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Nishida S, Konno T, Kohno T, Ohyanagi M, Nakano M, Ohwada K, Obata K, Kakuki T, Kakiuchi A, Kurose M, Takano K, Kojima T. Treatment with TNFα and lipolysis-stimulated lipoprotein receptor (LSR) antibody in the presence of HDAC inhibitors promotes apoptosis in human salivary duct adenocarcinoma. Tissue Barriers 2024:2437215. [PMID: 39676759 DOI: 10.1080/21688370.2024.2437215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/25/2024] [Accepted: 11/27/2024] [Indexed: 12/17/2024] Open
Abstract
Lipolysis-stimulated lipoprotein receptor (LSR), a lipid metabolism-related factor localized in tricellular tight junctions (tTJs), plays an important role in maintaining the epithelial homeostasis. LSR is highly expressed in well-differentiated cancers, and its expression decreases during malignancy. The LSR antibody inhibits cell growth and promotes apoptosis in some cancers. Histone deacetylases (HDACs) are thought to play a crucial role in carcinogenesis, and HDAC inhibitors promote differentiation and prevent cell proliferation and migration in cancers. HDAC inhibitors together with TNFα also induce apoptosis via TNFα-related apoptosis-inducing ligand (TRAIL) in some cancers. In this study, we investigated the apoptosis signaling induced by an anti-LSR antibody in human salivary duct adenocarcinoma (SDC) cell line A253, compared to TRAIL-induced apoptosis. A253 cells were treated with human recombinant TNFα with or without HDAC inhibitor trichostatin A (TSA) and quisinostat (JNJ-26481585). Treatment using TNFα with HDAC inhibitors markedly induced apoptosis in A253 cells and the anti-TNFα antibody prevented the induced apoptosis. A253 cells were treated with an antibody against the extracellular N-terminal domain of human LSR (LSR-N-ab) with or without HDAC inhibitors. Treatment with HDAC inhibitors induced LSR expression in the membranes of A253 cells. Treatment using LSR-N-ab with HDAC inhibitors markedly promoted apoptosis in A253 cells. The tricellular signaling pathway JNK inhibitor SP600125 and Hippo pathway MST1/2 inhibitor XMU-MP-1 prevented the apoptosis induced by treatment using TNFα or LSR-N-ab with HDAC inhibitors. Our findings indicated that treatment with TNFα or LSR-N-ab with HDAC inhibitors might be useful in the therapy for human SDC by enhancing apoptosis.
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Affiliation(s)
- Soshi Nishida
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takumi Konno
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takayuki Kohno
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiko Ohyanagi
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaya Nakano
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kizuku Ohwada
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kazufumi Obata
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takuya Kakuki
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akito Kakiuchi
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Makoto Kurose
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kenichi Takano
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takashi Kojima
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
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2
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Kawabata K, Takahashi T, Tanaka K, Kurokawa Y, Yamamoto K, Saito T, Momose K, Yamashita K, Makino T, Yokouchi T, Kawai K, Serada S, Fujimoto M, Nakajima K, Naka T, Eguchi H, Doki Y. Lipolysis-stimulated lipoprotein receptor promote lipid uptake and fatty acid oxidation in gastric cancer. Gastric Cancer 2024; 27:1258-1272. [PMID: 39294388 DOI: 10.1007/s10120-024-01552-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 09/02/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND Lipolysis-stimulated lipoprotein receptor (LSR), a lipid receptor, is associated with cancer progression. However, detailed effects on intracellular metabolism are unclear. We aimed to elucidate the mechanism of LSR-mediated lipid metabolism in gastric cancer. METHODS We investigated lipid metabolic changes induced by lipoprotein administration in gastric cancer cells and evaluated the significance of LSR expression and lipid droplets formation in gastric cancer patients. The efficacy of inhibiting β-oxidation in gastric cancer cells was also examined in vitro and vivo. RESULTS In gastric cancer cells, LSR promoted cellular uptake of lipoprotein and cell proliferation. Furthermore, the inhibition of LSR in gastric cancer cells expressing high levels of LSR counteracted both effects. Immunohistochemical analysis of human gastric cancer tissues showed that the increase in lipid droplets via LSR is a factor that influences prognosis. Lipidomics analysis of LSR-high-expressing gastric cancer cells revealed an increase in β-oxidation. Based on these results, we used etomoxir, a β-oxidation inhibitor, and found that it inhibited cell proliferation as well as the suppression of LSR. Similarly, in a mouse xenograft model of LSR-highly expressing gastric cancer cells, the tumor growth effect of high-fat diet feeding was counteracted by etomoxir, consistent with the Ki-67 labeling index. CONCLUSIONS We demonstrated that lipids are taken up into gastric cancer cells via LSR and cause an increase in β-oxidation, resulting in the promotion of cancer progression. Controlling LSR-mediated lipid metabolism may be a novel therapeutic strategy for gastric cancer.
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Affiliation(s)
- Kota Kawabata
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan.
| | - Koji Tanaka
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Kazuyoshi Yamamoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Takuro Saito
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Kota Momose
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Kotaro Yamashita
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Takashi Yokouchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Kunihiko Kawai
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Satoshi Serada
- Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Minoru Fujimoto
- Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Tetsuji Naka
- Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University School of Medicine, Yahaba, Japan
- Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan
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Otálora-Otálora BA, Payán-Gómez C, López-Rivera JJ, Pedroza-Aconcha NB, Aristizábal-Guzmán C, Isaza-Ruget MA, Álvarez-Moreno CA. Global transcriptomic network analysis of the crosstalk between microbiota and cancer-related cells in the oral-gut-lung axis. Front Cell Infect Microbiol 2024; 14:1425388. [PMID: 39228892 PMCID: PMC11368877 DOI: 10.3389/fcimb.2024.1425388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 07/15/2024] [Indexed: 09/05/2024] Open
Abstract
Background The diagnosis and treatment of lung, colon, and gastric cancer through the histologic characteristics and genomic biomarkers have not had a strong impact on the mortality rates of the top three global causes of death by cancer. Methods Twenty-five transcriptomic analyses (10 lung cancer, 10 gastric cancer, and 5 colon cancer datasets) followed our own bioinformatic pipeline based on the utilization of specialized libraries from the R language and DAVID´s gene enrichment analyses to identify a regulatory metafirm network of transcription factors and target genes common in every type of cancer, with experimental evidence that supports its relationship with the unlocking of cell phenotypic plasticity for the acquisition of the hallmarks of cancer during the tumoral process. The network's regulatory functional and signaling pathways might depend on the constant crosstalk with the microbiome network established in the oral-gut-lung axis. Results The global transcriptomic network analysis highlighted the impact of transcription factors (SOX4, TCF3, TEAD4, ETV4, and FOXM1) that might be related to stem cell programming and cancer progression through the regulation of the expression of genes, such as cancer-cell membrane receptors, that interact with several microorganisms, including human T-cell leukemia virus 1 (HTLV-1), the human papilloma virus (HPV), the Epstein-Barr virus (EBV), and SARS-CoV-2. These interactions can trigger the MAPK, non-canonical WNT, and IFN signaling pathways, which regulate key transcription factor overexpression during the establishment and progression of lung, colon, and gastric cancer, respectively, along with the formation of the microbiome network. Conclusion The global transcriptomic network analysis highlights the important interaction between key transcription factors in lung, colon, and gastric cancer, which regulates the expression of cancer-cell membrane receptors for the interaction with the microbiome network during the tumorigenic process.
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Affiliation(s)
| | - César Payán-Gómez
- Dirección Académica, Universidad Nacional de Colombia, Sede de La Paz, La Paz, Colombia
| | - Juan Javier López-Rivera
- Grupo de Investigación INPAC, Specialized Laboratory, Clinica Universitaria Colombia, Clínica Colsanitas S.A., Bogotá, Colombia
| | | | - Claudia Aristizábal-Guzmán
- Grupo de Investigación INPAC, Unidad de Investigación, Fundación Universitaria Sanitas, Bogotá, Colombia
| | - Mario Arturo Isaza-Ruget
- Keralty, Sanitas International Organization, Grupo de Investigación INPAC, Fundación Universitaria Sanitas, Bogotá, Colombia
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Massenet-Regad L, Poirot J, Jackson M, Hoffmann C, Amblard E, Onodi F, Bouhidel F, Djouadou M, Ouzaid I, Xylinas E, Medvedovic J, Soumelis V. Large-scale analysis of cell-cell communication reveals angiogenin-dependent tumor progression in clear cell renal cell carcinoma. iScience 2023; 26:108367. [PMID: 38025776 PMCID: PMC10663819 DOI: 10.1016/j.isci.2023.108367] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/25/2023] [Accepted: 10/26/2023] [Indexed: 12/01/2023] Open
Abstract
Cellular crosstalk in the tumor microenvironment (TME) is still largely uncharacterized, while it plays an essential role in shaping immunosuppression or anti-tumor response. Large-scale analyses are needed to better decipher cell-cell communication in cancer. In this work, we used original and publicly available single-cell RNA sequencing (scRNAseq) data to characterize in-depth the communication networks in human clear cell renal cell carcinoma (ccRCC). We identified 50 putative communication channels specifically used by cancer cells to interact with other cells, including two novel angiogenin-mediated interactions. Expression of angiogenin and its receptors was validated at the protein level in primary ccRCC. Mechanistically, angiogenin enhanced ccRCC cell line proliferation and down-regulated secretion of IL-6, IL-8, and MCP-1 proinflammatory molecules. This study provides novel biological insights into molecular mechanisms of ccRCC, and suggests angiogenin and its receptors as potential therapeutic targets in clear cell renal cancer.
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Affiliation(s)
- Lucile Massenet-Regad
- Université Paris Cité, INSERM, U976 HIPI, F-75010 Paris, France
- Université Paris-Saclay, F-91190 Saint Aubin, France
| | - Justine Poirot
- Université Paris Cité, INSERM, U976 HIPI, F-75010 Paris, France
- Université Paris-Saclay, F-91190 Saint Aubin, France
| | | | - Caroline Hoffmann
- INSERM U932, Department of Surgical Oncology, PSL University, Institut Curie, 75005 Paris, France
- Owkin France, 75010 Paris, France
| | - Elise Amblard
- Université Paris Cité, INSERM, U976 HIPI, F-75010 Paris, France
- CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble Alpes University, 38000 Grenoble, France
| | - Fanny Onodi
- Université Paris Cité, INSERM, U976 HIPI, F-75010 Paris, France
| | - Fatiha Bouhidel
- Department of Pathology, Saint-Louis Hospital, AP-HP.Nord, Université Paris Cité, 75010 Paris, France
| | - Malika Djouadou
- Department of Urology, Saint-Louis Hospital, AP-HP.Nord, Université Paris Cité, 75010 Paris, France
| | - Idir Ouzaid
- Department of Urology, Bichat-Claude Bernard Hospital, AP-HP.Nord, Université Paris Cité, 75018 Paris, France
| | - Evanguelos Xylinas
- Université Paris Cité, INSERM, U976 HIPI, F-75010 Paris, France
- Department of Urology, Bichat-Claude Bernard Hospital, AP-HP.Nord, Université Paris Cité, 75018 Paris, France
| | | | - Vassili Soumelis
- Université Paris Cité, INSERM, U976 HIPI, F-75010 Paris, France
- Owkin France, 75010 Paris, France
- Department of Immunology-Histocompatibility, Saint-Louis Hospital, AP-HP.Nord, Université Paris Cité, 75010 Paris, France
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Saito K, Konno T, Kohno T, Shimada H, Matsuura M, Okada T, Kura A, Ishii D, Kondoh M, Saito T, Kojima T. LSR antibody promotes apoptosis and disrupts epithelial barriers via signal pathways in endometrial cancer. Tissue Barriers 2022:2106113. [PMID: 35883247 PMCID: PMC10364657 DOI: 10.1080/21688370.2022.2106113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Lipolysis-stimulated lipoprotein receptor (LSR), a lipid metabolism-related factor localized in tricellular tight junctions (tTJs), plays an important role in maintaining the epithelial barrier. LSR is highly expressed in well-differentiated endometrial endometrioid carcinoma (EEC), and its expression decreases during malignancy. Angubindin-1, a novel LSR ligand peptide, regulates tTJs without cytotoxicity, enhances paracellular permeability, and regulates epithelial barrier via c-Jun N-terminal kinase (JNK)/cofilin. In this study, we investigated the immune-modulatory roles of an anti-LSR antibody in the treatment of EEC in vitro compared to those of angubindin-1. We prepared an antibody against the extracellular N-terminal domain of human LSR (LSR-N-ab) and angubindin-1. EEC cell-line Sawano cells in 2D and 2.5D cultures were treated with 100 μg/ml LSR-N-ab or 2.5 μg/ml angubindin-1 with or without protein tyrosine kinase 2β inhibitor PF431396 (PF43) and JNK inhibitor SP600125 (SP60) at 10 μM. Treatment with LSR-N-ab and angubindin-1 decreased LSR at the membranes of tTJs and the activity of phosphorylated LSR and phosphorylated cofilin in 2D culture. Treatment with LSR-N-ab and angubindin-1 decreased the epithelial barrier measured as TEER values in 2D culture and enhanced the epithelial permeability of FD-4 in 2.5D culture. Treatment with LSR-N-ab, but not angubindin-1, induced apoptosis in 2D culture. Pretreatment with PF43 and SP60 prevented all the changes induced by treatment with LSR-N-ab and angubindin-1. Treatment with LSR-N-ab and angubindin-1 enhanced the cell metabolism measured as the mitochondrial respiration levels in 2D culture. LSR-N-ab and angubindin-1 may be useful for therapy of human EEC via enhanced apoptosis or drug absorption.
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Affiliation(s)
- Kimihito Saito
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takumi Konno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takayuki Kohno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Shimada
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Motoki Matsuura
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tadahi Okada
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Arisa Kura
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Daichi Ishii
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masuo Kondoh
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Tsuyoshi Saito
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takashi Kojima
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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