Rol del eje NUAK1/hnRNPK en el metabolismo del cáncer colorrectal.
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Date
2026
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Publisher
Universidad de Concepción
Abstract
NUAK1 es una serina/treonina quinasa de la familia relacionada a AMPK, cuya actividad se ha vinculado a procesos metabólicos y protumorales. No obstante, los mecanismos que conectan a NUAK1 con la regulación metabólica y su impacto en la respuesta a quimioterapias en cáncer colorrectal permanecen poco definidos. En este trabajo demostramos que, en cáncer colorrectal, NUAK1 presenta una localización predominantemente nuclear. De acuerdo con esto, el análisis de su interactoma revela una fuerte asociación con proteínas involucradas en el procesamiento del ARNm. Entre estos interactores confirmamos la asociación con el factor de empalme hnRNPK, conocido por regular el procesamiento del pre-mRNA de G6PD, la enzima limitante de la vía de las pentosas fosfato (PPP). Esta interacción sugiere que NUAK1, a través de hnRNPK, podría modular la expresión de G6PD y, con ello, influir directamente en la actividad de la PPP.
Consistentemente, observamos que NUAK1 incrementa los niveles de G6PD y favorece el procesamiento de su pre-mRNA, efecto acompañado por una disminución en la interacción entre hnRNPK y dicho transcrito. Adicionalmente, análisis de metabolómica indican que NUAK1 redirige el flujo de glucosa hacia la PPP en células de cáncer colorrectal, promoviendo la generación de NADPH, regulando el estrés oxidativo y favoreciendo la síntesis lipídica dependiente de esta vía. Además, los datos sugieren un rol adicional de NUAK1 en el metabolismo de purinas y en la homeostasis energética.
Dado que la PPP contribuye a la resistencia a oxaliplatino, evaluamos el impacto de la inhibición de NUAK1 en este contexto. Encontramos que NUAK1 aumenta en el núcleo tras el tratamiento con oxaliplatino y que su inhibición bloquea la inducción de G6PD mediada por el fármaco. En concordancia, la inhibición de NUAK1 sensibiliza a líneas celulares de cáncer colorrectal a oxaliplatino, incrementando el estrés genotóxico. Del mismo modo, en organoides derivados de pacientes, la inhibición de NUAK1 potencia la eficacia del tratamiento.
En conjunto, nuestros resultados establecen a NUAK1 como un regulador clave de la vía de las pentosas fosfato y un determinante de la respuesta a oxaliplatino en cáncer colorrectal. Estos hallazgos posicionan al eje NUAK1/G6PD como un potencial blanco terapéutico para mejorar la eficacia de las terapias actuales.
NUAK1 is a serine/threonine kinase related to the AMPK family, and its activity has been linked to metabolic and pro-tumor processes. However, the mechanisms connecting NUAK1 to metabolic regulation and its impact on chemotherapy response in colorectal cancer are not fully understood. In this study, we show that NUAK1 displays predominantly nuclear localization in colorectal cancer cells. Consistent with this, analysis of its interactome reveals a strong association with proteins involved in mRNA processing. Among these interactors, we validated the interaction between NUAK1 and the splicing factor hnRNPK, a known regulator of the processing of G6PD pre-mRNA, the rate-limiting enzyme of the pentose phosphate pathway (PPP). This interaction suggests that NUAK1, through hnRNPK, may modulate G6PD expression and thereby influence PPP activity. Accordingly, we observed that NUAK1 increases G6PD levels and promotes the processing of its pre-mRNA, an effect accompanied by a decrease in the interaction between hnRNPK and this transcript. Metabolomic analyses indicate that NUAK1 redirects glucose flux toward the PPP in colorectal cancer cells, promoting NADPH production, regulating oxidative stress, and supporting PPP-dependent lipid synthesis. Additionally, the data suggests an extra role for NUAK1 in purine metabolism and energy homeostasis. Because the PPP contributes to oxaliplatin resistance, we evaluated the impact of NUAK1 inhibition in this context. We found that NUAK1 increases in the nucleus after oxaliplatin treatment and its inhibition blocks the drug-induced upregulation of G6PD. Consistently, NUAK1 inhibition sensitizes colorectal cancer cell lines to oxaliplatin, increasing genotoxic stress. Similarly, in patient-derived organoids, NUAK1 inhibition enhances oxaliplatin effectiveness. Taken together, our results identify NUAK1 as a key regulator of the pentose phosphate pathway and an important determinant of oxaliplatin response in colorectal cancer. These findings position the NUAK1/G6PD axis as a potential therapeutic target to improve current treatments.
NUAK1 is a serine/threonine kinase related to the AMPK family, and its activity has been linked to metabolic and pro-tumor processes. However, the mechanisms connecting NUAK1 to metabolic regulation and its impact on chemotherapy response in colorectal cancer are not fully understood. In this study, we show that NUAK1 displays predominantly nuclear localization in colorectal cancer cells. Consistent with this, analysis of its interactome reveals a strong association with proteins involved in mRNA processing. Among these interactors, we validated the interaction between NUAK1 and the splicing factor hnRNPK, a known regulator of the processing of G6PD pre-mRNA, the rate-limiting enzyme of the pentose phosphate pathway (PPP). This interaction suggests that NUAK1, through hnRNPK, may modulate G6PD expression and thereby influence PPP activity. Accordingly, we observed that NUAK1 increases G6PD levels and promotes the processing of its pre-mRNA, an effect accompanied by a decrease in the interaction between hnRNPK and this transcript. Metabolomic analyses indicate that NUAK1 redirects glucose flux toward the PPP in colorectal cancer cells, promoting NADPH production, regulating oxidative stress, and supporting PPP-dependent lipid synthesis. Additionally, the data suggests an extra role for NUAK1 in purine metabolism and energy homeostasis. Because the PPP contributes to oxaliplatin resistance, we evaluated the impact of NUAK1 inhibition in this context. We found that NUAK1 increases in the nucleus after oxaliplatin treatment and its inhibition blocks the drug-induced upregulation of G6PD. Consistently, NUAK1 inhibition sensitizes colorectal cancer cell lines to oxaliplatin, increasing genotoxic stress. Similarly, in patient-derived organoids, NUAK1 inhibition enhances oxaliplatin effectiveness. Taken together, our results identify NUAK1 as a key regulator of the pentose phosphate pathway and an important determinant of oxaliplatin response in colorectal cancer. These findings position the NUAK1/G6PD axis as a potential therapeutic target to improve current treatments.
Description
Tesis presentada para optar al grado de Doctor/a en Ciencias Biológicas Área Biología Celular y Molecular.
Keywords
Cáncer colorrectal, Metabolismo, Quimioterapia