RT info:eu-repo/semantics/article
T1 Deregulation of lactate permeability using a small-molecule transporter (Lactrans-1) disturbs intracellular pH and triggers cancer cell death
A1 Arias Betancur, Alain
A1 Fontova Pale, Pere
A1 Alonso Carrillo, Daniel
A1 Carreira Barral, Israel
A1 Duis, Janneke
A1 García Valverde, María
A1 Soto Cerrato, Vanessa
A1 Quesada Pato, Roberto
A1 Pérez Tomás, Ricardo
K1 Lactate
K1 Anionophores
K1 Click-tambjamines
K1 Cancer metabolism
K1 pH deregulation
K1 Small molecules
K1 Bioquímica
K1 Biochemistry
K1 Química orgánica
K1 Chemistry, Organic
AB Due to the relevance of lactic acidosis in cancer, several therapeutic strategies have been developed targeting its production and/or regulation. In this matter, inhibition approaches of key proteins such as lactate dehydrogenase or monocarboxylate transporters have showed promising results, however, metabolic plasticity and tumor heterogeneity limits their efficacy. In this study, we explored the anticancer potential of a new strategy based on disturbing lactate permeability independently of monocarboxylate transporters activity using a small molecule ionophore named Lactrans-1. Derived from click-tambjamines, Lactrans-1 facilitates transmembrane lactate transportation in liposome models and reduces cancer cell viability. The results showed that Lactrans-1 triggered both apoptosis and necrosis depending on the cell line tested, displaying a synergistic effect in combination with first-line standard chemotherapeutic cisplatin. The ability of this compound to transport outward lactate anions was confirmed in A549 and HeLa cells, two cancer cell lines having distinct rates of lactate production. In addition, through cell viability reversion experiments it was possible to establish a correlation between the amount of lactate transported and the cytotoxic effect exhibited. The movement of lactate anions was accompanied with intracellular pH disturbances that included basification of lysosomes and acidification of the cytosol and mitochondria. We also observed mitochondrial swelling, increased ROS production and activation of oxidative stress signaling pathways p38-MAPK and JNK/SAPK. Our findings provide evidence that enhancement of lactate permeability is critical for cellular pH homeostasis and effective to trigger cancer cell death, suggesting that Lactrans-1 may be a promising anticancer therapy.
PB Elsevier
SN 0006-2952
YR 2024
FD 2024-11
LK http://hdl.handle.net/10259/9573
UL http://hdl.handle.net/10259/9573
LA eng
NO This work was supported by Consejería de Educación de la Junta de Castilla y León [Project BU067P20] and Ministerio de Ciencia e Innovación [Project PID2020-117610RB-100]. A.A.-B. thanks to PFCHA/Becas Chile (Folio #72200156) for his pre-doctoral scholarship. P.F., D.A.-C. and I.C.-B. thank Consejería de Educación de la Junta de Castilla y León, European Regional Development Fund (ERDF) and European Social Fund (ESF) for their post-doctoral (P.F. and I.C.-B.) and pre-doctoral (D.A.-C.) contracts.
DS Repositorio Institucional de la Universidad de Burgos
RD 27-nov-2024