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Zhang H, Yang X, Xue Y, Huang Y, Mo Y, Huang Y, Zhang H, Zhang X, Zhao W, Jia B, Li N, Gao N, Yang Y, Xiang D, Wang S, Qin Gao Y, Liao J. A basigin antibody modulates MCTs to impact tumor metabolism and immunity. Cell Discov 2025; 11:44. [PMID: 40324980 PMCID: PMC12053622 DOI: 10.1038/s41421-025-00777-1] [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: 09/24/2024] [Accepted: 01/20/2025] [Indexed: 05/07/2025] Open
Abstract
Lactate metabolism and signaling intricately intertwine in the context of cancer and immunity. Basigin, working alongside monocarboxylate transporters MCT1 and MCT4, orchestrates the movement of lactate across cell membranes. Despite their potential in treating formidable tumors, the mechanisms by which basigin antibodies affect basigin and MCTs remain unclear. Our research demonstrated that basigin positively modulates MCT activity. We subsequently developed a basigin antibody that converts basigin into a negative modulator, thereby suppressing lactate transport and enhancing anti-tumor immunity. Additionally, the antibody alters metabolic profiles in NSCLC-PDOs and T cells. Cryo-EM structural analysis and molecular dynamics simulations reveal that the extracellular Ig2 domain and transmembrane domain of basigin regulate MCT1 activity through an allosteric mechanism. The antibody decreases MCT1 transition rate by reducing the flexibility of basigin's Ig2 domain and diminishing interactions between basigin's transmembrane domain and MCT1. These findings underscore the promise of basigin antibodies in combating tumors by modulating metabolism and immunity, and the value of a common therapeutic subunit shared by multiple transporter targets.
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Affiliation(s)
- Heng Zhang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Xuemei Yang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Yue Xue
- Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
| | - Yi Huang
- Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Yingxi Mo
- Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Yurun Huang
- Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Hong Zhang
- Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
| | - Xiaofei Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weixin Zhao
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bin Jia
- Lung Cancer Department, Tianjin Cancer Hospital, Tianjin, China
| | - Ningning Li
- State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China
| | - Ning Gao
- State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China
| | - Yue Yang
- Institute of Toxicology, School of Public Health, Lanzhou University, Lanzhou, Gansu, China
| | - Dongxi Xiang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, and Department of Biliary-Pancreatic Surgery, the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Shan Wang
- Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China.
| | - Yi Qin Gao
- Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
| | - Jun Liao
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
- Alphelix Biosciences, Foshan, Guangdong, China.
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Zhakupova A, Zeinolla A, Kokabi K, Sergazy S, Aljofan M. Drug Resistance: The Role of Sphingolipid Metabolism. Int J Mol Sci 2025; 26:3716. [PMID: 40332322 PMCID: PMC12027666 DOI: 10.3390/ijms26083716] [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: 03/04/2025] [Revised: 04/10/2025] [Accepted: 04/12/2025] [Indexed: 05/08/2025] Open
Abstract
A significant challenge in cancer treatment is the rising problem of drug resistance that reduces the effectiveness of therapeutic strategies. Current knowledge shows that multiple mechanisms play a role in cancer drug resistance. Another mechanism that has gained attention is the alteration in sphingolipid trafficking and the dysregulation of its metabolism, which was reported to cause cancer-associated drug resistance. Sphingolipids are lipids containing sphingosine and have multiple roles, ranging from lipid raft formation, apoptosis, and cell signaling to immune cell trafficking. Recent studies show that in developing cancer cells, altered or dysregulated sphingolipids are associated with drug efflux and promote the survival of cancer cells by bypassing apoptosis. Upregulated levels of the glucosylceramide synthase (GCS), an enzyme that functions in sphingolipid metabolism, lead to the upregulated ABCB1 gene that induces drug efflux from the cancer cells. These bypass mechanisms make drugs that induce apoptosis in tumor cells ineffective. By highlighting the current findings, this review aims to provide a mechanism of drug resistance caused by the dysregulation of glucosylceramide synthase, sphingosine kinase, and acid ceramidase enzymes as possible therapeutic targets to enhance the effectiveness of the currently used chemotherapeutic agents.
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Affiliation(s)
- Assem Zhakupova
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan; (A.Z.); (A.Z.); (K.K.)
| | - Adelina Zeinolla
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan; (A.Z.); (A.Z.); (K.K.)
| | - Kamilya Kokabi
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan; (A.Z.); (A.Z.); (K.K.)
| | - Shynggys Sergazy
- Drug Discovery and Development Laboratory, National Laboratory Astana, Astana 010000, Kazakhstan
- LLP “VICTUS PHARM”, Astana 010000, Kazakhstan
| | - Mohamad Aljofan
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan; (A.Z.); (A.Z.); (K.K.)
- Drug Discovery and Development Laboratory, National Laboratory Astana, Astana 010000, Kazakhstan
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Autsavapromporn N, Duangya A, Klunklin P, Chitapanarux I, Kranrod C, Jaikang C, Monum T, Paemanee A, Tokonami S. Serum biomarkers associated with health impacts of high residential radon exposure: a metabolomic pilot study. Sci Rep 2025; 15:5099. [PMID: 39934345 PMCID: PMC11814192 DOI: 10.1038/s41598-025-89753-z] [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: 12/18/2024] [Accepted: 02/07/2025] [Indexed: 02/13/2025] Open
Abstract
Long-term epidemiological evidence suggests that populations exposed to high natural radiation levels for extended periods may have an increased risk of cancer and other diseases. However, research on health effects in high-radon areas, particularly regarding disease-related biomarkers, remains limited. This study aimed to investigate serum metabolic biomarkers associated with diseases in individuals from areas with high radon exposure. Metabolic profiling was performed using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry on 30 healthy participants comprising 15 individuals from a low-residential radon exposure group and 15 from a high-residential radon exposure group. Multivariate analysis, receiver operating characteristic (ROC) curve analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied. Partial least-squares discriminant analysis revealed significant differences (P < 0.05) between the two groups, identifying 92 metabolites. ROC analysis (AUC ≥ 0.85) highlighted 12 key candidates associated with high radon exposure. KEGG pathway analysis linked D-sphingosine to lung cancer development and 3-methylhistidine to kidney disease, early preeclampsia, and Alzheimer's disease. These findings suggest that D-sphingosine and 3-methylhistidine are promising serum biomarkers for identifying high-risk individuals with prolonged radon exposure and contribute to the identification of novel biomarkers in future studies on high-radon exposure areas.
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Affiliation(s)
- Narongchai Autsavapromporn
- Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
| | - Aphidet Duangya
- Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Pitchayaponne Klunklin
- Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Imjai Chitapanarux
- Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Chutima Kranrod
- Institute of Radiation Emergency Medicine, Hirosaki University, Hirosaki, 036-8564, Aomori, Japan
| | - Churdsak Jaikang
- Toxicology Section, Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Tawachai Monum
- Toxicology Section, Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Atchara Paemanee
- National Omics Center, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Khlong Luang, Pathum Thani, 12120, Thailand
- Food Biotechnology Research Team, Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Khlong Luang, Pathum Thani, 12120, Thailand
| | - Shinji Tokonami
- Institute of Radiation Emergency Medicine, Hirosaki University, Hirosaki, 036-8564, Aomori, Japan
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Rahman MM, Kraft C, Clark C, Nicholson RJ, Marchetti M, Williams E, Zhang C, Holland WL, Summers SA, Edgar BA. Bwa, an ortholog of alkaline ceramidase-ACER2, promotes intestinal stem cell proliferation through pro-inflammatory cytokine signaling in Drosophila melanogaster. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.26.624044. [PMID: 39651270 PMCID: PMC11623631 DOI: 10.1101/2024.11.26.624044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Sphingolipids, including ceramides, are an important component of high-fat diets. These molecules can regulate fatty acid oxidation and intestinal stem cell proliferation, predisposing the gut to tumorigenesis. However, the molecular mechanisms involved in ceramide metabolism-mediated intestinal stem cell (ISC) proliferation and tumorigenesis are poorly understood. To understand how changes in sphingolipid metabolite flux affect intestinal stem cells, we manipulated the activities of each of the enzymes of the ceramide synthetic pathway using cell type-specific over-expression or depletion of the corresponding mRNAs in each intestinal cell type of the Drosophila midgut. We documented cell-autonomous and non-cell-autonomous effects, including alterations in cell size, number, differentiation, and proliferation. In our screen, the altered expression of several ceramide metabolism enzymes led to changes in ISC proliferation, cell sizes, and overall cellularity. Among other genes, over-expression of ceramidase homolog, Brain washing (bwa) in gut enteroblasts (EB) increased EB cell size and caused a non-cell-autonomous, 7-8-fold increase in ISC proliferation. Our analysis confirmed previous reports that bwa does not have ceramidase activity, and lipidomic studies indicated that bwa increases the saturation status of sphingolipids, free fatty acids, and other lipids. The pro-proliferative effects of bwa could be counter-acted by depleting a serine palmitoyltransferase, Lace , or a sphingosine acyltransferase, Schlank , which are needed for ceramide synthesis, or by co-expressing a ceramide desaturase enzyme, ifc , indicating that increased saturated ceramides were causal for ISC proliferation and the disruption of gut homeostasis. Accumulating saturated sphingolipids and fatty acids induced inflammatory signaling in the gut, and activated ISC proliferation through the pro-inflammatory cytokines, Upd3 and Upd2. We propose that saturated sphingolipids promote ISC proliferation through pro-inflammatory pathways.
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Kumar S, Singh A, Pandey P, Khopade A, Sawant KK. Application of sphingolipid-based nanocarriers in drug delivery: an overview. Ther Deliv 2024; 15:619-637. [PMID: 39072358 PMCID: PMC11412150 DOI: 10.1080/20415990.2024.2377066] [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: 12/01/2023] [Accepted: 07/03/2024] [Indexed: 07/30/2024] Open
Abstract
Sphingolipids (SL) are well recognized for their cell signaling through extracellular and intracellular pathways. Based on chemistry different types of SL are biosynthesized in mammalian cells and have specific function in cellular activity. SL has an ampiphilic structure with have hydrophobic body attached to the polar head enables their use as a drug delivery agent in the form of nanocarriers. SL-based liposomes can improve the solubility of lipophilic drugs through host and drug complexes and are more stable than conventional liposomal formulations. Preclinical studies of SL nanocarriers are reported on topical delivery, oral delivery, ocular delivery, chemotherapeutic delivery, cardiovascular delivery and Alzheimer's disease. The commercial challenges and patents related to SL nanoformulations are highlighted in this article.
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Affiliation(s)
- Samarth Kumar
- Formulation Research & Development-Non-Orals, Sun Pharmaceutical Industries Ltd, Vadodara, 390012, Gujarat, India
- Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India
| | - Ajit Singh
- Formulation Research & Development-Non-Orals, Sun Pharmaceutical Industries Ltd, Vadodara, 390012, Gujarat, India
| | - Prachi Pandey
- Krishna School of Pharmacy & Research, KPGU, Vadodara, Gujarat, 391243, India
| | - Ajay Khopade
- Formulation Research & Development-Non-Orals, Sun Pharmaceutical Industries Ltd, Vadodara, 390012, Gujarat, India
| | - Krutika K Sawant
- Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India
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Goswami S, Zhang Q, Celik CE, Reich EM, Yilmaz ÖH. Dietary fat and lipid metabolism in the tumor microenvironment. Biochim Biophys Acta Rev Cancer 2023; 1878:188984. [PMID: 37722512 PMCID: PMC10937091 DOI: 10.1016/j.bbcan.2023.188984] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/26/2023] [Accepted: 08/28/2023] [Indexed: 09/20/2023]
Abstract
Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism often includes the digestion and absorption of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.
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Affiliation(s)
- Swagata Goswami
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
| | - Qiming Zhang
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
| | - Cigdem Elif Celik
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Hacettepe Univ, Canc Inst, Department Basic Oncol, Ankara TR-06100, Turkiye
| | - Ethan M Reich
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Ömer H Yilmaz
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital and Beth Israel Deaconness Medical Center and Harvard Medical School, Boston, MA 02114, USA.
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Hishinuma E, Shimada M, Matsukawa N, Shima Y, Li B, Motoike IN, Shibuya Y, Hagihara T, Shigeta S, Tokunaga H, Saigusa D, Kinoshita K, Koshiba S, Yaegashi N. Identification of predictive biomarkers for endometrial cancer diagnosis and treatment response monitoring using plasma metabolome profiling. Cancer Metab 2023; 11:16. [PMID: 37821929 PMCID: PMC10568780 DOI: 10.1186/s40170-023-00317-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/27/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Endometrial cancer (EMC) is the most common female genital tract malignancy with an increasing prevalence in many countries including Japan, a fact that renders early detection and treatment necessary to protect health and fertility. Although early detection and treatment are necessary to further improve the prognosis of women with endometrial cancer, biomarkers that accurately reflect the pathophysiology of EMC patients are still unclear. Therefore, it is clinically critical to identify biomarkers to assess diagnosis and treatment efficacy to facilitate appropriate treatment and development of new therapies for EMC. METHODS In this study, wide-targeted plasma metabolome analysis was performed to identify biomarkers for EMC diagnosis and the prediction of treatment responses. The absolute quantification of 628 metabolites in plasma samples from 142 patients with EMC was performed using ultra-high-performance liquid chromatography with tandem mass spectrometry. RESULTS The concentrations of 111 metabolites increased significantly, while the concentrations of 148 metabolites decreased significantly in patients with EMC compared to healthy controls. Specifically, LysoPC and TGs, including unsaturated fatty acids, were reduced in patients with stage IA EMC compared to healthy controls, indicating that these metabolic profiles could be used as early diagnostic markers of EMC. In contrast, blood levels of amino acids such as histidine and tryptophan decreased as the risk of recurrence increased and the stages of EMC advanced. Furthermore, a marked increase in total TG and a decrease in specific TGs and free fatty acids including polyunsaturated fatty acids levels were observed in patients with EMC. These results suggest that the polyunsaturated fatty acids in patients with EMC are crucial for disease progression. CONCLUSIONS Our data identified specific metabolite profiles that reflect the pathogenesis of EMC and showed that these metabolites correlate with the risk of recurrence and disease stage. Analysis of changes in plasma metabolite profiles could be applied for the early diagnosis and monitoring of the course of treatment of EMC patients.
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Affiliation(s)
- Eiji Hishinuma
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
| | - Muneaki Shimada
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan.
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
- Department of Gynecology and Obstetrics, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan.
| | - Naomi Matsukawa
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
| | - Yoshiko Shima
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
| | - Bin Li
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
| | - Ikuko N Motoike
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
- Systems Bioinformatics, Graduate School of Information Sciences, Tohoku University, Sendai, 980-8579, Japan
| | - Yusuke Shibuya
- Department of Gynecology and Obstetrics, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan
| | - Tatsuya Hagihara
- Department of Gynecology and Obstetrics, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan
| | - Shogo Shigeta
- Department of Gynecology and Obstetrics, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan
| | - Hideki Tokunaga
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan
- Department of Gynecology and Obstetrics, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan
| | - Daisuke Saigusa
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
- Laboratory of Biomedical and Analytical Sciences, Faculty of Pharma-Science, Teikyo University, Tokyo, 173-8605, Japan
| | - Kengo Kinoshita
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
- Systems Bioinformatics, Graduate School of Information Sciences, Tohoku University, Sendai, 980-8579, Japan
| | - Seizo Koshiba
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
| | - Nobuo Yaegashi
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
- Department of Gynecology and Obstetrics, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan
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Alizadeh J, da Silva Rosa SC, Weng X, Jacobs J, Lorzadeh S, Ravandi A, Vitorino R, Pecic S, Zivkovic A, Stark H, Shojaei S, Ghavami S. Ceramides and ceramide synthases in cancer: Focus on apoptosis and autophagy. Eur J Cell Biol 2023; 102:151337. [PMID: 37392580 DOI: 10.1016/j.ejcb.2023.151337] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 05/18/2023] [Accepted: 06/23/2023] [Indexed: 07/03/2023] Open
Abstract
Different studies corroborate a role for ceramide synthases and their downstream products, ceramides, in modulation of apoptosis and autophagy in the context of cancer. These mechanisms of regulation, however, appear to be context dependent in terms of ceramides' fatty acid chain length, subcellular localization, and the presence or absence of their downstream targets. Our current understanding of the role of ceramide synthases and ceramides in regulation of apoptosis and autophagy could be harnessed to pioneer the development of new treatments to activate or inhibit a single type of ceramide synthase, thereby regulating the apoptosis induction or cross talk of apoptosis and autophagy in cancer cells. Moreover, the apoptotic function of ceramide suggests that ceramide analogues can pave the way for the development of novel cancer treatments. Therefore, in the current review paper we discuss the impact of ceramide synthases and ceramides in regulation of apoptosis and autophagy in context of different types of cancers. We also briefly introduce the latest information on ceramide synthase inhibitors, their application in diseases including cancer therapy, and discuss approaches for drug discovery in the field of ceramide synthase inhibitors. We finally discussed strategies for developing strategies to use lipids and ceramides analysis in biological fluids for developing early biomarkers for cancer.
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Affiliation(s)
- Javad Alizadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Simone C da Silva Rosa
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Xiaohui Weng
- Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA 92834, United States
| | - Joadi Jacobs
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Amir Ravandi
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, 66 Chancellors Cir, Winnipeg, MB R3T 2N2, Canada
| | - Rui Vitorino
- UnIC, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; Department of Medical Sciences, Institute of Biomedicine iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Stevan Pecic
- Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA 92834, United States
| | - Aleksandra Zivkovic
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetstrasse 1, 40225 Duesseldorf, Germany
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetstrasse 1, 40225 Duesseldorf, Germany
| | - Shahla Shojaei
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, 41-800 Zabrze, Poland; Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, MB R3T 2N2, Canada.
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Katz MG, Hadas Y, Vincek A, Freage-Kahn L, Shtraizent N, Madjarov JM, Pastuszko P, Eliyahu E. Acid ceramidase gene therapy ameliorates pulmonary arterial hypertension with right heart dysfunction. Respir Res 2023; 24:197. [PMID: 37568148 PMCID: PMC10416391 DOI: 10.1186/s12931-023-02487-2] [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: 07/29/2022] [Accepted: 05/03/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND Up-regulation of ceramides in pulmonary hypertension (PH), contributing to perturbations in sphingolipid homeostasis and the transition of cells to a senescence state. We assessed the safety, feasibility, and efficiency of acid ceramidase gene transfer in a rodent PH model. METHODS A model of PH was established by the combination of left pneumonectomy and injection of Sugen toxin. Magnetic resonance imaging and right heart catheterization confirmed development of PH. Animals were subjected to intratracheal administration of synthetic adeno-associated viral vector (Anc80L65) carrying the acid ceramidase (Anc80L65.AC), an empty capsid vector, or saline. Therapeutic efficacy was evaluated 8 weeks after gene delivery. RESULTS Hemodynamic assessment 4 weeks after PH model the development demonstrated an increase in the mean pulmonary artery pressure to 30.4 ± 2.13 mmHg versus 10.4 ± 1.65 mmHg in sham (p < 0.001), which was consistent with the definition of PH. We documented a significant increase in pulmonary vascular resistance in the saline-treated (6.79 ± 0.85 mm Hg) and empty capsid (6.94 ± 0.47 mm Hg) groups, but not in animals receiving Anc80L65.AC (4.44 ± 0.71 mm Hg, p < 0.001). Morphometric analysis demonstrated an increase in medial wall thickness in control groups in comparison to those treated with acid ceramidase. After acid ceramidase gene delivery, a significant decrease of pro-inflammatory factors, interleukins, and senescence markers was observed. CONCLUSION Gene delivery of acid ceramidase provided tropism to pulmonary tissue and ameliorated vascular remodeling with right ventricular dysfunction in pulmonary hypertension.
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Affiliation(s)
- Michael G Katz
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, P.O. Box 1030, New York, NY, 10029-6574, USA
- Department of Pediatric Cardiac Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yoav Hadas
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, P.O. Box 1030, New York, NY, 10029-6574, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adam Vincek
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, P.O. Box 1030, New York, NY, 10029-6574, USA
| | | | | | - Jeko M Madjarov
- Atrium Health Sanger Heart and Vascular Institute, Charlotte, NC, USA
- Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Peter Pastuszko
- Department of Pediatric Cardiac Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Efrat Eliyahu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, P.O. Box 1030, New York, NY, 10029-6574, USA.
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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10
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Zhu H, Chen HJ, Wen HY, Wang ZG, Liu SL. Engineered Lipidic Nanomaterials Inspired by Sphingomyelin Metabolism for Cancer Therapy. Molecules 2023; 28:5366. [PMID: 37513239 PMCID: PMC10383197 DOI: 10.3390/molecules28145366] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/08/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Sphingomyelin (SM) and its metabolites are crucial regulators of tumor cell growth, differentiation, senescence, and programmed cell death. With the rise in lipid-based nanomaterials, engineered lipidic nanomaterials inspired by SM metabolism, corresponding lipid targeting, and signaling activation have made fascinating advances in cancer therapeutic processes. In this review, we first described the specific pathways of SM metabolism and the roles of their associated bioactive molecules in mediating cell survival or death. We next summarized the advantages and specific applications of SM metabolism-based lipidic nanomaterials in specific cancer therapies. Finally, we discussed the challenges and perspectives of this emerging and promising SM metabolism-based nanomaterials research area.
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Affiliation(s)
- Han Zhu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, China
| | - Hua-Jie Chen
- Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Hai-Yan Wen
- Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Zhi-Gang Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, China
| | - Shu-Lin Liu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, China
- Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
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11
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Vos M, Klein C, Hicks AA. Role of Ceramides and Sphingolipids in Parkinson's Disease. J Mol Biol 2023:168000. [PMID: 36764358 DOI: 10.1016/j.jmb.2023.168000] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/24/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023]
Abstract
Sphingolipids, including the basic ceramide, are a subset of bioactive lipids that consist of many different species. Sphingolipids are indispensable for proper neuronal function, and an increasing number of studies have emerged on the complexity and importance of these lipids in (almost) all biological processes. These include regulation of mitochondrial function, autophagy, and endosomal trafficking, which are affected in Parkinson's disease (PD). PD is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Currently, PD cannot be cured due to the lack of knowledge of the exact pathogenesis. Nonetheless, important advances have identified molecular changes in mitochondrial function, autophagy, and endosomal function. Furthermore, recent studies have identified ceramide alterations in patients suffering from PD, and in PD models, suggesting a critical interaction between sphingolipids and related cellular processes in PD. For instance, autosomal recessive forms of PD cause mitochondrial dysfunction, including energy production or mitochondrial clearance, that is directly influenced by manipulating sphingolipids. Additionally, endo-lysosomal recycling is affected by genes that cause autosomal dominant forms of the disease, such as VPS35 and SNCA. Furthermore, endo-lysosomal recycling is crucial for transporting sphingolipids to different cellular compartments where they will execute their functions. This review will discuss mitochondrial dysfunction, defects in autophagy, and abnormal endosomal activity in PD and the role sphingolipids play in these vital molecular processes.
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Affiliation(s)
- Melissa Vos
- Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
| | - Christine Klein
- Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany
| | - Andrew A Hicks
- Institute for Biomedicine (affiliated to the University of Luebeck, Luebeck, Germany), Eurac Research, 39100 Bolzano, Italy. https://twitter.com/andrewhicks
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12
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Kang Y, Sundaramoorthy P, Gasparetto C, Feinberg D, Fan S, Long G, Sellars E, Garrett A, Tuchman SA, Reeves BN, Li Z, Liu B, Ogretmen B, Maines L, Ben-Yair VK, Smith C, Plasse T. Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma. Ann Hematol 2023; 102:369-383. [PMID: 36460794 DOI: 10.1007/s00277-022-05056-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 11/13/2022] [Indexed: 12/04/2022]
Abstract
Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.
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Affiliation(s)
- Yubin Kang
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, 2400 Pratt Street, Suite 5000, Durham, NC, DUMC 396127710, USA.
| | - Pasupathi Sundaramoorthy
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, 2400 Pratt Street, Suite 5000, Durham, NC, DUMC 396127710, USA
| | - Cristina Gasparetto
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, 2400 Pratt Street, Suite 5000, Durham, NC, DUMC 396127710, USA
| | - Daniel Feinberg
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, 2400 Pratt Street, Suite 5000, Durham, NC, DUMC 396127710, USA
| | - Shengjun Fan
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, 2400 Pratt Street, Suite 5000, Durham, NC, DUMC 396127710, USA
| | - Gwynn Long
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, 2400 Pratt Street, Suite 5000, Durham, NC, DUMC 396127710, USA
| | - Emily Sellars
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, 2400 Pratt Street, Suite 5000, Durham, NC, DUMC 396127710, USA
| | - Anderson Garrett
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, 2400 Pratt Street, Suite 5000, Durham, NC, DUMC 396127710, USA
| | - Sascha A Tuchman
- Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Brandi N Reeves
- Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Zhiguo Li
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA
| | - Bei Liu
- Division of Hematology, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Lynn Maines
- Apogee Biotechnology Corporation, Hummelstown, PA, USA
| | | | - Charles Smith
- Apogee Biotechnology Corporation, Hummelstown, PA, USA
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13
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Çelen İ, Jayasinghe A, Doh JH, Sabanayagam CR. Transcriptomic Signature of the Simulated Microgravity Response in Caenorhabditis elegans and Comparison to Spaceflight Experiments. Cells 2023; 12:270. [PMID: 36672205 PMCID: PMC9856674 DOI: 10.3390/cells12020270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/25/2022] [Accepted: 12/28/2022] [Indexed: 01/13/2023] Open
Abstract
Given the growing interest in human exploration of space, it is crucial to identify the effects of space conditions on biological processes. Here, we analyze the transcriptomic response of Caenorhabditis elegans to simulated microgravity and observe the maintained transcriptomic response after returning to ground conditions for four, eight, and twelve days. We show that 75% of the simulated microgravity-induced changes on gene expression persist after returning to ground conditions for four days while most of these changes are reverted after twelve days. Our results from integrative RNA-seq and mass spectrometry analyses suggest that simulated microgravity affects longevity-regulating insulin/IGF-1 and sphingolipid signaling pathways. Finally, we identified 118 genes that are commonly differentially expressed in simulated microgravity- and space-exposed worms. Overall, this work provides insight into the effect of microgravity on biological systems during and after exposure.
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Affiliation(s)
- İrem Çelen
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE 19711, USA
- Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA
| | - Aroshan Jayasinghe
- Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA
| | - Jung H. Doh
- Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA
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14
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Wang HYJ, Huang CY, Wei KC, Hung KC. A mass spectrometry imaging and lipidomic investigation reveals aberrant lipid metabolism in the orthotopic mouse glioma. J Lipid Res 2022; 63:100304. [PMID: 36273646 PMCID: PMC9761856 DOI: 10.1016/j.jlr.2022.100304] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/05/2022] [Accepted: 10/06/2022] [Indexed: 12/14/2022] Open
Abstract
Lipids perform multiple biological functions and reflect the physiology and pathology of cells, tissues, and organs. Here, we sought to understand lipid content in relation to tumor pathology by characterizing phospholipids and sphingolipids in the orthotopic mouse glioma using MALDI MS imaging (MSI) and LC-MS/MS. Unsupervised clustering analysis of the MALDI-MSI data segmented the coronal tumoral brain section into 10 histopathologically salient regions. Heterogeneous decrease of the common saturated phosphatidylcholines (PCs) in the tumor was accompanied by the increase of analogous PCs with one or two additional fatty acyl double bonds and increased lyso-PCs. Polyunsaturated fatty acyl-PCs and ether PCs highlighted the striatal tumor margins, whereas the distributions of other PCs differentiated the cortical and striatal tumor parenchyma. We detected a reduction of SM d18:1/18:0 and the heterogeneous mild increase of SM d18:1/16:0 in the tumor, whereas ceramides accumulated only in a small patch deep in the tumoral parenchyma. LC-MS/MS analyses of phospholipids and sphingolipids complemented the MALDI-MSI observation, providing a snapshot of these lipids in the tumor. Finally, the proposed mechanisms responsible for the tumoral lipid changes were contrasted with our interrogation of gene expression in human glioma. Together, these lipidomic results unveil the aberrant and heterogeneous lipid metabolism in mouse glioma where multiple lipid-associated signaling pathways underline the tumor features, promote the survival, growth, proliferation, and invasion of different tumor cell populations, and implicate the management strategy of a multiple-target approach for glioma and related brain malignancies.
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Affiliation(s)
- Hay-Yan J. Wang
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan,For correspondence: Hay-Yan J. Wang
| | - Chiung-Yin Huang
- Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan,Department of Neurosurgery, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan
| | - Kuo-Chen Wei
- Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan,Department of Neurosurgery, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan,Department of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan,School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kuo-Chen Hung
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Chang Gung University College of Medicine, Taiwan
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15
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Serum Metabolomics Profiling Reveals Metabolic Alterations Prior to a Diagnosis with Non-Small Cell Lung Cancer among Chinese Community Residents: A Prospective Nested Case-Control Study. Metabolites 2022; 12:metabo12100906. [PMID: 36295809 PMCID: PMC9610639 DOI: 10.3390/metabo12100906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/18/2022] [Accepted: 09/22/2022] [Indexed: 11/17/2022] Open
Abstract
The present high mortality of lung cancer in China stems mainly from the lack of feasible, non-invasive and early disease detection biomarkers. Serum metabolomics profiling to reveal metabolic alterations could expedite the disease detection process and suggest those patients who are harboring disease. Using a nested case-control design, we applied ultra-high-performance liquid chromatography/mass spectrometry (LC-MS)-based serum metabolomics to reveal the metabolomic alterations and to indicate the presence of non-small cell lung cancer (NSCLC) using serum samples collected prior to disease diagnoses. The studied serum samples were collected from 41 patients before a NSCLC diagnosis (within 3.0 y) and 38 matched the cancer-free controls from the prospective Shanghai Suburban Adult Cohort. The NSCLC patients markedly presented cellular metabolism alterations in serum samples collected prior to their disease diagnoses compared with the cancer-free controls. In total, we identified 18 significantly expressed metabolites whose relative abundance showed either an upward or a downward trend, with most of them being lipid and lipid-like molecules, organic acids, and nitrogen compounds. Choline metabolism in cancer, sphingolipid, and glycerophospholipid metabolism emerged as the significant metabolic disturbance of NSCLC. The metabolites involved in these biological processes may be the distinctive features associated with NSCLC prior to a diagnosis.
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16
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Pherez-Farah A, López-Sánchez RDC, Villela-Martínez LM, Ortiz-López R, Beltrán BE, Hernández-Hernández JA. Sphingolipids and Lymphomas: A Double-Edged Sword. Cancers (Basel) 2022; 14:2051. [PMID: 35565181 PMCID: PMC9104519 DOI: 10.3390/cancers14092051] [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: 04/04/2022] [Accepted: 04/14/2022] [Indexed: 11/24/2022] Open
Abstract
Lymphomas are a highly heterogeneous group of hematological neoplasms. Given their ethiopathogenic complexity, their classification and management can become difficult tasks; therefore, new approaches are continuously being sought. Metabolic reprogramming at the lipid level is a hot topic in cancer research, and sphingolipidomics has gained particular focus in this area due to the bioactive nature of molecules such as sphingoid bases, sphingosine-1-phosphate, ceramides, sphingomyelin, cerebrosides, globosides, and gangliosides. Sphingolipid metabolism has become especially exciting because they are involved in virtually every cellular process through an extremely intricate metabolic web; in fact, no two sphingolipids share the same fate. Unsurprisingly, a disruption at this level is a recurrent mechanism in lymphomagenesis, dissemination, and chemoresistance, which means potential biomarkers and therapeutical targets might be hiding within these pathways. Many comprehensive reviews describing their role in cancer exist, but because most research has been conducted in solid malignancies, evidence in lymphomagenesis is somewhat limited. In this review, we summarize key aspects of sphingolipid biochemistry and discuss their known impact in cancer biology, with a particular focus on lymphomas and possible therapeutical strategies against them.
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Affiliation(s)
- Alfredo Pherez-Farah
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Nuevo Leon, Mexico
| | | | - Luis Mario Villela-Martínez
- Facultad de Medicina, Universidad Autónoma de Sinaloa, Culiacán Rosales 80030, Sinaloa, Mexico
- Hospital Fernando Ocaranza, ISSSTE, Hermosillo 83190, Sonora, Mexico
- Centro Médico Dr. Ignacio Chávez, ISSSTESON, Hermosillo 83000, Sonora, Mexico
| | - Rocío Ortiz-López
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Nuevo Leon, Mexico
| | - Brady E Beltrán
- Hospital Edgardo Rebagliati Martins, Lima 15072, Peru
- Instituto de Investigaciones en Ciencias Biomédicas, Universidad Ricardo Palma, Lima 1801, Peru
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17
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Characterization and Roles of Membrane Lipids in Fatty Liver Disease. MEMBRANES 2022; 12:membranes12040410. [PMID: 35448380 PMCID: PMC9025760 DOI: 10.3390/membranes12040410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 12/12/2022]
Abstract
Obesity has reached global epidemic proportions and it affects the development of insulin resistance, type 2 diabetes, fatty liver disease and other metabolic diseases. Membrane lipids are important structural and signaling components of the cell membrane. Recent studies highlight their importance in lipid homeostasis and are implicated in the pathogenesis of fatty liver disease. Here, we discuss the numerous membrane lipid species and their metabolites including, phospholipids, sphingolipids and cholesterol, and how dysregulation of their composition and physiology contribute to the development of fatty liver disease. The development of new genetic and pharmacological mouse models has shed light on the role of lipid species on various mechanisms/pathways; these lipids impact many aspects of the pathophysiology of fatty liver disease and could potentially be targeted for the treatment of fatty liver disease.
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18
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Wang Y, Ouyang Q, Chang X, Yang M, He J, Tian Y, Sheng J. Anti-photoaging effects of flexible nanoliposomes encapsulated Moringa oleifera Lam. isothiocyanate in UVB-induced cell damage in HaCaT cells. Drug Deliv 2022; 29:871-881. [PMID: 35277099 PMCID: PMC8920399 DOI: 10.1080/10717544.2022.2039802] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Skin photoaging is premature skin aging damage that occurs after repeated exposure to ultraviolet (UV) radiation. Although isothiocyanates extracted from the moringa tree (Moringa oleifera Lam.) (MITC) exhibit excellent effects against skin photoaging, its application is restricted because of its characteristics, such as extremely low water solubility, bioavailability, and easy degradation. Currently, flexible nanoliposomes have gained increasing interest as a biocompatible polymer for applications such as transdermal drug delivery. We prepare amphiphilic hyaluronic acid (HA) conjugated with ceramide (CE) to modify nanoliposomes for MITC (HACE/MITC NPs) delivery. The HACE/MITC nanoparticles (NPs) are prepared and characterized for entrapment efficiency, particle size, polydispersity index, zeta potential, in vitro release, in vivo skin permeation, and in vitro protective effect of photoaging. The zeta potential of MITC NPs and HACE/MITC NPs is −24.46 mV and −24.93 mV, respectively. After modification of HACE, the entrapment efficient of MITC liposome increased from 62.54% to 70.67%, and the particle size decreased from 266.1 nm to 192.8 nm. In vivo skin permeation, permeated drug increased from 49.42 to 71.40%. Moreover, the results showed that the entrapment of MITC in nanoliposomes improves its stability, efficacy, and skin permeation. Further, HACE/MITC NPs are favorable for uptake by HaCaT cells without requiring changes in cell morphology, which significantly improves the activities of antioxidant enzymes, scavenges UVB-induced reactive oxygen species, protects skin from damage, and reduces MMP-1, MMP-3, and MMP-9 expression caused by radiation-induced photoaging. Our results strongly suggest that flexible nanoliposomes successfully improved the cell membrane permeation of MITC, and that anti-photoaging and HACE/MITC NPs can potentially be used as candidates for photoaging therapy.
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Affiliation(s)
- Yijin Wang
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Qianqian Ouyang
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
- Marine Biomedical Research Institution, Guangdong Medical University, Zhanjiang, PR China
- The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, China
| | - Xuefei Chang
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Min Yang
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Junpeng He
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Yang Tian
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
- Engineering Research Center of Development and Utilization of Food and Drug Homologous Resources, Ministry of Education, Yunnan Agricultural University, Kunming, China
| | - Jun Sheng
- Yunnan Province Engineering Research Center of Functional Food of Homologous of Drug and Food, Yunnan Agricultural University, Kunming, China
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19
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Performance of Oleic Acid and Soybean Oil in the Preparation of Oil-in-Water Microemulsions for Encapsulating a Highly Hydrophobic Molecule. COLLOIDS AND INTERFACES 2021. [DOI: 10.3390/colloids5040050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
This work analyzes the dispersion of a highly hydrophobic molecule, (9Z)-N-(1,3-dihydroxyoctadecan-2-yl)octadec-9-enamide (ceramide-like molecule), with cosmetic and pharmaceutical interest, by exploiting oil-in-water microemulsions. Two different oils, oleic acid and soybean oil, were tested as an oil phase while mixtures of laureth-5-carboxylic acid (Akypo) and 2-propanol were used for the stabilization of the dispersions. This allowed us to obtain stable aqueous-based formulations with a relatively reduced content of oily phase (around 3% w/w), that may enhance the bioavailability of this molecule by its solubilization in nanometric oil droplets (with a size range of 30–80 nm), that allow the incorporation of a ceramide-like molecule of up to 3% w/w, to remain stable for more than a year. The nanometric size of the droplet containing the active ingredient and the stability of the formulations provide the basis for evaluating the efficiency of microemulsions in preparing formulations to enhance the distribution and availability of ceramide-like molecules, helping to reach targets in cosmetic and pharmaceutical formulations.
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20
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Shammout ODA, Ashmawy NS, Shakartalla SB, Altaie AM, Semreen MH, Omar HA, Soliman SSM. Comparative sphingolipidomic analysis reveals significant differences between doxorubicin-sensitive and -resistance MCF-7 cells. PLoS One 2021; 16:e0258363. [PMID: 34637456 PMCID: PMC8509934 DOI: 10.1371/journal.pone.0258363] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/25/2021] [Indexed: 12/09/2022] Open
Abstract
Drug resistance is responsible for the failure of many available anticancer drugs. Several studies have demonstrated the association between the alteration in sphingolipids (SPLs) and the development of drug resistance. To investigate the association between SPLs metabolism and doxorubicin (dox)-resistance in MCF-7 cells, a comparative sphingolipidomics analysis between dox-sensitive (parental) and -resistant MCF-7 cell lines along with validation by gene expression analysis were conducted. A total of 31 SPLs representing 5 subcategories were identified. The data obtained revealed that SPLs were clustered into two groups differentiating parental from dox-resistant cells. Eight SPLs were significantly altered in response to dox-resistance including SM (d18:1/16), SM (d18:1/24:2), SM (d18:1/24:0), SM (d18:1/20:0), SM (d18:1/23:1), HexCer (d18:1/24:0), SM (d18:1/15:0), DHSM (d18:0/20:0). The current study is the first to conclusively ascertain the potential involvement of dysregulated SPLs in dox-resistance in MCF-7 cells. SPLs metabolism in dox-resistant MCF-7 cells is oriented toward the downregulation of ceramides (Cer) and the concomitant increase in sphingomyelin (SM). Gene expression analysis has revealed that dox-resistant cells tend to escape from the Cer-related apoptosis by the activation of SM-Cer and GluCer-LacCer-ganglioside pathways. The enzymes that were correlated to the alteration in SPLs metabolism of dox-resistant MCF-7 cells and significantly altered in gene expression can represent potential targets that can represent a winning strategy for the future development of promising anticancer drugs.
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Affiliation(s)
- Ola D. A. Shammout
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Naglaa S. Ashmawy
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Pharmacy, Department of Pharmacognosy, Ain Shams University, Cairo, Egypt
- Pharmacy Department, City University College of Ajman, Ajman, UAE
| | - Sarra B. Shakartalla
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Pharmacy, University of Gezira, Wadmedani, Sudan
| | - Alaa M. Altaie
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Mohammad H. Semreen
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Hany A. Omar
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Sameh S. M. Soliman
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- * E-mail:
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21
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Zakharova OV, Mastalygina EE, Golokhvast KS, Gusev AA. Graphene Nanoribbons: Prospects of Application in Biomedicine and Toxicity. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 11:2425. [PMID: 34578739 PMCID: PMC8469389 DOI: 10.3390/nano11092425] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/06/2021] [Accepted: 09/11/2021] [Indexed: 12/12/2022]
Abstract
Graphene nanoribbons are a type of graphene characterized by remarkable electrical and mechanical properties. This review considers the prospects for the application of graphene ribbons in biomedicine, taking into account safety aspects. According to the analysis of the recent studies, the topical areas of using graphene nanoribbons include mechanical, chemical, photo- and acoustic sensors, devices for the direct sequencing of biological macromolecules, including DNA, gene and drug delivery vehicles, and tissue engineering. There is evidence of good biocompatibility of graphene nanoribbons with human cell lines, but a number of researchers have revealed toxic effects, including cytotoxicity and genotoxicity. Moreover, the damaging effects of nanoribbons are often higher than those of chemical analogs, for instance, graphene oxide nanoplates. The possible mechanism of toxicity is the ability of graphene nanoribbons to damage the cell membrane mechanically, stimulate reactive oxidative stress (ROS) production, autophagy, and inhibition of proliferation, as well as apoptosis induction, DNA fragmentation, and the formation of chromosomal aberrations. At the same time, the biodegradability of graphene nanoribbons under the environmental factors has been proven. In general, this review allows us to conclude that graphene nanoribbons, as components of high-precision nanodevices and therapeutic agents, have significant potential for biomedical applications; however, additional studies of their safety are needed. Particular emphasis should be placed on the lack of information about the effect of graphene nanoribbons on the organism as a whole obtained from in vivo experiments, as well as about their ecological toxicity, accumulation, migration, and destruction within ecosystems.
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Affiliation(s)
- Olga V. Zakharova
- Research Institute for Environmental Science and Biotechnology, Derzhavin Tambov State University, 33 Internatsionalnaya St., 392000 Tambov, Russia;
- Engineering Center, Plekhanov Russian University of Economics, Stremyanny Lane 36, 117997 Moscow, Russia;
- Department of Functional Nanosystems and High-Temperature Materials, National University of Science and Technology MISiS, 4 Leninskiy prospekt, 119049 Moscow, Russia
| | - Elena E. Mastalygina
- Engineering Center, Plekhanov Russian University of Economics, Stremyanny Lane 36, 117997 Moscow, Russia;
- Laboratory of Physics-Chemistry of Synthetic and Natural Polymers Composites, Institute of Biochemical Physics Named after N.M. Emanuel RAS (IBCP RAS), Russian Academy of Sciences, 4 Kosygin St., 119991 Moscow, Russia
| | - Kirill S. Golokhvast
- Polytechnical Institute, Far Eastern Federal University, Sukhanova 8, 690950 Vladivostok, Russia;
- Siberian Federal Scientific Center for Agrobiotechnology RAS, Centralnaya 2B, 630501 Krasnoobsk, Russia
- Pacific Geographical Institute, Far Eastern Branch of the Russian Academy of Sciences, Radio 7, 690041 Vladivostok, Russia
| | - Alexander A. Gusev
- Research Institute for Environmental Science and Biotechnology, Derzhavin Tambov State University, 33 Internatsionalnaya St., 392000 Tambov, Russia;
- Engineering Center, Plekhanov Russian University of Economics, Stremyanny Lane 36, 117997 Moscow, Russia;
- Research Educational Center Sustainable Development of the Forest Complex, Voronezh State Forestry University Named after G F Morozov, 394087 Voronezh, Russia
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22
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Metabolic Depletion of Sphingolipids Does Not Alter Cell Cycle Progression in Chinese Hamster Ovary Cells. J Membr Biol 2021; 255:1-12. [PMID: 34392379 DOI: 10.1007/s00232-021-00198-7] [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: 07/06/2021] [Accepted: 08/02/2021] [Indexed: 10/20/2022]
Abstract
The cell cycle is a sequential multi-step process essential for growth and proliferation of cells comprising multicellular organisms. Although a number of proteins are known to modulate the cell cycle, the role of lipids in regulation of cell cycle is still emerging. In our previous work, we monitored the role of cholesterol in cell cycle progression in CHO-K1 cells. Since sphingolipids enjoy a functionally synergistic relationship with membrane cholesterol, in this work, we explored whether sphingolipids could modulate the eukaryotic cell cycle using CHO-K1 cells. Sphingolipids are essential components of eukaryotic cell membranes and are involved in a number of important cellular functions. To comprehensively monitor the role of sphingolipids on cell cycle progression, we carried out metabolic depletion of sphingolipids in CHO-K1 cells using inhibitors (fumonisin B1, myriocin, and PDMP) that block specific steps of the sphingolipid biosynthetic pathway and examined their effect on individual cell cycle phases. Our results show that metabolic inhibitors led to significant reduction in specific sphingolipids, yet such inhibition in sphingolipid biosynthesis did not show any effect on cell cycle progression in CHO-K1 cells. We speculate that any role of sphingolipids on cell cycle progression could be context and cell-type dependent, and cancer cells could be a better choice for monitoring such regulation, since sphingolipids are differentially modulated in these cells.
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23
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Qi D, Song X, Xue C, Yao W, Shen P, Yu H, Zhang Z. AKT1/FOXP3 axis-mediated expression of CerS6 promotes p53 mutant pancreatic tumorigenesis. Cancer Lett 2021; 522:105-118. [PMID: 34343636 DOI: 10.1016/j.canlet.2021.06.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/17/2021] [Accepted: 06/25/2021] [Indexed: 12/30/2022]
Abstract
Ceramide synthases (CerSs) catalyze the formation of ceramides from sphingoid bases and acyl-CoA substrates. Increasing evidence suggests that cancer cells generally exhibit altered sphingolipid metabolism in the tumorigenesis of multiple cancers. However, there is no evidence that CerSs are associated with pancreatic ductal carcinoma (PDAC). In the present study, we examined CerS expression in clinical tissue and conducted data mining to investigate the clinical significance of CerSs in the TCGA-PAAD database. We found that high CerS6 expression positively correlated with progression and predicted worse prognosis in PDAC patients, establishing CerS6 as a potential biomarker for PDAC. Furthermore, CerS6 promoted cell proliferation, colony formation and invasion by producing C16-ceramide and was required for tumor formation. Mechanistically, AKT1 interacted with and phosphorylated FOXP3 at S418, which decreased the binding of FOXP3 to the CERS6 promoter and in turn induced CerS6 expression by reconstituting an activated state on the CERS6 promoter. The AKT1/FOXP3 axis mediated the CerS6 expression and promoted p53 mutant pancreatic tumorigenesis by producing excessive C16-ceramide, which induced the accumulation of mutant p53. Thus, our study explores the relationship between PI3K/AKT signaling and sphingolipid metabolism, revealing an oncogenic role for CerS6, which may represent a potential target for PDAC treatment.
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Affiliation(s)
- Dachuan Qi
- General Surgery Department II of Shanghai Fourth People's Hospital Affiliated to Tongji University, Shanghai, 200434, China.
| | - Xuwei Song
- General Surgery Department II of Shanghai Fourth People's Hospital Affiliated to Tongji University, Shanghai, 200434, China
| | - Chunhua Xue
- General Surgery Department II of Shanghai Fourth People's Hospital Affiliated to Tongji University, Shanghai, 200434, China
| | - Wenyan Yao
- General Surgery Department II of Shanghai Fourth People's Hospital Affiliated to Tongji University, Shanghai, 200434, China
| | - Penghui Shen
- General Surgery Department II of Shanghai Fourth People's Hospital Affiliated to Tongji University, Shanghai, 200434, China
| | - Hua Yu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Nutrition and Health Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China; Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China.
| | - Zhiqi Zhang
- General Surgery Department II of Shanghai Fourth People's Hospital Affiliated to Tongji University, Shanghai, 200434, China.
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24
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Khairat SHM, Omar MA, Ragab FAF, Roy S, Turab Naqvi AA, Abdelsamie AS, Hirsch AKH, Galal SA, Hassan MI, El Diwani HI. Design, synthesis, and biological evaluation of novel benzimidazole derivatives as sphingosine kinase 1 inhibitor. Arch Pharm (Weinheim) 2021; 354:e2100080. [PMID: 34128259 DOI: 10.1002/ardp.202100080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/17/2021] [Accepted: 04/23/2021] [Indexed: 11/08/2022]
Abstract
Sphingosine kinase 1 (SphK1) has emerged as an attractive drug target for different diseases. Recently, discovered SphK1 inhibitors have been recommended in cancer therapeutics; however, selectivity and potency are great challenges. In this study, a novel series of benzimidazoles was synthesized and evaluated as SphK1 inhibitors. Our design strategy is twofold: It aimed first to study the effect of replacing the 5-position of the benzimidazole ring with a polar carboxylic acid group on the SphK1-inhibitory activity and cytotoxicity. Our second aim was to optimize the structures of the benzimidazoles through the elongation of the chain. The enzyme inhibition potentials against all the synthesized compounds toward SphK1 were evaluated, and the results revealed that most of the studied compounds inhibited SphK1 effectively. The binding affinity of the benzimidazole derivatives toward SphK1 was measured by fluorescence binding and molecular docking. Compounds 33, 37, 39, 41, 42, 43, and 45 showed an appreciable binding affinity. Therefore, the SphK1-inhibitory potentials of compounds 33, 37, 39, 41, 42, 43, and 45 were studied and IC50 values were determined, to reveal high potency. The study showed that these compounds inhibited SphK1 with effective IC50 values. Among the studied compounds, compound 41 was the most effective one with the lowest IC50 value and a high cytotoxicity on a wide spectrum of cell lines. Molecular docking revealed that most of these compounds fit well into the ATP-binding site of SphK1 and form hydrogen bond interactions with catalytically important residues. Overall, the findings suggest the therapeutic potential of benzimidazoles in the clinical management of SphK1-associated diseases.
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Affiliation(s)
- Sarah H M Khairat
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt
| | - Mohamed A Omar
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt
| | - Fatma A F Ragab
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Sonam Roy
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Ahmad A Turab Naqvi
- Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany
| | - Ahmed S Abdelsamie
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt.,Department of Pharmacy, Saarland University, Saarbrücken, Germany
| | - Anna K H Hirsch
- Department of Pharmacy, Saarland University, Saarbrücken, Germany.,Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Shadia A Galal
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Hoda I El Diwani
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt
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25
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The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy. Cancers (Basel) 2021; 13:cancers13102475. [PMID: 34069611 PMCID: PMC8161379 DOI: 10.3390/cancers13102475] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/12/2021] [Accepted: 05/16/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Sphingolipids are membrane-associated lipids that are involved in signal transduction pathways regulating cell death, growth, and migration. In cancer cells, sphingolipids regulate pathways relevant to cancer therapy, such as invasion, metastasis, apoptosis, and lethal mitophagy. Notable sphingolipids include ceramide, a sphingolipid that induces death and lethal mitophagy, and sphingosine-1 phosphate, a sphingolipid that induces survival and chemotherapeutic resistance. These sphingolipids participate in regulating the process of mitophagy, where cells encapsulate damaged mitochondria in double-membrane vesicles (called autophagosomes) for degradation. Lethal mitophagy is an anti-tumorigenic mechanism mediated by ceramide, where cells degrade many mitochondria until the cancer cell dies in an apoptosis-independent manner. Abstract Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is determined by specific ceramide synthases, and this fatty acyl length also determines the sphingolipid’s specialized functions within the cell. One function in particular, the regulation of the selective autophagy of mitochondria, or mitophagy, is closely regulated by ceramide, a key regulatory sphingolipid. Mitophagy alterations have important implications for cancer cell proliferation, response to chemotherapeutics, and mitophagy-mediated cell death. This review will focus on the alterations of ceramide synthases in cancer and sphingolipid regulation of lethal mitophagy, concerning cancer therapy.
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26
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Peters S, Kaiser L, Fink J, Schumacher F, Perschin V, Schlegel J, Sauer M, Stigloher C, Kleuser B, Seibel J, Schubert-Unkmeir A. Click-correlative light and electron microscopy (click-AT-CLEM) for imaging and tracking azido-functionalized sphingolipids in bacteria. Sci Rep 2021; 11:4300. [PMID: 33619350 PMCID: PMC7900124 DOI: 10.1038/s41598-021-83813-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 02/05/2021] [Indexed: 11/21/2022] Open
Abstract
Sphingolipids, including ceramides, are a diverse group of structurally related lipids composed of a sphingoid base backbone coupled to a fatty acid side chain and modified terminal hydroxyl group. Recently, it has been shown that sphingolipids show antimicrobial activity against a broad range of pathogenic microorganisms. The antimicrobial mechanism, however, remains so far elusive. Here, we introduce ‘click-AT-CLEM’, a labeling technique for correlated light and electron microscopy (CLEM) based on the super-resolution array tomography (srAT) approach and bio-orthogonal click chemistry for imaging of azido-tagged sphingolipids to directly visualize their interaction with the model Gram-negative bacterium Neisseria meningitidis at subcellular level. We observed ultrastructural damage of bacteria and disruption of the bacterial outer membrane induced by two azido-modified sphingolipids by scanning electron microscopy and transmission electron microscopy. Click-AT-CLEM imaging and mass spectrometry clearly revealed efficient incorporation of azido-tagged sphingolipids into the outer membrane of Gram-negative bacteria as underlying cause of their antimicrobial activity.
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Affiliation(s)
- Simon Peters
- Institute for Hygiene and Microbiology, Julius-Maximilian University Wuerzburg, Wuerzburg, Germany
| | - Lena Kaiser
- Institute for Hygiene and Microbiology, Julius-Maximilian University Wuerzburg, Wuerzburg, Germany
| | - Julian Fink
- Institute for Organic Chemistry, Julius-Maximilian University Wuerzburg, Wuerzburg, Germany
| | - Fabian Schumacher
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.,Department of Toxicology, University of Potsdam, Nuthetal, Germany.,Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany
| | - Veronika Perschin
- Imaging Core Facility, Biocenter, Julius-Maximilian University Wuerzburg, Wuerzburg, Germany
| | - Jan Schlegel
- Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilian University Wuerzburg, Wuerzburg, Germany
| | - Markus Sauer
- Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilian University Wuerzburg, Wuerzburg, Germany
| | - Christian Stigloher
- Imaging Core Facility, Biocenter, Julius-Maximilian University Wuerzburg, Wuerzburg, Germany
| | - Burkhard Kleuser
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.,Department of Toxicology, University of Potsdam, Nuthetal, Germany
| | - Jürgen Seibel
- Institute for Organic Chemistry, Julius-Maximilian University Wuerzburg, Wuerzburg, Germany
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27
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Alternative splicing of ceramide synthase 2 alters levels of specific ceramides and modulates cancer cell proliferation and migration in Luminal B breast cancer subtype. Cell Death Dis 2021; 12:171. [PMID: 33568634 PMCID: PMC7876150 DOI: 10.1038/s41419-021-03436-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 01/10/2023]
Abstract
Global dysregulation of RNA splicing and imbalanced sphingolipid metabolism has emerged as promoters of cancer cell transformation. Here, we present specific signature of alternative splicing (AS) events of sphingolipid genes for each breast cancer subtype from the TCGA-BRCA dataset. We show that ceramide synthase 2 (CERS2) undergoes a unique cassette exon event specifically in Luminal B subtype tumors. We validated this exon 8 skipping event in Luminal B cancer cells compared to normal epithelial cells, and in patient-derived tumor tissues compared to matched normal tissues. Differential AS-based survival analysis shows that this AS event of CERS2 is a poor prognostic factor for Luminal B patients. As Exon 8 corresponds to catalytic Lag1p domain, overexpression of AS transcript of CERS2 in Luminal B cancer cells leads to a reduction in the level of very-long-chain ceramides compared to overexpression of protein-coding (PC) transcript of CERS2. We further demonstrate that this AS event-mediated decrease of very-long-chain ceramides leads to enhanced cancer cell proliferation and migration. Therefore, our results show subtype-specific AS of sphingolipid genes as a regulatory mechanism that deregulates sphingolipids like ceramides in breast tumors, and can be explored further as a suitable therapeutic target.
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28
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Lipid Metabolism in Tumor-Associated Fibroblasts. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1316:117-131. [PMID: 33740247 DOI: 10.1007/978-981-33-6785-2_8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Tumor- or cancer-associated fibroblasts (TAFs), one of the most abundant stromal cell types in various carcinomas, consist of a heterogeneous cell population. Typically, TAFs are assigned with pro-tumor activities to promote tumor growth and progression. One of the key features of solid tumors is the metabolic reprogramming that induces alterations of bioenergetics and biosynthesis in both tumor cells and TAFs. Therefore, this review emphasizes TAFs lipid metabolism related to both TAFs differentiation process and TAFs crosstalk with cancer cells. We hope that this review will help understand lipid metabolism in tumor microenvironment, and support the rational design of metabolism-based approaches to improve the efficacy of cancer therapy.
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29
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Velazquez FN, Hernandez-Corbacho M, Trayssac M, Stith JL, Bonica J, Jean B, Pulkoski-Gross MJ, Carroll BL, Salama MF, Hannun YA, Snider AJ. Bioactive sphingolipids: Advancements and contributions from the laboratory of Dr. Lina M. Obeid. Cell Signal 2020; 79:109875. [PMID: 33290840 PMCID: PMC8244749 DOI: 10.1016/j.cellsig.2020.109875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023]
Abstract
Sphingolipids and their synthetic enzymes have emerged as critical mediators in numerous diseases including inflammation, aging, and cancer. One enzyme in particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P), has been extensively implicated in these processes. SK catalyzes the phosphorylation of sphingosine to S1P and exists as two isoforms, SK1 and SK2. In this review, we will discuss the contributions from the laboratory of Dr. Lina M. Obeid that have defined the roles for several bioactive sphingolipids in signaling and disease with an emphasis on her work defining SK1 in cellular fates and pathobiologies including proliferation, senescence, apoptosis, and inflammation.
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Affiliation(s)
- Fabiola N Velazquez
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maria Hernandez-Corbacho
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Magali Trayssac
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jeffrey L Stith
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Joseph Bonica
- Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Bernandie Jean
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Michael J Pulkoski-Gross
- Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Brittany L Carroll
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Mohamed F Salama
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Yusuf A Hannun
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Ashley J Snider
- Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721, USA.
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30
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Burrello J, Biemmi V, Dei Cas M, Amongero M, Bolis S, Lazzarini E, Bollini S, Vassalli G, Paroni R, Barile L. Sphingolipid composition of circulating extracellular vesicles after myocardial ischemia. Sci Rep 2020; 10:16182. [PMID: 32999414 PMCID: PMC7527456 DOI: 10.1038/s41598-020-73411-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 09/16/2020] [Indexed: 12/11/2022] Open
Abstract
Sphingolipids are structural components of cell membrane, displaying several functions in cell signalling. Extracellular vesicles (EV) are lipid bilayer membrane nanoparticle and their lipid composition may be different from parental cells, with a significant enrichment in sphingolipid species, especially in pathological conditions. We aimed at optimizing EV isolation from plasma and describing the differential lipid content of EV, as compared to whole plasma. As pilot study, we evaluated the diagnostic potential of lipidomic signature of circulating EV in patients with a diagnosis of ST-segment-elevation myocardial infarction (STEMI). STEMI patients were evaluated before reperfusion and 24-h after primary percutaneous coronary intervention. Twenty sphingolipid species were quantified by liquid-chromatography tandem-mass-spectrometry. EV-ceramides, -dihydroceramides, and -sphingomyelins increased in STEMI vs. matched controls and decreased after reperfusion. Their levels correlated to hs-troponin, leucocyte count, and ejection fraction. Plasma sphingolipids levels were 500-to-700-fold higher as compared to EV content; nevertheless, only sphingomyelins differed in STEMI vs. control patients. Different sphingolipid species were enriched in EV and their linear combination by machine learning algorithms accurately classified STEMI patients at pre-PCI evaluation. In conclusion, EV lipid signature discriminates STEMI patients. These findings may contribute to the identification of novel biomarkers and signaling mechanisms related to cardiac ischemia.
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Affiliation(s)
- J Burrello
- Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Via Tesserete 48, 6900, Lugano, Switzerland
| | - V Biemmi
- Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Via Tesserete 48, 6900, Lugano, Switzerland.,Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
| | - M Dei Cas
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - M Amongero
- Department of Mathematical Sciences G. L. Lagrange, Polytechnic University of Torino, Torino, Italy
| | - S Bolis
- Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Via Tesserete 48, 6900, Lugano, Switzerland
| | - E Lazzarini
- Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Via Tesserete 48, 6900, Lugano, Switzerland
| | - S Bollini
- Regenerative Medicine Laboratory, Dept. of Experimental Medicine (DIMES), University of Genova, Genova, Italy
| | - G Vassalli
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.,Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Foundation, Lugano, Switzerland
| | - R Paroni
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - L Barile
- Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Via Tesserete 48, 6900, Lugano, Switzerland. .,Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland. .,Institute of Life Science, Scuola Superiore Sant'Anna, Pisa, Italy.
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31
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Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity. Cell Rep 2020; 28:1879-1893.e7. [PMID: 31412253 PMCID: PMC6889821 DOI: 10.1016/j.celrep.2019.07.044] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 01/03/2019] [Accepted: 07/15/2019] [Indexed: 12/20/2022] Open
Abstract
Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via S1P receptor 1 (S1PR1) signaling, and it controls the differentiation of regulatory T cells (Tregs) and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1-mediated intracellular S1P levels modulate T cell functionality remains unknown. We show here that SphK1-deficient T cells maintain central memory phenotype and exhibit higher mitochondrial respiration and reduced differentiation to Tregs. Mechanistically, we discovered a direct correlation between SphK1-generated S1P and lipid transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) activity, which in turn regulates lipolysis in T cells. Genetic and pharmacologic inhibition of SphK1 improved metabolic fitness and anti-tumor activity of T cells against murine melanoma. Further, inhibition of SphK1 and PD1 together led to improved control of melanoma. Overall, these data highlight the clinical potential of limiting SphK1/S1P signaling for enhancing anti-tumor-adoptive T cell therapy.
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32
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Takahashi K, Fujiya M, Konishi H, Murakami Y, Iwama T, Sasaki T, Kunogi T, Sakatani A, Ando K, Ueno N, Kashima S, Moriichi K, Tanabe H, Okumura T. Heterogenous Nuclear Ribonucleoprotein H1 Promotes Colorectal Cancer Progression through the Stabilization of mRNA of Sphingosine-1-Phosphate Lyase 1. Int J Mol Sci 2020; 21:4514. [PMID: 32630435 PMCID: PMC7350029 DOI: 10.3390/ijms21124514] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/18/2020] [Accepted: 06/23/2020] [Indexed: 12/31/2022] Open
Abstract
The oncogenic properties of heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) have been reported, although the tumor-promoting mechanism remains unclear. We herein report the mechanism underlying colorectal cancer cell progression mediated by hnRNP H1. The growth of colorectal cancer cells was suppressed by hnRNP H1 downregulation. A terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed the anti-apoptotic effect of hnRNP H1 in colorectal cancer cells. An RNA immunoprecipitation assay revealed that hnRNP H1 bound to sphingosine-1-phosphate lyase 1 (SGPL1). Reverse transcription-polymerase chain reaction revealed the high expression of hnRNP H1 mRNA in colorectal cancer cells and Spearman's rank correlation coefficient showed a strong positive correlation between hnRNP H1 mRNA and SGPL1 mRNA. An siRNA of hnRNP H1 decreased SGPL1 mRNA expression in colorectal cancer cells, but not in non-tumorous cells. These findings suggested that hnRNP H1 increased SGPL1 mRNA expression specifically in cancer cells through direct binding. Targeted knockdown of hnRNP H1 or SGPL1 with siRNAs upregulated p53 phosphorylation and p53-associated molecules, resulting in cell growth inhibition, while hnRNP H1 upregulated the mRNA of SGPL1 and inhibited p53 activation, thereby promoting tumor cell growth. This is a novel mechanism underlying colorectal cancer cell progression mediated by hnRNP H1-SGPL1 mRNA stabilization.
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Affiliation(s)
- Keitaro Takahashi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Mikihiro Fujiya
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan;
| | - Hiroaki Konishi
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan;
| | - Yuki Murakami
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Takuya Iwama
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Takahiro Sasaki
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Takehito Kunogi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Aki Sakatani
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
- Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago, 900 East 57th Street, 9th floor, Chicago, IL 60637, USA
| | - Katsuyoshi Ando
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Nobuhiro Ueno
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Shin Kashima
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Kentaro Moriichi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Hiroki Tanabe
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan; (K.T.); (Y.M.); (T.I.); (T.S.); (T.K.); (A.S.); (K.A.); (N.U.); (S.K.); (K.M.); (H.T.); (T.O.)
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Roy S, Mahapatra AD, Mohammad T, Gupta P, Alajmi MF, Hussain A, Rehman MT, Datta B, Hassan MI. Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1. Pharmaceuticals (Basel) 2020; 13:E118. [PMID: 32526899 PMCID: PMC7346089 DOI: 10.3390/ph13060118] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 05/30/2020] [Accepted: 06/01/2020] [Indexed: 12/17/2022] Open
Abstract
Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC50 values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation.
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Affiliation(s)
- Sonam Roy
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; (S.R.); (T.M.); (P.G.)
| | - Amarjyoti Das Mahapatra
- Department of Chemistry, Indian Institute of Technology, Palaj, Gandhinagar, Gujarat 382355, India;
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; (S.R.); (T.M.); (P.G.)
| | - Preeti Gupta
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; (S.R.); (T.M.); (P.G.)
| | - Mohamed F. Alajmi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.F.A.); (A.H.); (M.T.R.)
| | - Afzal Hussain
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.F.A.); (A.H.); (M.T.R.)
| | - Md. Tabish Rehman
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.F.A.); (A.H.); (M.T.R.)
| | - Bhaskar Datta
- Department of Chemistry, Indian Institute of Technology, Palaj, Gandhinagar, Gujarat 382355, India;
| | - Md. Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; (S.R.); (T.M.); (P.G.)
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34
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Sun H, Zhou Y, Skaro MF, Wu Y, Qu Z, Mao F, Zhao S, Xu Y. Metabolic Reprogramming in Cancer Is Induced to Increase Proton Production. Cancer Res 2020; 80:1143-1155. [PMID: 31932456 DOI: 10.1158/0008-5472.can-19-3392] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 12/05/2019] [Accepted: 01/09/2020] [Indexed: 11/16/2022]
Abstract
Considerable metabolic reprogramming has been observed in a conserved manner across multiple cancer types, but their true causes remain elusive. We present an analysis of around 50 such reprogrammed metabolisms (RM) including the Warburg effect, nucleotide de novo synthesis, and sialic acid biosynthesis in cancer. Analyses of the biochemical reactions conducted by these RMs, coupled with gene expression data of their catalyzing enzymes, in 7,011 tissues of 14 cancer types, revealed that all RMs produce more H+ than their original metabolisms. These data strongly support a model that these RMs are induced or selected to neutralize a persistent intracellular alkaline stress due to chronic inflammation and local iron overload. To sustain these RMs for survival, cells must find metabolic exits for the nonproton products of these RMs in a continuous manner, some of which pose major challenges, such as nucleotides and sialic acids, because they are electrically charged. This analysis strongly suggests that continuous cell division and other cancerous behaviors are ways for the affected cells to remove such products in a timely and sustained manner. As supporting evidence, this model can offer simple and natural explanations to a range of long-standing open questions in cancer research including the cause of the Warburg effect. SIGNIFICANCE: Inhibiting acidifying metabolic reprogramming could be a novel strategy for treating cancer.
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Affiliation(s)
- Huiyan Sun
- Cancer Systems Biology Center, The China-Japan Union Hospital, Jilin University, Changchun, China
- School of Artificial Intelligence, Jilin University, Changchun, China
- Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, Georgia
| | - Yi Zhou
- Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, Georgia
| | - Michael Francis Skaro
- Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, Georgia
| | - Yiran Wu
- iHuman Institute, Shanghai Tech University, Shanghai, China
| | - Zexing Qu
- Cancer Systems Biology Center, The China-Japan Union Hospital, Jilin University, Changchun, China
- College of Chemistry, Jilin University, Changchun, China
| | - Fenglou Mao
- Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, Georgia
| | - Suwen Zhao
- iHuman Institute, Shanghai Tech University, Shanghai, China
| | - Ying Xu
- Cancer Systems Biology Center, The China-Japan Union Hospital, Jilin University, Changchun, China.
- School of Artificial Intelligence, Jilin University, Changchun, China
- Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, Georgia
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35
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Jeon S, Song J, Lee D, Kim GT, Park SH, Shin DY, Shin KO, Park K, Shim SM, Park TS. Inhibition of sphingosine 1-phosphate lyase activates human keratinocyte differentiation and attenuates psoriasis in mice. J Lipid Res 2020; 61:20-32. [PMID: 31690639 PMCID: PMC6939600 DOI: 10.1194/jlr.ra119000254] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 10/29/2019] [Indexed: 11/20/2022] Open
Abstract
Sphingosine 1-phosphate (S1P) lyase is an intracellular enzyme that catalyzes the irreversible degradation of S1P and has been suggested as a therapeutic target for the treatment of psoriasis vulgaris. Because S1P induces differentiation of keratinocytes, we examined whether modulation of S1P lyase and altered intracellular S1P levels regulate proliferation and differentiation of human neonatal epidermal keratinocyte (HEKn) cells. To identify the physiological functions of S1P lyase in skin, we inhibited S1P lyase in HEKn cells with an S1P lyase-specific inhibitor (SLI) and with S1P lyase 1 (SGPL1)-specific siRNA (siSGPL1). In HEKn cells, pharmacological treatment with the SLI caused G1 arrest by upregulation of p21 and p27 and induced keratin 1, an early differentiation marker. Similarly, genetic suppression by siSGPL1 arrested the cell cycle at the G1 phase and activated differentiation. In addition, enzyme suppression by siSGPL1 upregulated keratin 1 and differentiation markers including involucrin and loricrin. When hyperproliferation of HEKn cells was induced by interleukin (IL)-17 and IL-22, pharmacologic inhibition of S1P lyase by SLI decreased proliferation and activated differentiation of HEKn cells simultaneously. In addition, SLI administration ameliorated imiquimod-induced psoriatic symptoms including erythema, scaling, and epidermal thickness in vivo. We thus demonstrated that S1P lyase inhibition reduces cell proliferation and induces keratinocyte differentiation, and that inhibition may attenuate psoriasiform changes. Collectively, these findings suggest that S1P lyase is a modulating factor for proliferation and differentiation, and support its potential as a therapeutic target for psoriasis in human keratinocytes.
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Affiliation(s)
- Suwon Jeon
- Department of Life Science, Gachon University, Sungnam 13120, Republic of Korea
| | - Jaehwi Song
- Department of Life Science, Gachon University, Sungnam 13120, Republic of Korea
| | - Dongyup Lee
- Department of Life Science, Gachon University, Sungnam 13120, Republic of Korea
| | - Goon-Tae Kim
- Department of Life Science, Gachon University, Sungnam 13120, Republic of Korea
| | - Si-Hyun Park
- Department of Life Science, Gachon University, Sungnam 13120, Republic of Korea
| | - Dong-Yoon Shin
- College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Kyong-Oh Shin
- Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Republic of Korea
| | - Kyungho Park
- Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Republic of Korea
| | - Soon-Mi Shim
- Department of Food Science and Technology, Sejong University, Seoul 05006, Republic of Korea.
| | - Tae-Sik Park
- Department of Life Science, Gachon University, Sungnam 13120, Republic of Korea.
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36
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Gupta P, Mohammad T, Dahiya R, Roy S, Noman OMA, Alajmi MF, Hussain A, Hassan MI. Evaluation of binding and inhibition mechanism of dietary phytochemicals with sphingosine kinase 1: Towards targeted anticancer therapy. Sci Rep 2019; 9:18727. [PMID: 31822735 PMCID: PMC6904568 DOI: 10.1038/s41598-019-55199-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 11/08/2019] [Indexed: 12/13/2022] Open
Abstract
Sphingosine kinase 1 (SphK1) has recently gained attention as a potential drug target for its association with cancer and other inflammatory diseases. Here, we have investigated the binding affinity of dietary phytochemicals viz., ursolic acid, capsaicin, DL-α tocopherol acetate, quercetin, vanillin, citral, limonin and simvastatin with the SphK1. Docking studies revealed that all these compounds bind to the SphK1 with varying affinities. Fluorescence binding and isothermal titration calorimetric measurements suggested that quercetin and capsaicin bind to SphK1 with an excellent affinity, and significantly inhibits its activity with an admirable IC50 values. The binding mechanism of quercetin was assessed by docking and molecular dynamics simulation studies for 100 ns in detail. We found that quercetin acts as a lipid substrate competitive inhibitor, and it interacts with important residues of active-site pocket through hydrogen bonds and other non-covalent interactions. Quercetin forms a stable complex with SphK1 without inducing any significant conformational changes in the protein structure. In conclusion, we infer that quercetin and capsaicin provide a chemical scaffold to develop potent and selective inhibitors of SphK1 after required modifications for the clinical management of cancer.
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Affiliation(s)
- Preeti Gupta
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Rashmi Dahiya
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Sonam Roy
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Omar Mohammed Ali Noman
- Department of Pharmacognosy College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Mohamed F Alajmi
- Department of Pharmacognosy College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
| | - Afzal Hussain
- Department of Pharmacognosy College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
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37
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von Gerichten J, Lamprecht D, Opálka L, Soulard D, Marsching C, Pilz R, Sencio V, Herzer S, Galy B, Nordström V, Hopf C, Gröne HJ, Trottein F, Sandhoff R. Bacterial immunogenic α-galactosylceramide identified in the murine large intestine: dependency on diet and inflammation. J Lipid Res 2019; 60:1892-1904. [PMID: 31484693 DOI: 10.1194/jlr.ra119000236] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/22/2019] [Indexed: 12/22/2022] Open
Abstract
The glycosphingolipid, α-galactosylceramide (αGalCer), when presented by CD1d on antigen-presenting cells, efficiently activates invariant natural killer T (iNKT) cells. Thereby, it modulates immune responses against tumors, microbial and viral infections, and autoimmune diseases. Recently, the production of αGalCer by Bacteroidetes from the human gut microbiome was elucidated. Using hydrophilic interaction chromatography coupled to MS2, we screened murine intestinal tracts to identify and quantify αGalCers, and we investigated the αGalCer response to different dietary and physiologic conditions. In both the cecum and the colon of mice, we found 1-15 pmol of αGalCer per milligram of protein; in contrast, mice lacking microbiota (germ-free mice) and fed identical diet did not harbor αGalCer. The identified αGalCer contained a β(R)-hydroxylated hexadecanoyl chain N-linked to C18-sphinganine, which differed from what has been reported with Bacteroides fragilis Unlike β-anomeric structures, but similar to αGalCers from B. fragilis, the synthetic form of the murine αGalCer induced iNKT cell activation in vitro. Last, we observed a decrease in αGalCer production in mice exposed to conditions that alter the composition of the gut microbiota, including Western type diet, colitis, and influenza A virus infection. Collectively, this study suggests that αGalCer is produced by commensals in the mouse intestine and reveals that stressful conditions causing dysbiosis alter its synthesis. The consequences of this altered production on iNKT cell-mediated local and systemic immune responses are worthy of future studies.
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Affiliation(s)
- Johanna von Gerichten
- Lipid Pathobiochemistry Group, Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.,Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Dominic Lamprecht
- Lipid Pathobiochemistry Group, Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Lukáš Opálka
- Lipid Pathobiochemistry Group, Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.,Skin Barrier Research Group, Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Daphnée Soulard
- Centre d'Infection et d'Immunité de Lille, Inserm U1019, CNRS UMR 8204, University of Lille, CHU Lille, Institut Pasteur de Lille, Lille, France
| | - Christian Marsching
- Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences, Mannheim, Germany
| | - Robert Pilz
- Lipid Pathobiochemistry Group, Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.,Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Valentin Sencio
- Centre d'Infection et d'Immunité de Lille, Inserm U1019, CNRS UMR 8204, University of Lille, CHU Lille, Institut Pasteur de Lille, Lille, France
| | - Silke Herzer
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Bruno Galy
- Division of Virus-Associated Carcinogenesis, German Cancer Research Center, Heidelberg, Germany
| | - Viola Nordström
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Carsten Hopf
- Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences, Mannheim, Germany
| | - Hermann-Josef Gröne
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.,Institute of Pharmacology, University of Marburg, Marburg, Germany
| | - François Trottein
- Centre d'Infection et d'Immunité de Lille, Inserm U1019, CNRS UMR 8204, University of Lille, CHU Lille, Institut Pasteur de Lille, Lille, France
| | - Roger Sandhoff
- Lipid Pathobiochemistry Group, Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
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Kumar S, Kushwaha PP, Gupta S. Emerging targets in cancer drug resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:161-177. [PMID: 35582722 PMCID: PMC8992633 DOI: 10.20517/cdr.2018.27] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 03/08/2019] [Accepted: 03/14/2019] [Indexed: 02/05/2023]
Abstract
Drug resistance is a complex phenomenon that frequently develops as a failure to chemotherapy during cancer treatment. Malignant cells increasingly generate resistance to various chemotherapeutic drugs through distinct mechanisms and pathways. Understanding the molecular mechanisms involved in drug resistance remains an important area of research for identification of precise targets and drug discovery to improve therapeutic outcomes. This review highlights the role of some recent emerging targets and pathways which play critical role in driving drug resistance.
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Affiliation(s)
- Shashank Kumar
- School of Basic and Applied Sciences, Department of Biochemistry and Microbial Sciences, Central University of Punjab, Bathinda 151001, India
| | - Prem Prakash Kushwaha
- School of Basic and Applied Sciences, Department of Biochemistry and Microbial Sciences, Central University of Punjab, Bathinda 151001, India
| | - Sanjay Gupta
- Department of Urology, Case Western Reserve University, Cleveland, Ohio 44106, USA
- The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106, USA
- Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA
- Divison of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA
- Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106, USA
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39
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Kiamehr M, Heiskanen L, Laufer T, Düsterloh A, Kahraman M, Käkelä R, Laaksonen R, Aalto-Setälä K. Dedifferentiation of Primary Hepatocytes is Accompanied with Reorganization of Lipid Metabolism Indicated by Altered Molecular Lipid and miRNA Profiles. Int J Mol Sci 2019; 20:ijms20122910. [PMID: 31207892 PMCID: PMC6627955 DOI: 10.3390/ijms20122910] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023] Open
Abstract
Aim: Primary human hepatocytes (PHHs) undergo dedifferentiation upon the two-dimensional (2D) culture, which particularly hinders their utility in long-term in vitro studies. Lipids, as a major class of biomolecules, play crucial roles in cellular energy storage, structure, and signaling. Here, for the first time, we mapped the alterations in the lipid profile of the dedifferentiating PHHs and studied the possible role of lipids in the loss of the phenotype of PHHs. Simultaneously, differentially expressed miRNAs associated with changes in the lipids and fatty acids (FAs) of the dedifferentiating PHHs were investigated. Methods: PHHs were cultured in monolayer and their phenotype was monitored morphologically, genetically, and biochemically for five days. The lipid and miRNA profile of the PHHs were analyzed by mass spectrometry and Agilent microarray, respectively. In addition, 24 key genes involved in the metabolism of lipids and FAs were investigated by qPCR. Results: The typical morphology of PHHs was lost from day 3 onward. Additionally, ALB and CYP genes were downregulated in the cultured PHHs. Lipidomics revealed a clear increase in the saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) containing lipids, but a decrease in the polyunsaturated fatty acids (PUFA) containing lipids during the dedifferentiation of PHHs. In line with this, FASN, SCD, ELOVL1, ELOVL3, and ELOVL7 were upregulated but ELOVL2 was downregulated in the dedifferentiated PHHs. Furthermore, differentially expressed miRNAs were identified, and the constantly upregulated miR-27a and miR-21, and downregulated miR-30 may have regulated the synthesis, accumulation and secretion of PHH lipids during the dedifferentiation. Conclusion: Our results showed major alterations in the molecular lipid species profiles, lipid-metabolizing enzyme expression as wells as miRNA profiles of the PHHs during their prolonged culture, which in concert could play important roles in the PHHs’ loss of phenotype. These findings promote the understanding from the dedifferentiation process and could help in developing optimal culture conditions, which better meet the needs of the PHHs and support their original phenotype.
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Affiliation(s)
- Mostafa Kiamehr
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.
| | | | - Thomas Laufer
- Hummingbird Diagnostics GmbH, 69120 Heidelberg, Germany.
- Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
| | | | - Mustafa Kahraman
- Hummingbird Diagnostics GmbH, 69120 Heidelberg, Germany.
- Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany.
| | - Reijo Käkelä
- Helsinki University Lipidomics Unit, Helsinki Institute for Life Science (HiLIFE) and Molecular and Integrative Biosciences Research Programme, University of Helsinki, FI-00014 Helsinki, Finland.
| | - Reijo Laaksonen
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.
- Zora Biosciences, 02150 Espoo, Finland.
| | - Katriina Aalto-Setälä
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.
- Heart Hospital, Tampere University Hospital, 33520 Tampere, Finland.
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40
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Resveratrol Action on Lipid Metabolism in Cancer. Int J Mol Sci 2019; 20:ijms20112704. [PMID: 31159437 PMCID: PMC6601040 DOI: 10.3390/ijms20112704] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 05/27/2019] [Accepted: 05/28/2019] [Indexed: 12/12/2022] Open
Abstract
Cancer diseases have the leading position in human mortality nowadays. The age of oncologic patients is still decreasing, and the entire scientific society is eager for new ways to fight against cancer. One of the most discussed issues is prevention by means of natural substances. Resveratrol is a naturally occurring plant polyphenol with proven antioxidant, anti-inflammatory, and anticancer effects. Tumor cells display specific changes in the metabolism of various lipids. Resveratrol alters lipid metabolism in cancer, thereby affecting storage of energy, cell signaling, proliferation, progression, and invasiveness of cancer cells. At the whole organism level, it contributes to the optimal metabolism extent with respect to the demands of the organism. Thus, resveratrol could be used as a preventive and anticancer agent. In this review, we focus on some of the plethora of lipid pathways and signal molecules which are affected by resveratrol during carcinogenesis.
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Hu SJ, Jiang SS, Zhang J, Luo D, Yu B, Yang LY, Zhong HH, Yang MW, Liu LY, Hong FF, Yang SL. Effects of apoptosis on liver aging. World J Clin Cases 2019; 7:691-704. [PMID: 30968034 PMCID: PMC6448073 DOI: 10.12998/wjcc.v7.i6.691] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/10/2019] [Accepted: 01/26/2019] [Indexed: 02/05/2023] Open
Abstract
As an irreversible and perennial process, aging is accompanied by functional and morphological declines in organs. Generally, aging liver exhibits a decline in volume and hepatic blood flow. Even with a preeminent regenerative capacity to restore its functions after liver cell loss, its biosynthesis and metabolism abilities decline, and these are difficult to restore to previous standards. Apoptosis is a programmed death process via intrinsic and extrinsic pathways, in which Bcl-2 family proteins and apoptosis-related genes, such as p21 and p53, are involved. Apoptosis inflicts both favorable and adverse influences on liver aging. Apoptosis eliminates transformed abnormal cells but promotes age-related liver diseases, such as nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, and liver cancer. We summarize the roles of apoptosis in liver aging and age-related liver diseases.
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Affiliation(s)
- Shao-Jie Hu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Sha-Sha Jiang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jin Zhang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Dan Luo
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Bo Yu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Liang-Yan Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hua-Hua Zhong
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Mei-Wen Yang
- Department of Nurse, Nanchang University Hospital, Nanchang 330006, Jiangxi Province, China
| | - Li-Yu Liu
- Department of Nurse, Nanchang University Hospital, Nanchang 330006, Jiangxi Province, China
| | - Fen-Fang Hong
- Experimental Teaching Center, Nanchang University, Nanchang 330031, Jiangxi Province, China
| | - Shu-Long Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
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Xu J, Zhao W, Sun J, Huang Y, Wang P, Venkataramanan R, Yang D, Ma X, Rana A, Li S. Novel glucosylceramide synthase inhibitor based prodrug copolymer micelles for delivery of anticancer agents. J Control Release 2018; 288:212-226. [PMID: 30223045 PMCID: PMC6177216 DOI: 10.1016/j.jconrel.2018.09.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/07/2018] [Accepted: 09/12/2018] [Indexed: 01/04/2023]
Abstract
In order to improve the efficacy of chemotherapy for cancers, we have developed a novel prodrug micellar formulation to co-deliver ceramide-generating anticancer agents and ceramide degradation inhibitor (PPMP). The prodrug nanocarrier is based on a well-defined POEG-b-PPPMP diblock copolymer. The hydrophilic block of POEG-b-PPPMP is POEG, and the hydrophobic block is composed of a number of PPMP units, which could work synergistically with loaded anticancer drugs. POEG-b-PPPMP was readily synthesized via a one-step reversible addition-fragment transfer (RAFT) polymerization from a PPMP monomer. The newly synthesized polymers were self-assembled into micelles and served as a carrier for several hydrophobic anticancer drugs including DOX, PTX and C6-ceramide. POEG-b-PPPMP prodrug polymer exhibited intrinsic antitumor activity in vitro and in vivo. In addition, POEG-b-PPPMP prodrug polymer was comparable to free PPMP in selectively enhancing the production of pro-apoptotic ceramide species as well as down-regulating the mRNA expression of GCS. DOX-loaded POEG-b-PPPMP micelles exhibited an excellent stability of 42 days at 4 °C. Moreover, DOX loaded in POEG-b-PPPMP micelles showed higher levels of cytotoxicity than DOX loaded in a pharmacologically inert polymer (POEG-b-POM) and Doxil formulation in several tumor cell lines. Consistently, in a 4T1.2 murine breast cancer model, the tumor inhibition followed the order of DOX/POEG-b-PPPMP > DOX/POEG-b-POM ≥ Doxil > POEG-b-PPPMP > POEG-b-POM. Our data suggest that POEG-b-PPPMP micelles are a promising dual-functional carrier that warrants more studies in the future.
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Affiliation(s)
- Jieni Xu
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Whenchen Zhao
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jingjing Sun
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yixian Huang
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Pengcheng Wang
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Da Yang
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Xiaochao Ma
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Ajay Rana
- Department of Surgery/Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Song Li
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Zheng X, Li W, Ren L, Liu J, Pang X, Chen X, Kang D, Wang J, Du G. The sphingosine kinase-1/sphingosine-1-phosphate axis in cancer: Potential target for anticancer therapy. Pharmacol Ther 2018; 195:85-99. [PMID: 30347210 DOI: 10.1016/j.pharmthera.2018.10.011] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Sphingolipid metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate (S1P), play many important roles in cellular activities. Ceramide and sphingosine inhibit cell proliferation and induce cell apoptosis while S1P has the opposite effect. Maintaining a metabolic balance of sphingolipids is essential for growth and development of cells. Sphingosine kinase (SPHK) is an important regulator for keeping this balance. It controls the level of S1P and plays important roles in proliferation, migration, and invasion of cancer cells and tumor angiogenesis. There are two isoenzymes of sphingosine kinase, SPHK1 and SPHK2. SPHK1 is ubiquitously expressed in most cancers where it promotes survival and proliferation, while SPHK2 is restricted to only certain tissues and its functions are not well characterized. SPHK1 is currently considered as a novel target for the treatment of cancers. Targeting SPHK1 would provide new strategies for cancer treatment and improve the prognosis of cancer patients. Here we review and summarize the current research findings on the SPHK1-S1P axis in cancer from many aspects including structure, expression, regulation, mechanism, and potential inhibitors.
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Affiliation(s)
- Xiangjin Zheng
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Wan Li
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Liwen Ren
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Jinyi Liu
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Xiaocong Pang
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Xiuping Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - De Kang
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Jinhua Wang
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
| | - Guanhua Du
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
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Dei Cas M, Ghidoni R. Cancer Prevention and Therapy with Polyphenols: Sphingolipid-Mediated Mechanisms. Nutrients 2018; 10:nu10070940. [PMID: 30037082 PMCID: PMC6073226 DOI: 10.3390/nu10070940] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/18/2018] [Accepted: 07/19/2018] [Indexed: 12/12/2022] Open
Abstract
Polyphenols, chemically characterized by a polyhydroxylated phenolic structure, are well known for their widespread pharmacological properties: anti-inflammatory, antibiotic, antiseptic, antitumor, antiallergic, cardioprotective and others. Their distribution in food products is also extensive especially in plant foods such as vegetables, cereals, legumes, fruits, nuts and certain beverages. The latest scientific literature outlines a resilient interconnection between cancer modulation and dietary polyphenols by sphingolipid-mediated mechanisms, usually correlated with a modification of their metabolism. We aim to extensively survey this relationship to show how it could be advantageous in cancer treatment or prevention by nutrients. From this analysis it emerges that a combination of classical chemotherapy with nutrients and especially with polyphenols dietary sources may improve efficacy and decreases negative side effects of the antineoplastic drug. In this multifaceted scenario, sphingolipids play a pivotal role as bioactive molecules, emerging as the mediators of cell proliferation in cancer and modulator of chemotherapeutics.
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Affiliation(s)
- Michele Dei Cas
- Department of Health Sciences, University of Milan, 20142 Milan, Italy.
| | - Riccardo Ghidoni
- Department of Health Sciences, University of Milan, 20142 Milan, Italy.
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Xia F, Li A, Chai Y, Xiao X, Wan J, Li P, Wang Y. UPLC/Q-TOFMS-Based Metabolomics Approach to Reveal the Protective Role of Other Herbs in An-Gong-Niu-Huang Wan Against the Hepatorenal Toxicity of Cinnabar and Realgar. Front Pharmacol 2018; 9:618. [PMID: 29950994 PMCID: PMC6008407 DOI: 10.3389/fphar.2018.00618] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 05/23/2018] [Indexed: 01/26/2023] Open
Abstract
An-Gong-Niu-Huang Wan (AGNH) is a well-known traditional Chinese medicine (TCM) recipe containing cinnabar (HgS) and realgar (As2S2). However, the application of AGNH is limited by the hepato- and nephrotoxicity of cinnabar and realgar. It should be noted that cinnabar and realgar in AGNH are not used alone, but rather combined with other herbs as formula to use. In this study, the protective effects and mechanisms of the other herbs in AGNH against the hepatorenal toxicity induced by cinnabar and realgar were investigated. The combination use of the other herbs in AGNH alleviated inflammatory cell infiltration and damage in the liver and kidney and restored the disturbed serum metabolic profile induced by cinnabar and realgar insults. By UPLC/Q-TOFMS combined with pattern recognition approaches, we identified 41 endogenous metabolites in the sera of mice that were related to the hepatorenal toxicity of cinnabar and realgar, 36 of which were restored to normal levels when various kinds of herbs were combined as compound recipe. These metabolites function as modulators in inflammation-associated glycerophospholipid, arachidonic acid, linoleic acid, sphingolipid, and ether lipid metabolic pathways. Notably, lysophosphatidylcholines (LysoPCs) were the most elevated among all of the metabolites detected after cinnabar and realgar treatment, while these LysoPCs did not show overt differences between the AGNH and saline control groups, which was associated with relatively unaffected or even up-regulated expression of lysophosphatidylcholine acyltransferase 1 (LPCAT1) and autotaxin (ATX). These findings indicated that other herbs in AGNH could have a protective effect against cinnabar- and realgar-induced hepatic and renal damage via modulating the disordered homeostasis of the glycerophospholipid, arachidonic acid, linoleic acid, ether lipid, and sphingolipid metabolism.
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Affiliation(s)
- Fangbo Xia
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Ao Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.,College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Yushuang Chai
- Guangzhou Baiyunshan Zhongyi Pharmaceutical Co., Ltd., Guangzhou, China
| | - Xiao Xiao
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Jianbo Wan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Peng Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
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Sundaramoorthy P, Gasparetto C, Kang Y. The combination of a sphingosine kinase 2 inhibitor (ABC294640) and a Bcl-2 inhibitor (ABT-199) displays synergistic anti-myeloma effects in myeloma cells without a t(11;14) translocation. Cancer Med 2018; 7:3257-3268. [PMID: 29761903 PMCID: PMC6051232 DOI: 10.1002/cam4.1543] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 04/06/2018] [Accepted: 04/09/2018] [Indexed: 12/31/2022] Open
Abstract
Multiple myeloma (MM) remains an incurable disease in need of the development of novel therapeutic agents and drug combinations. ABT‐199 is a specific Bcl‐2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co‐expression of Mcl‐1 and Bcl‐xL. These limitations preclude its use in a broader patient population. We have recently found that a sphingosine kinase 2‐specific inhibitor (ABC294640) induces apoptosis in primary human CD138+ cells and MM cell lines. ABC294640 is currently in phase I/II clinical trials for myeloma (clinicaltrials.gov: #NCT01410981). Interestingly, ABC294640 down‐regulates c‐Myc and Mcl‐1, but does not have any effects on Bcl‐2. We first evaluated the combinatorial anti‐myeloma effect of ABC294640 and ABT‐199 in vitro in 7 MM cell lines, all of which harbor no t(11;14) translocation. Combination index calculation demonstrated a synergistic anti‐myeloma effect of the combination of ABC294640 and ABT‐199. This synergistic anti‐myeloma effect was maintained even in the presence of bone marrow (BM) stromal cells. The combination of ABC294640 and ABT‐199 led to enhanced cleavage of PARP and caspase‐3/9 and increased Annexin‐V expression, consistent with the induction of apoptosis by the combination treatment. In addition, the combination of ABC294640 and ABT‐199 resulted in the down‐regulation of the anti‐apoptotic proteins Mcl‐1, Bcl‐2, and Bcl‐xL and the cleavage of Bax and Bid. The combination induced both the mitochondrial mediated‐ and caspase‐mediated apoptosis pathways. Finally, the combination of ABC294640 and ABT‐199 resulted in augmented anti‐myeloma effect in vivo in a mouse xenograft model. These findings demonstrate that the co‐administration of ABC294640 and ABT‐199 exhibits synergistic anti‐myeloma activity in vitro and in vivo, providing justification for a clinical study of this novel combination in patients with relapsed/refractory multiple myeloma.
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Affiliation(s)
- Pasupathi Sundaramoorthy
- Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, USA
| | - Cristina Gasparetto
- Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, USA
| | - Yubin Kang
- Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, USA
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Knific T, Vouk K, Smrkolj Š, Prehn C, Adamski J, Rižner TL. Models including plasma levels of sphingomyelins and phosphatidylcholines as diagnostic and prognostic biomarkers of endometrial cancer. J Steroid Biochem Mol Biol 2018; 178:312-321. [PMID: 29360580 DOI: 10.1016/j.jsbmb.2018.01.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Accepted: 01/15/2018] [Indexed: 01/05/2023]
Abstract
In endometrial cancer, biomarkers for preoperative identification of patients with low risk for disease progression would enable stratification according to the extent of surgery needed, and would avoid the complications that can be associated with radical surgery. A panel of proteins, amino acids, enzymes, and miRNA has been investigated as potential biomarkers for endometrial cancer. At the time of the manuscript submission targeted metabolomics/lipidomics approaches have not been applied to biomarker research in endometrial cancer. Using electrospray ionization-tandem mass spectrometry we quantified 163 metabolites in 126 plasma samples (61 patients with endometrial cancer, 65 control patients). Three single phosphatidylcholines were identified with significantly decreased levels in patients with endometrial cancer. A diagnostic model was defined as the ratio between acylcarnitine C16 and phosphatidylcholine PCae C40:1, the ratio between proline and tyrosine, and the ratio between the two phosphatidylcholines PCaa C42:0 and PCae C44:5; which provided sensitivity of 85.25%, specificity of 69.23%, and AUC of 0.837. Addition of smoking status further improved the constructed diagnostic model (AUC = 0.855). The presence of the major prognostic factors of deep myometrial invasion and lymphovascular invasion were also associated with altered metabolite concentrations. A prognostic model for deep myometrial invasion included the ratio between two hydroxysphingomyelins SMOH C14:1 and SMOH C24:1, and the ratio between two phosphatidylcholines PCaa C40:2 and PCaa C42:6, which provided sensitivity of 81.25%, specificity of 86.36%, and AUC of 0.857. The model for lymphovascular invasion included the ratio between two phosphatidylcholines PCaa C34:4 and PCae C38:3, and the ratio between acylcarnitine C16:2 and phosphatidylcholine PCaa C38:1, which provided sensitivity of 88.89%, specificity of 84.31%, and AUC of 0.935.
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Affiliation(s)
- Tamara Knific
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000, Ljubljana, Slovenia
| | - Katja Vouk
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000, Ljubljana, Slovenia
| | - Špela Smrkolj
- University Medical Centre, Department of Obstetrics and Gynaecology, 1000 Ljubljana, Slovenia
| | - Cornelia Prehn
- Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Jerzy Adamski
- Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Lehrstuhl für Experimentelle Genetik, Technische Universität München, 85350 Freising, Weihenstephan, Germany; German Center for Diabetes Research (DZD), 85764 München, Neuherberg, Germany
| | - Tea Lanišnik Rižner
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000, Ljubljana, Slovenia.
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Rego A, Cooper KF, Snider J, Hannun YA, Costa V, Côrte-Real M, Chaves SR. Acetic acid induces Sch9p-dependent translocation of Isc1p from the endoplasmic reticulum into mitochondria. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:576-583. [PMID: 29496584 DOI: 10.1016/j.bbalip.2018.02.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 02/01/2018] [Accepted: 02/25/2018] [Indexed: 01/08/2023]
Abstract
Changes in sphingolipid metabolism have been linked to modulation of cell fate in both yeast and mammalian cells. We previously assessed the role of sphingolipids in cell death regulation using a well characterized yeast model of acetic acid-induced regulated cell death, finding that Isc1p, inositol phosphosphingolipid phospholipase C, plays a pro-death role in this process. Indeed, isc1∆ mutants exhibited a higher resistance to acetic acid associated with reduced mitochondrial alterations. Here, we show that Isc1p is regulated by Sch9p under acetic acid stress, since both single and double mutants lacking Isc1p or/and Sch9p have the same resistant phenotype, and SCH9 deletion leads to a higher retention of Isc1p in the endoplasmic reticulum upon acetic acid exposure. We also found that the higher resistance of all mutants correlates with higher levels of endogenous mitochondrial phosphorylated long chain bases (LCBPs), suggesting that changing the sphingolipid balance in favour of LCBPs in mitochondria results in increased survival to acetic acid. In conclusion, our results suggest that Sch9p pathways modulate acetic acid-induced cell death, through the regulation of Isc1p cellular distribution, thus affecting the sphingolipid balance that regulates cell fate.
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Affiliation(s)
- António Rego
- Departamento de Biologia, Centro de Biologia Molecular e Ambiental, Universidade do Minho, Braga, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Katrina F Cooper
- Department of Molecular Biology, Graduate School of Biological Sciences, Rowan University, Stratford, NJ 08084, USA
| | - Justin Snider
- Stony Brook Cancer Center, Stony Brook University, Health Science Center, Stony Brook, NY, USA
| | - Yusuf A Hannun
- Stony Brook Cancer Center, Stony Brook University, Health Science Center, Stony Brook, NY, USA
| | - Vítor Costa
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Departamento de Biologia Molecular, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Manuela Côrte-Real
- Departamento de Biologia, Centro de Biologia Molecular e Ambiental, Universidade do Minho, Braga, Portugal.
| | - Susana R Chaves
- Departamento de Biologia, Centro de Biologia Molecular e Ambiental, Universidade do Minho, Braga, Portugal
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Smith NJ, Fuller M, Saville JT, Cox TM. Reduced cerebral vascularization in experimental neuronopathic Gaucher disease. J Pathol 2018; 244:120-128. [PMID: 28981147 DOI: 10.1002/path.4992] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 08/15/2017] [Accepted: 09/12/2017] [Indexed: 11/10/2022]
Abstract
The glycosphingolipidosis, Gaucher disease, in which a range of neurological manifestations occur, results from a deficiency of acid β-glucocerebrosidase, with subsequent accumulation of β-glucocerebroside, its upstream substrates, and the non-acylated congener β-glucosylsphingosine. However, the mechanisms by which end-organ dysfunction arise are poorly understood. Here, we report strikingly diminished cerebral microvascular density in a murine model of disease, and provide a detailed analysis of the accompanying cerebral glycosphingolipidome in these animals, with marked elevations of β-glucosylsphingosine. Further in vitro studies confirmed a concentration-dependent impairment of endothelial cytokinesis upon exposure to quasi-pathological concentrations of β-glucosylsphingosine. These findings support a premise for pathogenic disruption of cerebral angiogenesis as an end-organ effect, with potential for therapeutic modulation in neuronopathic Gaucher disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Nicholas Jc Smith
- Department of Neurology and Clinical Neurophysiology, Women's and Children's Health Network, Adelaide, South Australia, Australia.,School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.,Department of Medicine, University of Cambridge, Cambridge, UK
| | - Maria Fuller
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.,Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, Adelaide, South Australia, Australia
| | - Jennifer T Saville
- Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, Adelaide, South Australia, Australia
| | - Timothy M Cox
- Department of Medicine, University of Cambridge, Cambridge, UK
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Srihari S, Kwong R, Tran K, Simpson R, Tattam P, Smith E. Metabolic deregulation in prostate cancer. Mol Omics 2018; 14:320-329. [DOI: 10.1039/c8mo00170g] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Using RNAseq data from prostate cancer tissues we identified up to six metabolic subtypes of prostate cancer that show distinct disease-free and/or metastasis-free survival.
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Affiliation(s)
| | - Ray Kwong
- MaxwellPlus+
- Fortitude Valley
- Australia
| | - Khoa Tran
- MaxwellPlus+
- Fortitude Valley
- Australia
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