leuk Lymphoma 2021; 62:3170-3180. [PMID: 34369229 DOI: 10.1080/10428194.2021.1957873] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/19/2021] [Accepted: 07/10/2021] [Indexed: 12/15/2022]
Abstract
Forkhead box M1 (FoxM1) is a transcription factor that plays an important role in the etiology of many cancers, however, its role has not been elucidated in B-precursor acute lymphoblastic leukemia (B-pre-ALL). In the current study, we showed that the downregulation of FoxM1 by its inhibitor thiostrepton inhibited cell viability and induced caspase-dependent apoptosis in a panel of B-pre-ALL cell lines. Thiostrepton led downregulation of FoxM1 accompanied by decreased expression of Aurora kinase A, B, matrix metalloproteinases, and oncogene SKP2 as well as MTH1. Downregulation of the FoxM1/SKP2/MTH1 axis led to increase in the Bax/Bcl2 ratio and suppression of antiapoptotic proteins. Thiostrepton-mediated apoptosis was prevented by N-acetyl cysteine, a scavenger of reactive oxygen species. Co-treatment of B-pre-ALL with subtoxic doses of thiostrepton and bortezomib potentiated the proapoptotic action. Altogether, our results suggest that targeting FoxM1expression could be an attractive strategy for the treatment of B-pre-ALL.
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Affiliation(s)
- Shilpa Kuttikrishnan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- College of Pharmacy, Qatar University, Doha, Qatar
| | - Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Feras Q Alali
- College of Pharmacy, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Laboratory of Animal Research Center, Qatar University, Doha, Qatar
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26
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Klinhom-On N, Seubwai W, Sawanyawisuth K, Obchoei S, Mahalapbutr P, Wongkham S. FOXM1 inhibitor, Siomycin A, synergizes and restores 5-FU cytotoxicity in human cholangiocarcinoma cell lines via targeting thymidylate synthase. Life Sci 2021; 286:120072. [PMID: 34688691 DOI: 10.1016/j.lfs.2021.120072] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 10/06/2021] [Accepted: 10/18/2021] [Indexed: 12/26/2022]
Abstract
AIMS 5-Fluorouracil (5-FU), a thymidylate synthase (TS) inhibitor, has been used as the first-line chemotherapeutic drug for cholangiocarcinoma (CCA). The side effects and drug resistance have developed the limits of the clinical application of 5-FU in CCA treatment. Upregulation of Forkhead box M1 (FOXM1) and TS were shown to play a significant role in 5-FU resistance. In this study, the effect of Siomycin A (SioA), a FOXM1 inhibitor, on enhancing 5-FU cytotoxicity and reversing 5-FU resistance in CCA cell lines were demonstrated. MAIN METHODS Human CCA cell lines, KKU-100 and KKU-213A were used. Cell viability was determined using MTT assay. Expression of FOXM1 and TS proteins were determined using Western blotting. FOXM1 mRNA expression was quantitated using real-time PCR. The combination and dose reduction (DRI) were analyzed according to the Chou and Talalay method. KEY FINDING Single drug treatment of 5-FU and SioA effectively inhibited CCA cell growth in dose and time dependent fashions. The two CCA cell lines had different responses to 5-FU but exhibited similar sensitivity to SioA. FOXM1 and TS expression were increased in the 5-FU treated cells but were suppressed in the SioA treated cells. A direct binding of SioA, to TS and 5,10-methylene-tetrahydrofolate as an inactive ternary complex was simulated. The combined treatment of 5-FU with SioA showed a synergistic effect with a high DRI and restored 5-FU sensitivity in the 5-FU resistant cells. SIGNIFICANCE Targeting FOXM1 using SioA in combination with 5-FU might be a strategy to overcome the 5-FU resistance in CCA.
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Affiliation(s)
- Nathakan Klinhom-On
- Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, 40002, Thailand
| | - Wunchana Seubwai
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, 40002, Thailand
| | - Kanlayanee Sawanyawisuth
- Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, 40002, Thailand
| | - Sumalee Obchoei
- Department of Biochemistry, Faculty of Science, Prince of Songkla University, 90110, Thailand
| | - Panupong Mahalapbutr
- Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, 40002, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, 40002, Thailand.
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27
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Chesnokov MS, Halasi M, Borhani S, Arbieva Z, Shah BN, Oerlemans R, Khan I, Camacho CJ, Gartel AL. Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells. Cell Death Dis 2021; 12:704. [PMID: 34262016 PMCID: PMC8280155 DOI: 10.1038/s41419-021-03978-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/08/2021] [Accepted: 06/15/2021] [Indexed: 12/13/2022]
Abstract
FOXM1 transcription factor is an oncogene and a master regulator of chemoresistance in multiple cancers. Pharmacological inhibition of FOXM1 is a promising approach but has proven to be challenging. We performed a network-centric transcriptomic analysis to identify a novel compound STL427944 that selectively suppresses FOXM1 by inducing the relocalization of nuclear FOXM1 protein to the cytoplasm and promoting its subsequent degradation by autophagosomes. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic treatments (platinum-based agents, 5-fluorouracil, and taxanes). RNA-seq analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 toward the FOXM1 pathway. Collectively, the novel autophagy-dependent mode of FOXM1 suppression by STL427944 validates a unique pathway to overcome tumor chemoresistance and improve the efficacy of treatment with conventional cancer drugs.
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Affiliation(s)
| | - Marianna Halasi
- University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA
- Massachusetts General Hospital, Department of Surgery, Boston, MA, USA
| | - Soheila Borhani
- University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA
| | - Zarema Arbieva
- University of Illinois at Chicago, Genome Research Core, Chicago, IL, USA
| | - Binal N Shah
- University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA
| | - Rick Oerlemans
- University of Pittsburgh, College of Medicine, Pittsburgh, PA, USA
| | - Irum Khan
- University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA
| | - Carlos J Camacho
- University of Pittsburgh, College of Medicine, Pittsburgh, PA, USA.
| | - Andrei L Gartel
- University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA.
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28
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Liang SK, Hsu CC, Song HL, Huang YC, Kuo CW, Yao X, Li CC, Yang HC, Hung YL, Chao SY, Wu SC, Tsai FR, Chen JK, Liao WN, Cheng SC, Tsou TC, Wang IC. FOXM1 is required for small cell lung cancer tumorigenesis and associated with poor clinical prognosis. Oncogene 2021; 40:4847-4858. [PMID: 34155349 DOI: 10.1038/s41388-021-01895-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 05/26/2021] [Accepted: 06/04/2021] [Indexed: 12/12/2022]
Abstract
Small cell lung cancer (SCLC) continues to cause poor clinical outcomes due to limited advances in sustained treatments for rapid cancer cell proliferation and progression. The transcriptional factor Forkhead Box M1 (FOXM1) regulates cell proliferation, tumor initiation, and progression in multiple cancer types. However, its biological function and clinical significance in SCLC remain unestablished. Analysis of the Cancer Cell Line Encyclopedia and SCLC datasets in the present study disclosed significant upregulation of FOXM1 mRNA in SCLC cell lines and tissues. Gene set enrichment analysis (GSEA) revealed that FOXM1 is positively correlated with pathways regulating cell proliferation and DNA damage repair, as evident from sensitization of FOXM1-depleted SCLC cells to chemotherapy. Furthermore, Foxm1 knockout inhibited SCLC formation in the Rb1fl/flTrp53fl/flMycLSL/LSL (RPM) mouse model associated with increased levels of neuroendocrine markers, Ascl1 and Cgrp, and decrease in Yap1. Consistently, FOXM1 depletion in NCI-H1688 SCLC cells reduced migration and enhanced apoptosis and sensitivity to cisplatin and etoposide. SCLC with high FOXM1 expression (N = 30, 57.7%) was significantly correlated with advanced clinical stage, extrathoracic metastases, and decrease in overall survival (OS), compared with the low-FOXM1 group (7.90 vs. 12.46 months). Moreover, the high-FOXM1 group showed shorter progression-free survival after standard chemotherapy, compared with the low-FOXM1 group (3.90 vs. 8.69 months). Our collective findings support the utility of FOXM1 as a prognostic biomarker and potential molecular target for SCLC.
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Affiliation(s)
- Sheng-Kai Liang
- Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, 300, Taiwan
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Chia-Chan Hsu
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Hsiang-Lin Song
- Department of Pathology, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Yu-Chi Huang
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, 300, Taiwan
- Brain Research Center, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Chun-Wei Kuo
- Department of Pathology, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Xiang Yao
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Chien-Cheng Li
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Hui-Chen Yang
- Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, 300, Taiwan
| | - Yu-Ling Hung
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, 300, Taiwan
- Brain Research Center, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Sheng-Yang Chao
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Shun-Chi Wu
- Department of Engineering and System Science, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Feng-Ren Tsai
- Department of Engineering and System Science, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Jen-Kun Chen
- Institute of Biomedical Engineering & Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, 350, Taiwan
| | - Wei-Neng Liao
- Institute of Biomedical Engineering & Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, 350, Taiwan
| | - Shih-Chin Cheng
- School of Life Sciences, Xiamen University, Xiamen, Fujian Province, 361102, China
| | - Tsui-Chun Tsou
- National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, 350, Taiwan
| | - I-Ching Wang
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, 300, Taiwan.
- Brain Research Center, National Tsing Hua University, Hsinchu, 300, Taiwan.
- Department of Life Sciences, National Tsing Hua University, Hsinchu, 300, Taiwan.
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29
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Liu C, Barger CJ, Karpf AR. FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer. Cancers (Basel) 2021; 13:3065. [PMID: 34205406 PMCID: PMC8235333 DOI: 10.3390/cancers13123065] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 02/08/2023] Open
Abstract
Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.
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Affiliation(s)
| | | | - Adam R. Karpf
- Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68918-6805, USA; (C.L.); (C.J.B.)
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30
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Fajardo-Orduña GR, Ledesma-Martínez E, Aguiñiga-Sánchez I, Mora-García MDL, Weiss-Steider B, Santiago-Osorio E. Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review. Int J Mol Sci 2021; 22:ijms22094955. [PMID: 34066940 PMCID: PMC8124548 DOI: 10.3390/ijms22094955] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022] Open
Abstract
Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).
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Affiliation(s)
- Guadalupe Rosario Fajardo-Orduña
- Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, FES Zaragoza, National Autonomous University of Mexico, 09230 Mexico City, Mexico; (G.R.F.-O.); (E.L.-M.); (I.A.-S.); (B.W.-S.)
| | - Edgar Ledesma-Martínez
- Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, FES Zaragoza, National Autonomous University of Mexico, 09230 Mexico City, Mexico; (G.R.F.-O.); (E.L.-M.); (I.A.-S.); (B.W.-S.)
| | - Itzen Aguiñiga-Sánchez
- Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, FES Zaragoza, National Autonomous University of Mexico, 09230 Mexico City, Mexico; (G.R.F.-O.); (E.L.-M.); (I.A.-S.); (B.W.-S.)
- Department of Biomedical Sciences, School of Medicine, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, 09230 Mexico City, Mexico
| | - María de Lourdes Mora-García
- Immunobiology Laboratory, Research Unit on Cell Differentiation and Cancer, FES Zaragoza, National Autonomous University of Mexico, 09230 Mexico City, Mexico;
| | - Benny Weiss-Steider
- Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, FES Zaragoza, National Autonomous University of Mexico, 09230 Mexico City, Mexico; (G.R.F.-O.); (E.L.-M.); (I.A.-S.); (B.W.-S.)
| | - Edelmiro Santiago-Osorio
- Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, FES Zaragoza, National Autonomous University of Mexico, 09230 Mexico City, Mexico; (G.R.F.-O.); (E.L.-M.); (I.A.-S.); (B.W.-S.)
- Correspondence: ; Tel.: +52-55-57-73-41-08
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31
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Curcio C, Brugiapaglia S, Bulfamante S, Follia L, Cappello P, Novelli F. The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer. Molecules 2021; 26:1642. [PMID: 33804240 PMCID: PMC7998946 DOI: 10.3390/molecules26061642] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/02/2021] [Accepted: 03/11/2021] [Indexed: 02/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism-resulting in its increased uptake-and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.
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Affiliation(s)
- Claudia Curcio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Silvia Brugiapaglia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Sara Bulfamante
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Laura Follia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Computer Science Department, University of Turin, 10126 Turin, Italy
| | - Paola Cappello
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
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Kalathil D, John S, Nair AS. FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis. Front Oncol 2021; 10:626836. [PMID: 33680951 PMCID: PMC7927600 DOI: 10.3389/fonc.2020.626836] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/30/2020] [Indexed: 12/13/2022] Open
Abstract
Forkhead box transcription factor, FOXM1 is implicated in several cellular processes such as proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis, apoptosis, and redox signaling. In addition to being a boon for the normal functioning of a cell, FOXM1 turns out to be a bane by manifesting in several disease scenarios including cancer. It has been given an oncogenic status based on several evidences indicating its role in tumor development and progression. FOXM1 is highly expressed in several cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in angiogenesis, invasion, migration, self- renewal and drug resistance. In this review, we attempt to understand various mechanisms underlying FOXM1 gene and protein regulation in cancer including the different signaling pathways, post-transcriptional and post-translational modifications. Identifying crucial molecules associated with these processes can aid in the development of potential pharmacological approaches to curb FOXM1 mediated tumorigenesis.
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Affiliation(s)
- Dhanya Kalathil
- Cancer Research Program-4, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Samu John
- Cancer Research Program-4, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.,Research Centre, University of Kerala, Thiruvananthapuram, India
| | - Asha S Nair
- Cancer Research Program-4, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.,Research Centre, University of Kerala, Thiruvananthapuram, India
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Briest F, Koziolek EJ, Albrecht J, Schmidt F, Bernsen MR, Haeck J, Kühl AA, Sedding D, Hartung T, Exner S, Welzel M, Fischer C, Grötzinger C, Brenner W, Baum RP, Grabowski P. Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? - A preclinical assessment in vitro and in vivo. Neoplasia 2020; 23:80-98. [PMID: 33246310 PMCID: PMC7701025 DOI: 10.1016/j.neo.2020.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib. METHODS AND RESULTS In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone. CONCLUSIONS We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model.
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Affiliation(s)
- Franziska Briest
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Department of Biology, Chemistry, and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität (FU) Berlin, Berlin, Germany.
| | - Eva J Koziolek
- German Cancer Consortium (DKTK), Germany; Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jakob Albrecht
- Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany
| | - Fränze Schmidt
- German Cancer Consortium (DKTK), Germany; Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute for Biochemistry and Biotechnology, Martin-Luther-University (MLU) Halle-Wittenberg, Halle (Saale), Germany
| | | | - Joost Haeck
- Department of Radiology, Erasmus MC, Rotterdam, The Netherlands
| | - Anja A Kühl
- iPATH.Berlin, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Dagmar Sedding
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Institute of Biology, Humboldt-Universität (HU) Berlin, Berlin, Germany
| | - Teresa Hartung
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Samantha Exner
- Department of Hepatology and Gastroenterology and Molecular Cancer Research Center, Tumor Targeting Laboratory, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Martina Welzel
- Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany
| | - Christian Fischer
- Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany
| | - Carsten Grötzinger
- German Cancer Consortium (DKTK), Germany; Department of Hepatology and Gastroenterology and Molecular Cancer Research Center, Tumor Targeting Laboratory, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Winfried Brenner
- German Cancer Consortium (DKTK), Germany; Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany; Berlin Experimental Radionuclide Imaging Center (BERIC), Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Richard P Baum
- Department of Nuclear Medicine, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; CURANOSTICUM Wiesbaden-Frankfurt, DKD Helios Clinic, Wiesbaden, Germany
| | - Patricia Grabowski
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Department of Gastroenterology and Endocrinology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; Department of Medical Immunology, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
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Khan I, Eklund EE, Gartel AL. Therapeutic Vulnerabilities of Transcription Factors in AML. Mol Cancer Ther 2020; 20:229-237. [PMID: 33158995 DOI: 10.1158/1535-7163.mct-20-0115] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 08/13/2020] [Accepted: 10/19/2020] [Indexed: 11/16/2022]
Abstract
Acute myeloid leukemia (AML) is characterized by impaired myeloid lineage differentiation, uncontrolled proliferation, and inhibition of proapoptotic pathways. In spite of a relatively homogeneous clinical disease presentation, risk of long-term survival in AML varies from 20% to 80% depending on molecular disease characteristics. In recognition of the molecular heterogeneity of AML, the European Leukemia Net (ELN) and WHO classification systems now incorporate cytogenetics and increasing numbers of gene mutations into AML prognostication. Several of the genomic AML subsets are characterized by unique transcription factor alterations that are highlighted in this review. There are many mechanisms of transcriptional deregulation in leukemia. We broadly classify transcription factors based on mechanisms of transcriptional deregulation including direct involvement of transcription factors in recurrent translocations, loss-of-function mutations, and intracellular relocalization. Transcription factors, due to their pleiotropic effects, have been attractive but elusive targets. Indirect targeting approaches include inhibition of upstream kinases such as TAK1 for suppression of NFκB signaling and downstream effectors such as FGF signaling in HOXA-upregulated leukemia. Other strategies include targeting scaffolding proteins like BrD4 in the case of MYC or coactivators such as menin to suppress HOX expression; disrupting critical protein interactions in the case of β-catenin:TCF/LEF, and preventing transcription factor binding to DNA as in the case of PU.1 or FOXM1. We comprehensively describe the mechanism of deregulation of transcription factors in genomic subsets of AML, consequent pathway addictions, and potential therapeutic strategies.
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Affiliation(s)
- Irum Khan
- Department of Medicine, University of Illinois, Chicago, Illinois
| | - Elizabeth E Eklund
- Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.,Jesse Brown VA Medical Center, Chicago, Illinois
| | - Andrei L Gartel
- Department of Medicine, University of Illinois, Chicago, Illinois.
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Cai X, Xiao W, Shen J, Lian H, Lu Y, Liu X, Gu J. Thiostrepton and miR-216b synergistically promote osteosarcoma cell cytotoxicity and apoptosis by targeting FoxM1. Oncol Lett 2020; 20:391. [PMID: 33193851 PMCID: PMC7656114 DOI: 10.3892/ol.2020.12254] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 09/07/2020] [Indexed: 01/08/2023] Open
Abstract
Osteosarcoma is a common primary bone cancer that there are currently no effective treatment strategies for. Forkhead box M1 (FoxM1) is key in the development of osteosarcoma, and microRNA (miR)-216b serves an antitumor role by targeting FoxM1. Moreover, thiostrepton (TST), a natural thiazole antibiotic, induces antitumor effects and specifically targets FoxM1. Therefore, the present study investigated whether thiostrepton and miR-216b synergistically inhibited osteosarcoma cells by targeting FoxM1. The MTT assay, reverse transcription-quantitative PCR, a dual-luciferase reporter assay and flow cytometry were performed. Compared with the human osteoblast cell line hFOB1.19, miR-216b expression was significantly downregulated in the osteosarcoma cell lines U2OS, MG63 and Saos-2. By contrast, FoxM1 expression was significantly upregulated in osteosarcoma cell lines compared with the hFOB1.19 cell line. The results indicated that miR-216b targeted the 3′-untranslated region of FoxM1. Moreover, the results suggested that miR-216b cooperated with TST to decrease cell cytotoxicity and increase cell apoptosis. In addition, miR-216b cooperated with TST to increase Bax expression and decrease Bcl-2 expression. In conclusion, the combination of TST and miR-216b synergistically promoted osteosarcoma cell cytotoxicity and apoptosis by targeting FoxM1. Therefore, the present study suggested that the combination of TST and miR-216b may serve as a promising therapeutic strategy for osteosarcoma.
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Affiliation(s)
- Xiaobing Cai
- Department of Orthopedics, Chongming Branch of Tongji Univercity Affiliated the Tenth People's Hospital, Shanghai 202157, P.R. China
| | - Wenyu Xiao
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Juexin Shen
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Hui Lian
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Yi Lu
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Xianmiao Liu
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
| | - Jisheng Gu
- Department of Orthopedics, Jiangwan Hospital, Shanghai 200434, P.R. China
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Kang K, Choi Y, Kim HH, Yoo KH, Yu S. Predicting FOXM1-Mediated Gene Regulation through the Analysis of Genome-Wide FOXM1 Binding Sites in MCF-7, K562, SK-N-SH, GM12878 and ECC-1 Cell Lines. Int J Mol Sci 2020; 21:ijms21176141. [PMID: 32858881 PMCID: PMC7503762 DOI: 10.3390/ijms21176141] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/16/2020] [Accepted: 08/24/2020] [Indexed: 12/25/2022] Open
Abstract
Forkhead box protein M1 (FOXM1) is a key transcription factor (TF) that regulates a common set of genes related to the cell cycle in various cell types. However, the mechanism by which FOXM1 controls the common gene set in different cellular contexts is unclear. In this study, a comprehensive meta-analysis of genome-wide FOXM1 binding sites in ECC-1, GM12878, K562, MCF-7, and SK-N-SH cell lines was conducted to predict FOXM1-driven gene regulation. Consistent with previous studies, different TF binding motifs were identified at FOXM1 binding sites, while the NFY binding motif was found at 81% of common FOXM1 binding sites in promoters of cell cycle-related genes. The results indicated that FOXM1 might control the gene set through interaction with the NFY proteins, while cell type-specific genes were predicted to be regulated by enhancers with FOXM1 and cell type-specific TFs. We also found that the high expression level of FOXM1 was significantly associated with poor prognosis in nine types of cancer. Overall, these results suggest that FOXM1 is predicted to function as a master regulator of the cell cycle through the interaction of NFY-family proteins, and therefore the inhibition of FOXM1 could be an attractive strategy for cancer therapy.
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Affiliation(s)
- Keunsoo Kang
- Department of Microbiology, College of Science & Technology, Dankook University, Cheonan 31116, Korea;
- Correspondence: (K.K.); (S.Y.); Tel.: +82-41-550-3456 (K.K.); +82-43-649-1418 (S.Y.)
| | | | - Hoo Hyun Kim
- Department of Microbiology, College of Science & Technology, Dankook University, Cheonan 31116, Korea;
| | - Kyung Hyun Yoo
- Laboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea;
- Research Institute of Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
| | - Sungryul Yu
- Department of Clinical Laboratory Science, Semyung University, Jecheon 27136, Korea
- Correspondence: (K.K.); (S.Y.); Tel.: +82-41-550-3456 (K.K.); +82-43-649-1418 (S.Y.)
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Bird KE, Xander C, Murcia S, Schmalstig AA, Wang X, Emanuele MJ, Braunstein M, Bowers AA. Thiopeptides Induce Proteasome-Independent Activation of Cellular Mitophagy. ACS Chem Biol 2020; 15:2164-2174. [PMID: 32589399 PMCID: PMC7442609 DOI: 10.1021/acschembio.0c00364] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Thiopeptide antibiotics are emerging clinical candidates that exhibit potent antibacterial activity against a variety of intracellular pathogens, including Mycobacterium tuberculosis (Mtb). Many thiopeptides directly inhibit bacterial growth by disrupting protein synthesis. However, recent work has shown that one thiopeptide, thiostrepton (TSR), can also induce autophagy in infected macrophages, which has the potential to be exploited for host-directed therapies against intracellular pathogens, such as Mtb. To better define the therapeutic potential of this class of antibiotics, we studied the host-directed effects of a suite of natural thiopeptides that spans five structurally diverse thiopeptide classes, as well as several analogs. We discovered that thiopeptides as a class induce selective autophagic removal of mitochondria, known as mitophagy. This activity is independent of other biological activities, such as proteasome inhibition or antibiotic activity. We also find that many thiopeptides exhibit potent activity against intracellular Mtb in macrophage infection models. However, the thiopeptide-induced mitophagy occurs outside of pathogen-containing autophagosomes and does not appear to contribute to thiopeptide control of intracellular Mtb. These results expand basic understanding of thiopeptide biology and provide key guidance for the development of new thiopeptide antibiotics and host-directed therapeutics.
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Affiliation(s)
- Kelly E. Bird
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Christian Xander
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Sebastian Murcia
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Alan A. Schmalstig
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Xianxi Wang
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Michael J. Emanuele
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Miriam Braunstein
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Albert A. Bowers
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA
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Vinogradov AA, Suga H. Introduction to Thiopeptides: Biological Activity, Biosynthesis, and Strategies for Functional Reprogramming. Cell Chem Biol 2020; 27:1032-1051. [PMID: 32698017 DOI: 10.1016/j.chembiol.2020.07.003] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/21/2020] [Accepted: 07/01/2020] [Indexed: 12/16/2022]
Abstract
Thiopeptides (also known as thiazolyl peptides) are structurally complex natural products with rich biological activities. Known for over 70 years for potent killing of Gram-positive bacteria, thiopeptides are experiencing a resurgence of interest in the last decade, primarily brought about by the genomic revolution of the 21st century. Every area of thiopeptide research-from elucidating their biological function and biosynthesis to expanding their structural diversity through genome mining-has made great strides in recent years. These advances lay the foundation for and inspire novel strategies for thiopeptide engineering. Accordingly, a number of diverse approaches are being actively pursued in the hope of developing the next generation of natural-product-inspired therapeutics. Here, we review the contemporary understanding of thiopeptide biological activities, biosynthetic pathways, and approaches to structural and functional reprogramming, with a special focus on the latter.
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Affiliation(s)
- Alexander A Vinogradov
- Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
| | - Hiroaki Suga
- Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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Thiostrepton Reactivates Latent HIV-1 through the p-TEFb and NF-κB Pathways Mediated by Heat Shock Response. Antimicrob Agents Chemother 2020; 64:AAC.02328-19. [PMID: 32094131 DOI: 10.1128/aac.02328-19] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 02/17/2020] [Indexed: 01/18/2023] Open
Abstract
Antiretroviral therapy (ART) suppresses HIV-1 replication but fails to cure the infection. The presence of an extremely stable viral latent reservoir, primarily in resting memory CD4+ T cells, remains a major obstacle to viral eradication. The "shock and kill" strategy targets these latently infected cells and boosts immune recognition and clearance, and thus, it is a promising approach for an HIV-1 functional cure. Although some latency-reversing agents (LRAs) have been reported, no apparent clinical progress has been made, so it is still vital to seek novel and effective LRAs. Here, we report that thiostrepton (TSR), a proteasome inhibitor, reactivates latent HIV-1 effectively in cellular models and in primary CD4+ T cells from ART-suppressed individuals ex vivo TSR does not induce global T cell activation, severe cytotoxicity, or CD8+ T cell dysfunction, making it a prospective LRA candidate. We also observed a significant synergistic effect of reactivation when TSR was combined with JQ1, prostratin, or bryostatin-1. Interestingly, six TSR analogues also show reactivation abilities that are similar to or more effective than that of TSR. We further verified that TSR upregulated expression of heat shock proteins (HSPs) in CD4+ T cells, which subsequently activated positive transcriptional elongation factor b (p-TEFb) and NF-κB signals, leading to viral reactivation. In summary, we identify TSR as a novel LRA which could have important significance for applications to an HIV-1 functional cure in the future.
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Forkhead box M1 transcription factor: a novel target for pulmonary arterial hypertension therapy. World J Pediatr 2020; 16:113-119. [PMID: 31190319 DOI: 10.1007/s12519-019-00271-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 05/23/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Forkhead box M1 (FoxM1), a member of forkhead family, plays a key role in carcinogenesis, progression, invasion, metastasis and drug resistance. Based on the similarities between cancer and pulmonary arterial hypertension, studies on the roles and mechanisms of FoxM1 in pulmonary arterial hypertension have been increasing. This article aims to review recent advances in the mechanisms of signal transduction associated with FoxM1 in pulmonary arterial hypertension. DATA SOURCES Articles were retrieved from PubMed and MEDLINE published after 1990, including-but not limited to-FoxM1 and pulmonary arterial hypertension. RESULTS FoxM1 is overexpressed in pulmonary artery smooth muscle cells in both pulmonary arterial hypertension patients and animal models, and promotes pulmonary artery smooth muscle cell proliferation and inhibits cell apoptosis via regulating cell cycle progression. Multiple signaling molecules and pathways, including hypoxia-inducible factors, transforming growth factor-β/Smad, SET domain-containing 3/vascular endothelial growth factor, survivin, cell cycle regulatory genes and DNA damage response network, are reported to cross talk with FoxM1 in pulmonary arterial hypertension. Proteasome inhibitors are effective in the prevention and treatment of pulmonary arterial hypertension by inhibiting the expression and transcriptional activity of FoxM1. CONCLUSIONS FoxM1 has a crucial role in the pathogenesis of pulmonary arterial hypertension and may represent a novel therapeutic target. But more details of interaction between FoxM1 and other signaling pathways need to be clarified in the future.
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Tang JH, Yang L, Chen JX, Li QR, Zhu LR, Xu QF, Huang GH, Zhang ZX, Xiang Y, Du L, Zhou Z, Lv SQ. Bortezomib inhibits growth and sensitizes glioma to temozolomide (TMZ) via down-regulating the FOXM1-Survivin axis. Cancer Commun (Lond) 2019; 39:81. [PMID: 31796105 PMCID: PMC6892143 DOI: 10.1186/s40880-019-0424-2] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/13/2019] [Indexed: 12/13/2022] Open
Abstract
Background High-grade glioma (HGG) is a fatal human cancer. Bortezomib, a proteasome inhibitor, has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation. This study aimed to explore the chemotherapeutic effect and the underlying mechanism of bortezomib on gliomas. Methods U251 and U87 cell viability and proliferation were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, tumor cell spheroid growth, and colony formation assay. Cell apoptosis and cell cycle were detected by flow cytometry. Temozolomide (TMZ)-insensitive cell lines were induced by long-term TMZ treatment, and cells with stem cell characteristics were enriched with stem cell culture medium. The mRNA levels of interested genes were measured via reverse transcription-quantitative polymerase chain reaction, and protein levels were determined via Western blotting/immunofluorescent staining in cell lines and immunohistochemical staining in paraffin-embedded sections. Via inoculating U87 cells subcutaneously, glioma xenograft models in nude mice were established for drug experiments. Patient survival data were analyzed using the Kaplan–Meier method. Results Bortezomib inhibited the viability and proliferation of U251 and U87 cells in a dose- and time-dependent manner by inducing apoptosis and cell cycle arrest. Bortezomib also significantly inhibited the spheroid growth, colony formation, and stem-like cell proliferation of U251 and U87 cells. When administrated in combination, bortezomib showed synergistic effect with TMZ in vitro and sensitized glioma to TMZ treatment both in vitro and in vivo. Bortezomib reduced both the mRNA and protein levels of Forkhead Box M1 (FOXM1) and its target gene Survivin. The FOXM1–Survivin axis was markedly up-regulated in established TMZ-insensitive glioma cell lines and HGG patients. Expression levels of FOXM1 and Survivin were positively correlated with each other and both related to poor prognosis in glioma patients. Conclusions Bortezomib was found to inhibit glioma growth and improved TMZ chemotherapy efficacy, probably via down-regulating the FOXM1–Survivin axis. Bortezomib might be a promising agent for treating malignant glioma, alone or in combination with TMZ.
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Affiliation(s)
- Jun-Hai Tang
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P. R. China
| | - Lin Yang
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P. R. China
| | - Ju-Xiang Chen
- Department of Neurosurgery, Changzheng Hospital and Shanghai Institute of Neurosurgery, Second Military Medical University, Shanghai, 200003, P. R. China
| | - Qing-Rui Li
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, P. R. China
| | - Li-Rong Zhu
- Department of Ultrasound, Children Hospital, Chongqing Medical University, Chongqing, 400010, P. R. China
| | - Qing-Fu Xu
- Department of Neurosurgery, The Second Xiangya Hospital, Central South University, Changsha, 410008, Hunan, P. R. China
| | - Guo-Hao Huang
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P. R. China
| | - Zuo-Xin Zhang
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P. R. China
| | - Yan Xiang
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P. R. China
| | - Lei Du
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P. R. China
| | - Zheng Zhou
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P. R. China.
| | - Sheng-Qing Lv
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P. R. China.
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Zanin R, Pegoraro S, Ros G, Ciani Y, Piazza S, Bossi F, Bulla R, Zennaro C, Tonon F, Lazarevic D, Stupka E, Sgarra R, Manfioletti G. HMGA1 promotes breast cancer angiogenesis supporting the stability, nuclear localization and transcriptional activity of FOXM1. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:313. [PMID: 31311575 PMCID: PMC6636010 DOI: 10.1186/s13046-019-1307-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023]
Abstract
Background Breast cancer is the most common malignancy in women worldwide. Among the breast cancer subtypes, triple-negative breast cancer (TNBC) is the most aggressive and the most difficult to treat. One of the master regulators in TNBC progression is the architectural transcription factor HMGA1. This study aimed to further explore the HMGA1 molecular network to identify molecular mechanisms involved in TNBC progression. Methods RNA from the MDA-MB-231 cell line, silenced for HMGA1 expression, was sequenced and, with a bioinformatic analysis, molecular partners HMGA1 could cooperate with in regulating common downstream gene networks were identified. Among the putative partners, the FOXM1 transcription factor was selected. The relationship occurring between HMGA1 and FOXM1 was explored by qRT-PCR, co-immunoprecipitation and protein stability assays. Subsequently, the transcriptional activity of HMGA1 and FOXM1 was analysed by luciferase assay on the VEGFA promoter. The impact on angiogenesis was assessed in vitro, evaluating the tube formation ability of endothelial cells exposed to the conditioned medium of MDA-MB-231 cells silenced for HMGA1 and FOXM1 and in vivo injecting MDA-MB-231 cells, silenced for the two factors, in zebrafish larvae. Results Here, we discover FOXM1 as a novel molecular partner of HMGA1 in regulating a gene network implicated in several breast cancer hallmarks. HMGA1 forms a complex with FOXM1 and stabilizes it in the nucleus, increasing its transcriptional activity on common target genes, among them, VEGFA, the main inducer of angiogenesis. Furthermore, we demonstrate that HMGA1 and FOXM1 synergistically drive breast cancer cells to promote tumor angiogenesis both in vitro in endothelial cells and in vivo in a zebrafish xenograft model. Moreover, using a dataset of breast cancer patients we show that the co-expression of HMGA1, FOXM1 and VEGFA is a negative prognostic factor of distant metastasis-free survival and relapse-free survival. Conclusions This study reveals FOXM1 as a crucial interactor of HMGA1 and proves that their cooperative action supports breast cancer aggressiveness, by promoting tumor angiogenesis. Therefore, the possibility to target HMGA1/FOXM1 in combination should represent an attractive therapeutic option to counteract breast cancer angiogenesis. Electronic supplementary material The online version of this article (10.1186/s13046-019-1307-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Rossella Zanin
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
| | - Silvia Pegoraro
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy.
| | - Gloria Ros
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
| | - Yari Ciani
- Laboratorio Nazionale CIB, Area Science Park, Padriciano 99, Trieste, Italy.,Present address: Department of Cellular, Computational and Integrative Biology - (CIBIO), University of Trento, Via Sommarive 9, 38123, Trento, Italy
| | - Silvano Piazza
- Department of Cellular, Computational and Integrative Biology - (CIBIO), University of Trento, Via Sommarive 9, 38123, Povo, Trento, Italy
| | - Fleur Bossi
- Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.) "Burlo Garofolo", via dell'Istria 65/1, 34134, Trieste, Italy
| | - Roberta Bulla
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
| | - Cristina Zennaro
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149, Trieste, Italy
| | - Federica Tonon
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149, Trieste, Italy
| | - Dejan Lazarevic
- Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Elia Stupka
- Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Present address: Life Sciences Business Health Catalyst, Cambridge, Via Sommarive 9, 38123, USA
| | - Riccardo Sgarra
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
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Clinical and biological implications of Hippo pathway dysregulation in sarcomas. FORUM OF CLINICAL ONCOLOGY 2019. [DOI: 10.2478/fco-2018-0002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Sarcomas are mesenchymal malignant tumors with poor prognosis and limited treatment options. Hippo pathway is a recently discovered pathway normally involved in organ development and wound healing. Hippo signaling is often altered in solid tumors. The molecular elements of Hippo signaling include MST1/2 and LATS1/2 kinases which phosphorylate and regulate the activity of YAP and TAZ co-transcriptional activators. Hippo pathway cross-talks with several molecular pathways with known oncogenic function. In sarcomas Hippo signaling plays a pivotal role in tumorigenesis, evolution and resistance in chemotherapy regimens. Targeting Hippo pathway could potentially improve prognosis and outcome of sarcoma patients.
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44
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The Role of Forkhead Box Proteins in Acute Myeloid Leukemia. Cancers (Basel) 2019; 11:cancers11060865. [PMID: 31234353 PMCID: PMC6627614 DOI: 10.3390/cancers11060865] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/29/2019] [Accepted: 06/18/2019] [Indexed: 12/20/2022] Open
Abstract
Forkhead box (FOX) proteins are a group of transcriptional factors implicated in different cellular functions such as differentiation, proliferation and senescence. A growing number of studies have focused on the relationship between FOX proteins and cancers, particularly hematological neoplasms such as acute myeloid leukemia (AML). FOX proteins are widely involved in AML biology, including leukemogenesis, relapse and drug sensitivity. Here we explore the role of FOX transcription factors in the major AML entities, according to "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia", and in the context of the most recurrent gene mutations identified in this heterogeneous disease. Moreover, we report the new evidences about the role of FOX proteins in drug sensitivity, mechanisms of chemoresistance, and possible targeting for personalized therapies.
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Park AK, Lee JY, Cheong H, Ramaswamy V, Park SH, Kool M, Phi JH, Choi SA, Cavalli F, Taylor MD, Kim SK. Subgroup-specific prognostic signaling and metabolic pathways in pediatric medulloblastoma. BMC Cancer 2019; 19:571. [PMID: 31185958 PMCID: PMC6560914 DOI: 10.1186/s12885-019-5742-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 05/22/2019] [Indexed: 02/08/2023] Open
Abstract
Background Using a pathway-focused approach, we aimed to provide a subgroup-specific basis for finding novel therapeutic strategies and further refinement of the risk stratification in pediatric medulloblastoma. Method Based on genome-wide Cox regression and Gene Set Enrichment Analysis, we investigated prognosis-related signaling pathways and core genes in pediatric medulloblastoma subgroups using 530 patient data from Medulloblastoma Advanced Genomic International Consortium (MAGIC) project. We further examined the relationship between expression of the prognostic core genes and frequent chromosome aberrations using broad range copy number change data. Results In SHH subgroup, relatively high expression of the core genes involved in p53, PLK1, FOXM1, and Aurora B signaling pathways are associated with poor prognosis, and their average expression synergistically increases with co-occurrence of losses of 17p, 14q, or 10q, or gain of 17q. In Group 3, in addition to high MYC expression, relatively elevated expression of PDGFRA, IGF1R, and FGF2 and their downstream genes in PI3K/AKT and MAPK/ERK pathways are related to poor survival outcome, and their average expression is increased with the presence of isochromosome 17q [i(17q)] and synergistically down-regulated with simultaneous losses of 16p, 8q, or 4q. In Group 4, up-regulation of the genes encoding various immune receptors and those involved in NOTCH, NF-κB, PI3K/AKT, or RHOA signaling pathways are associated with worse prognosis. Additionally, the expressions of Notch genes correlate with those of the prognostic immune receptors. Besides the Group 4 patients with previously known prognostic aberration, loss of chromosome 11, those with loss of 8q but without i(17q) show excellent survival outcomes and low average expression of the prognostic core genes whereas those harboring 10q loss, 1q gain, or 12q gain accompanied by i(17q) show bad outcomes. Finally, several metabolic pathways known to be reprogrammed in cancer cells are detected as prognostic pathways including glutamate metabolism in SHH subgroup, pentose phosphate pathway and TCA cycle in Group 3, and folate-mediated one carbon-metabolism in Group 4. Conclusions The results underscore several subgroup-specific pathways for potential therapeutic interventions: SHH-GLI-FOXM1 pathway in SHH subgroup, receptor tyrosine kinases and their downstream pathways in Group 3, and immune and inflammatory pathways in Group 4. Electronic supplementary material The online version of this article (10.1186/s12885-019-5742-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ae Kyung Park
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, Korea
| | - Ji Yeoun Lee
- Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea.,Department of Anatomy, Neural Development and Anomaly Lab, Seoul National University College of Medicine, Seoul, Korea.,Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Heesun Cheong
- Division of Cancer Biology, National Cancer Center, Goyang, Korea
| | - Vijay Ramaswamy
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada
| | - Sung-Hye Park
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Marcel Kool
- Division of Paediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ji Hoon Phi
- Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea
| | - Seung Ah Choi
- Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea
| | - Florence Cavalli
- Programme in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada
| | - Michael D Taylor
- Programme in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada. .,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
| | - Seung-Ki Kim
- Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea. .,Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation. Sci Rep 2019; 9:6915. [PMID: 31061434 PMCID: PMC6502821 DOI: 10.1038/s41598-019-43399-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 04/18/2019] [Indexed: 12/12/2022] Open
Abstract
Limb-girdle muscular dystrophy type 2D (LGMD2D) is characterized by a progressive proximal muscle weakness. LGMD2D is caused by mutations in the gene encoding α-sarcoglycan (α-SG), a dystrophin-associated glycoprotein that plays a key role in the maintenance of sarcolemma integrity in striated muscles. We report here on the development of a new in vitro high-throughput screening assay that allows the monitoring of the proper localization of the most prevalent mutant form of α-SG (R77C substitution). Using this assay, we screened a library of 2560 FDA-approved drugs and bioactive compounds and identified thiostrepton, a cyclic antibiotic, as a potential drug to repurpose for LGMD2D treatment. Characterization of the thiostrepton effect revealed a positive impact on R77C-α-SG and other missense mutant protein localization (R34H, I124T, V247M) in fibroblasts overexpressing these proteins. Finally, further investigations of the molecular mechanisms of action of the compound revealed an inhibition of the chymotrypsin-like activity of the proteasome 24 h after thiostrepton treatment and a synergistic effect with bortezomib, an FDA-approved proteasome inhibitor. This study reports on the first in vitro model for LGMD2D that is compatible with high-throughput screening and proposes a new therapeutic option for LGMD2D caused by missense mutations of α-SG.
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Marchand B, Pitarresi JR, Reichert M, Suzuki K, Laczkó D, Rustgi AK. PRRX1 isoforms cooperate with FOXM1 to regulate the DNA damage response in pancreatic cancer cells. Oncogene 2019; 38:4325-4339. [PMID: 30705403 PMCID: PMC6542713 DOI: 10.1038/s41388-019-0725-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 12/10/2018] [Accepted: 12/21/2018] [Indexed: 12/12/2022]
Abstract
PRRX1 is a homeodomain transcriptional factor, which has two isoforms, PRXX1A and PRRX1B. The PRRX1 isoforms have been demonstrated to be important in pancreatic cancer, especially in the regulation of epithelial-to-mesenchymal transition (EMT) in Pancreatic Ductal Adenocarcinoma (PDAC) and of mesenchymal-to-epithelial transition (MET) in liver metastasis. In order to determine the functional underpinnings of PRRX1 and its isoforms, we have unraveled a new interplay between PRRX1 and the FOXM1 transcriptional factors. Our detailed biochemical analysis reveals the direct physical interaction between PRRX1 and FOXM1 proteins that requires the PRRX1A/B 200-222/217 amino acid (aa) region and the FOXM1 Forkhead domain. Additionally, we demonstrate the cooperation between PRRX1 and FOXM1 in the regulation of FOXM1-dependent transcriptional activity. Moreover, we establish FOXM1 as a critical downstream target of PRRX1 in pancreatic cancer cells. We demonstrate a novel role for PRRX1 in the regulation of genes involved in DNA repair pathways. Indeed, we show that expression of PRRX1 isoforms may limit the induction of DNA damage in pancreatic cancer cells. Finally, we demonstrate that targeting FOXM1 with the small molecule inhibitor FDI6 suppress pancreatic cancer cell proliferation and induces their apoptotic cell death. FDI6 sensitizes pancreatic cancer cells to Etoposide and Gemcitabine induced apoptosis. Our data provide new insights into PRRX1's involvement in regulating DNA damage and provide evidence of a possible PRRX1-FOXM1 axis that is critical for PDAC cells.
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Affiliation(s)
- Benoît Marchand
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Jason R Pitarresi
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Maximilian Reichert
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- II. Medizinische Klinik, Technical University of Munich, 81675, Munich, Germany
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kensuke Suzuki
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Dorottya Laczkó
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Anil K Rustgi
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Hsu YB, Lan MC, Kuo YL, Huang CYF, Lan MY. A preclinical evaluation of thiostrepton, a natural antibiotic, in nasopharyngeal carcinoma. Invest New Drugs 2019; 38:264-273. [DOI: 10.1007/s10637-019-00779-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 04/03/2019] [Indexed: 12/18/2022]
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Barger CJ, Branick C, Chee L, Karpf AR. Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer. Cancers (Basel) 2019; 11:cancers11020251. [PMID: 30795624 PMCID: PMC6406812 DOI: 10.3390/cancers11020251] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 02/13/2019] [Accepted: 02/18/2019] [Indexed: 01/22/2023] Open
Abstract
FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations that promote FOXM1 expression in cancer. Additionally, we used human fallopian tube epithelial (FTE) cells to dissect the role of Retinoblastoma (Rb)-E2F and Cyclin E1 in FOXM1 regulation, and a novel human embryonic kidney cell (HEK293T) CRISPR FOXM1 knockout model to define isoform-specific transcriptional programs. FOXM1 expression, at the mRNA and protein level, was significantly elevated in tumors with FOXM1 amplification, p53 inactivation, and Rb-E2F deregulation. FOXM1 expression was remarkably high in testicular germ cell tumors (TGCT), high-grade serous ovarian cancer (HGSC), and basal breast cancer (BBC). FOXM1 expression in cancer was associated with genomic instability, as measured using aneuploidy signatures. FTE models confirmed a role for Rb-E2F signaling in FOXM1 regulation and in particular identified Cyclin E1 as a novel inducer of FOXM1 expression. Among the three FOXM1 isoforms, FOXM1c showed the highest expression in normal and tumor tissues and cancer cell lines. The CRISPR knockout model demonstrated that FOXM1b and FOXM1c are transcriptionally active, while FOXM1a is not. Finally, we were unable to confirm the existence of a FOXM1 auto-regulatory loop. This study provides significant and novel information regarding the frequency, causes, and consequences of elevated FOXM1 expression in human cancer.
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Affiliation(s)
- Carter J Barger
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Connor Branick
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Linda Chee
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Adam R Karpf
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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50
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Bach DH, Long NP, Luu TTT, Anh NH, Kwon SW, Lee SK. The Dominant Role of Forkhead Box Proteins in Cancer. Int J Mol Sci 2018; 19:E3279. [PMID: 30360388 PMCID: PMC6213973 DOI: 10.3390/ijms19103279] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/19/2018] [Accepted: 10/20/2018] [Indexed: 12/16/2022] Open
Abstract
Forkhead box (FOX) proteins are multifaceted transcription factors that are significantly implicated in cancer, with various critical roles in biological processes. Herein, we provide an overview of several key members of the FOXA, FOXC, FOXM1, FOXO and FOXP subfamilies. Important pathophysiological processes of FOX transcription factors at multiple levels in a context-dependent manner are discussed. We also specifically summarize some major aspects of FOX transcription factors in association with cancer research such as drug resistance, tumor growth, genomic alterations or drivers of initiation. Finally, we suggest that targeting FOX proteins may be a potential therapeutic strategy to combat cancer.
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Affiliation(s)
- Duc-Hiep Bach
- College of Pharmacy, Seoul National University, Seoul 08826, Korea.
| | | | | | - Nguyen Hoang Anh
- College of Pharmacy, Seoul National University, Seoul 08826, Korea.
| | - Sung Won Kwon
- College of Pharmacy, Seoul National University, Seoul 08826, Korea.
| | - Sang Kook Lee
- College of Pharmacy, Seoul National University, Seoul 08826, Korea.
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