Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma

Autores
Celi Castillo, Ana Beatriz; Mechali, Ana; Beltramone, Natalia; Casal, Juan José; Capurro, Claudia Graciela; Di Giusto, Gisela; Ford, Paula; Rivarola, Valeria
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Acid-base homeostasis is critical for maintaining physiological functions. In cancer, an acidic tumor microenvironment, driven by altered cellular metabolism, plays a pivotal role in tumor progression by fostering aggressive phenotypes, immune evasion, and resistance to therapy, often at the detriment of surrounding normal tissues. The Na⁺/H⁺ exchanger isoform 1 (NHE1) is a key regulator of intracellular pH and a critical factor in cancer cell survival and proliferation. This study aimed to evaluate the effect of mild alkalosis, combined with NHE1 inhibition, on cell viability in normal renal cells and clear cell renal cell carcinoma (ccRCC) cells. Our findings reveal that this therapeutic combination selectively induces cell death in ccRCC cells while sparing normal renal cells. Mechanistically, we demonstrate that NHE1 activity is higher in ccRCC cells than in normal cells. Mild alkalosis enhances NHE1 activity in normal cells but inhibits its activity in cancer cells. Furthermore, prolonged alkaline exposure alters the subcellular localization of NHE1 in the plasma membrane, with distinct patterns observed between normal and cancer cells. These results suggest that targeting NHE1 activity in conjunction with alkalosis represents a promising strategy for ccRCC treatment, providing a potential therapeutic avenue to exploit the differential pH regulation between cancerous and normal cells.
Fil: Celi Castillo, Ana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Mechali, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Beltramone, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Casal, Juan José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Capurro, Claudia Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Di Giusto, Gisela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Ford, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Rivarola, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Materia
CLEAR CELL RENAL CELL CARCINOMA
pH
NHE1
MILD ALKALOSIS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/284690
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/284690
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell CarcinomaCeli Castillo, Ana BeatrizMechali, AnaBeltramone, NataliaCasal, Juan JoséCapurro, Claudia GracielaDi Giusto, GiselaFord, PaulaRivarola, ValeriaCLEAR CELL RENAL CELL CARCINOMApHNHE1MILD ALKALOSIShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Acid-base homeostasis is critical for maintaining physiological functions. In cancer, an acidic tumor microenvironment, driven by altered cellular metabolism, plays a pivotal role in tumor progression by fostering aggressive phenotypes, immune evasion, and resistance to therapy, often at the detriment of surrounding normal tissues. The Na⁺/H⁺ exchanger isoform 1 (NHE1) is a key regulator of intracellular pH and a critical factor in cancer cell survival and proliferation. This study aimed to evaluate the effect of mild alkalosis, combined with NHE1 inhibition, on cell viability in normal renal cells and clear cell renal cell carcinoma (ccRCC) cells. Our findings reveal that this therapeutic combination selectively induces cell death in ccRCC cells while sparing normal renal cells. Mechanistically, we demonstrate that NHE1 activity is higher in ccRCC cells than in normal cells. Mild alkalosis enhances NHE1 activity in normal cells but inhibits its activity in cancer cells. Furthermore, prolonged alkaline exposure alters the subcellular localization of NHE1 in the plasma membrane, with distinct patterns observed between normal and cancer cells. These results suggest that targeting NHE1 activity in conjunction with alkalosis represents a promising strategy for ccRCC treatment, providing a potential therapeutic avenue to exploit the differential pH regulation between cancerous and normal cells.Fil: Celi Castillo, Ana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Mechali, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Beltramone, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Casal, Juan José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Capurro, Claudia Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Di Giusto, Gisela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Ford, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Rivarola, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaResearch Square Company2025-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/284690Celi Castillo, Ana Beatriz; Mechali, Ana; Beltramone, Natalia; Casal, Juan José; Capurro, Claudia Graciela; et al.; Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma; Research Square Company; Research Square; 2-2025; 1-132693-5015CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.researchsquare.com/article/rs-5875263/v1info:eu-repo/semantics/altIdentifier/doi/10.21203/rs.3.rs-5875263/v1info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:31:25Zoai:ri.conicet.gov.ar:11336/284690instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-08-25 14:31:26.001CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma
title Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma
spellingShingle Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma
Celi Castillo, Ana Beatriz
CLEAR CELL RENAL CELL CARCINOMA
pH
NHE1
MILD ALKALOSIS
title_short Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma
title_full Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma
title_fullStr Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma
title_full_unstemmed Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma
title_sort Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma
dc.creator.none.fl_str_mv Celi Castillo, Ana Beatriz
Mechali, Ana
Beltramone, Natalia
Casal, Juan José
Capurro, Claudia Graciela
Di Giusto, Gisela
Ford, Paula
Rivarola, Valeria
author Celi Castillo, Ana Beatriz
author_facet Celi Castillo, Ana Beatriz
Mechali, Ana
Beltramone, Natalia
Casal, Juan José
Capurro, Claudia Graciela
Di Giusto, Gisela
Ford, Paula
Rivarola, Valeria
author_role author
author2 Mechali, Ana
Beltramone, Natalia
Casal, Juan José
Capurro, Claudia Graciela
Di Giusto, Gisela
Ford, Paula
Rivarola, Valeria
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CLEAR CELL RENAL CELL CARCINOMA
pH
NHE1
MILD ALKALOSIS
topic CLEAR CELL RENAL CELL CARCINOMA
pH
NHE1
MILD ALKALOSIS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Acid-base homeostasis is critical for maintaining physiological functions. In cancer, an acidic tumor microenvironment, driven by altered cellular metabolism, plays a pivotal role in tumor progression by fostering aggressive phenotypes, immune evasion, and resistance to therapy, often at the detriment of surrounding normal tissues. The Na⁺/H⁺ exchanger isoform 1 (NHE1) is a key regulator of intracellular pH and a critical factor in cancer cell survival and proliferation. This study aimed to evaluate the effect of mild alkalosis, combined with NHE1 inhibition, on cell viability in normal renal cells and clear cell renal cell carcinoma (ccRCC) cells. Our findings reveal that this therapeutic combination selectively induces cell death in ccRCC cells while sparing normal renal cells. Mechanistically, we demonstrate that NHE1 activity is higher in ccRCC cells than in normal cells. Mild alkalosis enhances NHE1 activity in normal cells but inhibits its activity in cancer cells. Furthermore, prolonged alkaline exposure alters the subcellular localization of NHE1 in the plasma membrane, with distinct patterns observed between normal and cancer cells. These results suggest that targeting NHE1 activity in conjunction with alkalosis represents a promising strategy for ccRCC treatment, providing a potential therapeutic avenue to exploit the differential pH regulation between cancerous and normal cells.
Fil: Celi Castillo, Ana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Mechali, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Beltramone, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Casal, Juan José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Capurro, Claudia Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Di Giusto, Gisela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Ford, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Rivarola, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
description Acid-base homeostasis is critical for maintaining physiological functions. In cancer, an acidic tumor microenvironment, driven by altered cellular metabolism, plays a pivotal role in tumor progression by fostering aggressive phenotypes, immune evasion, and resistance to therapy, often at the detriment of surrounding normal tissues. The Na⁺/H⁺ exchanger isoform 1 (NHE1) is a key regulator of intracellular pH and a critical factor in cancer cell survival and proliferation. This study aimed to evaluate the effect of mild alkalosis, combined with NHE1 inhibition, on cell viability in normal renal cells and clear cell renal cell carcinoma (ccRCC) cells. Our findings reveal that this therapeutic combination selectively induces cell death in ccRCC cells while sparing normal renal cells. Mechanistically, we demonstrate that NHE1 activity is higher in ccRCC cells than in normal cells. Mild alkalosis enhances NHE1 activity in normal cells but inhibits its activity in cancer cells. Furthermore, prolonged alkaline exposure alters the subcellular localization of NHE1 in the plasma membrane, with distinct patterns observed between normal and cancer cells. These results suggest that targeting NHE1 activity in conjunction with alkalosis represents a promising strategy for ccRCC treatment, providing a potential therapeutic avenue to exploit the differential pH regulation between cancerous and normal cells.
publishDate 2025
dc.date.none.fl_str_mv 2025-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/284690
Celi Castillo, Ana Beatriz; Mechali, Ana; Beltramone, Natalia; Casal, Juan José; Capurro, Claudia Graciela; et al.; Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma; Research Square Company; Research Square; 2-2025; 1-13
2693-5015
CONICET Digital
CONICET
url http://hdl.handle.net/11336/284690
identifier_str_mv Celi Castillo, Ana Beatriz; Mechali, Ana; Beltramone, Natalia; Casal, Juan José; Capurro, Claudia Graciela; et al.; Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma; Research Square Company; Research Square; 2-2025; 1-13
2693-5015
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.researchsquare.com/article/rs-5875263/v1
info:eu-repo/semantics/altIdentifier/doi/10.21203/rs.3.rs-5875263/v1
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Research Square Company
publisher.none.fl_str_mv Research Square Company
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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