TY - JOUR
T1 - SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration
AU - Eloranta, Katja
AU - Pihlajoki, Marjut
AU - Liljeström, Emmi
AU - Nousiainen, Ruth
AU - Soini, Tea
AU - Lohi, Jouko
AU - Cairo, Stefano
AU - Wilson, David B.
AU - Parkkila, Seppo
AU - Heikinheimo, Markku
N1 - Funding Information:
This study was supported by Doctoral Program in Clinical Research at University of Helsinki Funds, Finska Läkaresällskapet, Helsinki University Central Hospital Research Grants, Päivikki and Sakari Sohlberg Foundation, and Sigrid Jusélius Foundation and Lasten Syöpäsäätiö Väre (Väre Foundation). Acknowledgments
Publisher Copyright:
Copyright © 2023 Eloranta, Pihlajoki, Liljeström, Nousiainen, Soini, Lohi, Cairo, Wilson, Parkkila and Heikinheimo.
PY - 2023/1/26
Y1 - 2023/1/26
N2 - Background: In 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. Methods: We 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. Results: CAIX 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. Conclusion: Hypoxia induces CAIX expression in HB cells, and the CAIX inhibitor SLC-0111 has in vitro activity against these malignant cells.
AB - Background: In 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. Methods: We 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. Results: CAIX 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. Conclusion: Hypoxia induces CAIX expression in HB cells, and the CAIX inhibitor SLC-0111 has in vitro activity against these malignant cells.
KW - carbonic anhydrase IX
KW - hepatoblastoma
KW - pediatric oncology
KW - targeted therapy
KW - tumor hypoxia
UR - http://www.scopus.com/inward/record.url?scp=85147654818&partnerID=8YFLogxK
U2 - 10.3389/fonc.2023.1118268
DO - 10.3389/fonc.2023.1118268
M3 - Article
C2 - 36776327
AN - SCOPUS:85147654818
SN - 2234-943X
VL - 13
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1118268
ER -