SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration
BackgroundIn response to hypoxia, tumor cells undergo transcriptional reprogramming including upregulation of carbonic anhydrase (CA) IX, a metalloenzyme that maintains acid-base balance. CAIX overexpression has been shown to correlate with poor prognosis in various cancers, but the role of this CA...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1118268/full |
| _version_ | 1828053715720863744 |
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| author | Katja Eloranta Marjut Pihlajoki Emmi Liljeström Ruth Nousiainen Tea Soini Jouko Lohi Stefano Cairo Stefano Cairo Stefano Cairo David B. Wilson David B. Wilson Seppo Parkkila Seppo Parkkila Seppo Parkkila Markku Heikinheimo Markku Heikinheimo Markku Heikinheimo |
| author_facet | Katja Eloranta Marjut Pihlajoki Emmi Liljeström Ruth Nousiainen Tea Soini Jouko Lohi Stefano Cairo Stefano Cairo Stefano Cairo David B. Wilson David B. Wilson Seppo Parkkila Seppo Parkkila Seppo Parkkila Markku Heikinheimo Markku Heikinheimo Markku Heikinheimo |
| author_sort | Katja Eloranta |
| collection | DOAJ |
| description | BackgroundIn response to hypoxia, tumor cells undergo transcriptional reprogramming including upregulation of carbonic anhydrase (CA) IX, a metalloenzyme that maintains acid-base balance. CAIX overexpression has been shown to correlate with poor prognosis in various cancers, but the role of this CA isoform in hepatoblastoma (HB) has not been examined.MethodsWe surveyed the expression of CAIX in HB specimens and assessed the impact of SLC-0111, a CAIX inhibitor, on cultured HB cells in normoxic and hypoxic conditions.ResultsCAIX immunoreactivity was detected in 15 out of 21 archival pathology HB specimens. The CAIX-positive cells clustered in the middle of viable tumor tissue or next to necrotic areas. Tissue expression of CAIX mRNA was associated with metastasis and poor clinical outcome of HB. Hypoxia induced a striking upregulation of CAIX mRNA and protein in three HB cell models: the immortalized human HB cell line HUH6 and patient xenograft-derived lines HB-295 and HB-303. Administration of SLC-0111 abrogated the hypoxia-induced upregulation of CAIX and decreased HB cell viability, both in monolayer and spheroid cultures. In addition, SLC-0111 reduced HB cell motility in a wound healing assay. Transcriptomic changes triggered by SLC-0111 administration differed under normoxic vs. hypoxic conditions, although SLC-0111 elicited upregulation of several tumor suppressor genes under both conditions.ConclusionHypoxia induces CAIX expression in HB cells, and the CAIX inhibitor SLC-0111 has in vitro activity against these malignant cells. |
| first_indexed | 2024-04-10T20:12:04Z |
| format | Article |
| id | doaj.art-27559198441c48d5a3bbac36626af92e |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T20:12:04Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-27559198441c48d5a3bbac36626af92e2023-01-26T10:16:06ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-01-011310.3389/fonc.2023.11182681118268SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migrationKatja Eloranta0Marjut Pihlajoki1Emmi Liljeström2Ruth Nousiainen3Tea Soini4Jouko Lohi5Stefano Cairo6Stefano Cairo7Stefano Cairo8David B. Wilson9David B. Wilson10Seppo Parkkila11Seppo Parkkila12Seppo Parkkila13Markku Heikinheimo14Markku Heikinheimo15Markku Heikinheimo16Pediatric Research Center, Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, FinlandPediatric Research Center, Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, FinlandPediatric Research Center, Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, FinlandPediatric Research Center, Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, FinlandPediatric Research Center, Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, FinlandDepartment of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, FinlandXentech, Evry, Evry, FranceIstituto di Ricerca Pediatrica, Padova, ItalyChampions Oncology, Hackensack, NJ, United StatesDepartment of Pediatrics, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, United StatesDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United StatesFaculty of Medicine and Health Technology, Tampere University, Tampere, FinlandFICAN Mid, Tampere University, Tampere, Finland0Fimlab Ltd, Tampere University Hospital, Tampere, FinlandPediatric Research Center, Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, FinlandDepartment of Pediatrics, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, United States1Faculty of Medicine and Health Technology, Center for Child, Adolescent, and Maternal Health Research, Tampere University, Tampere, FinlandBackgroundIn response to hypoxia, tumor cells undergo transcriptional reprogramming including upregulation of carbonic anhydrase (CA) IX, a metalloenzyme that maintains acid-base balance. CAIX overexpression has been shown to correlate with poor prognosis in various cancers, but the role of this CA isoform in hepatoblastoma (HB) has not been examined.MethodsWe surveyed the expression of CAIX in HB specimens and assessed the impact of SLC-0111, a CAIX inhibitor, on cultured HB cells in normoxic and hypoxic conditions.ResultsCAIX immunoreactivity was detected in 15 out of 21 archival pathology HB specimens. The CAIX-positive cells clustered in the middle of viable tumor tissue or next to necrotic areas. Tissue expression of CAIX mRNA was associated with metastasis and poor clinical outcome of HB. Hypoxia induced a striking upregulation of CAIX mRNA and protein in three HB cell models: the immortalized human HB cell line HUH6 and patient xenograft-derived lines HB-295 and HB-303. Administration of SLC-0111 abrogated the hypoxia-induced upregulation of CAIX and decreased HB cell viability, both in monolayer and spheroid cultures. In addition, SLC-0111 reduced HB cell motility in a wound healing assay. Transcriptomic changes triggered by SLC-0111 administration differed under normoxic vs. hypoxic conditions, although SLC-0111 elicited upregulation of several tumor suppressor genes under both conditions.ConclusionHypoxia induces CAIX expression in HB cells, and the CAIX inhibitor SLC-0111 has in vitro activity against these malignant cells.https://www.frontiersin.org/articles/10.3389/fonc.2023.1118268/fullcarbonic anhydrase IXhepatoblastomapediatric oncologytumor hypoxiatargeted therapy |
| spellingShingle | Katja Eloranta Marjut Pihlajoki Emmi Liljeström Ruth Nousiainen Tea Soini Jouko Lohi Stefano Cairo Stefano Cairo Stefano Cairo David B. Wilson David B. Wilson Seppo Parkkila Seppo Parkkila Seppo Parkkila Markku Heikinheimo Markku Heikinheimo Markku Heikinheimo SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration Frontiers in Oncology carbonic anhydrase IX hepatoblastoma pediatric oncology tumor hypoxia targeted therapy |
| title | SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration |
| title_full | SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration |
| title_fullStr | SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration |
| title_full_unstemmed | SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration |
| title_short | SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration |
| title_sort | slc 0111 an inhibitor of carbonic anhydrase ix attenuates hepatoblastoma cell viability and migration |
| topic | carbonic anhydrase IX hepatoblastoma pediatric oncology tumor hypoxia targeted therapy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1118268/full |
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