Producción CyT
Congreso
Autoría
Gatti, Mora
;
Lechuga, Julia
;
SABATER, AGUSTINA AYELEN
;
Pascual, Gastón
;
Seniuk, Rocío
;
Cotignola, Javier
;
Vazquez, Elba
;
Gueron, Geraldine
;
Sanchis, Pablo
Fecha
2024
Editorial y Lugar de Edición
Medicina
Resumen
Información suministrada por el agente en
SIGEVA
Pancreatic cancer (PC) remains one of the most lethal malignancies, with a 5-year survival rate of just 13%. PC tumors are characterized by a highly fibrotic stroma, composed predominantly of collagen fibers. Our previous findings demonstrated that a collagen-rich environment activates Protein Kinase A (PKA) signaling in prostate cancer, leading to metabolic rewiring in tumor cells. Given the pivotal role of a fibrotic stroma in both PKA activation and PC progression, this study aimed at elucid...
Pancreatic cancer (PC) remains one of the most lethal malignancies, with a 5-year survival rate of just 13%. PC tumors are characterized by a highly fibrotic stroma, composed predominantly of collagen fibers. Our previous findings demonstrated that a collagen-rich environment activates Protein Kinase A (PKA) signaling in prostate cancer, leading to metabolic rewiring in tumor cells. Given the pivotal role of a fibrotic stroma in both PKA activation and PC progression, this study aimed at elucidating the role of PKA in the metabolic phenotype of PC. PANC-1 cells, a PC cell line, were treated with the potent PKA inhibitor H89 across a concentration gradient from 1 μM to 80 μM. Concentrations above 20 μM significantly impaired cell viability (P<0.05), prompting us to focus on 2.5 and 10 μM H89 to assess metabolic effects without inducing cell death. At the cellular level, PKA inhibition led to a significant decrease in ATP levels, increased lipid accumulation (Bodipy 493/503 staining), and higher levels of lipid peroxidation (Bodipy 665/676 probe; P<0.05). Additionally, blocking PKA activity resulted in an increased mitochondrial membrane potential, as indicated by JC-1 staining. At the molecular level, we observed significant upregulation of HIF1A1 and VDR, alongside dysregulation of EHHADH and ALDH1L2, suggesting enhanced lipid biosynthesis in H89-treated cells. Furthermore, the metabolic transporters SLC16A1 and GLUT1 were markedly upregulated upon PKA inhibition. Collectively, these findings highlight PKA as a crucial regulator of the metabolic phenotype in PC and underscore the profound lipid metabolic reprogramming induced by PKA inhibition, offering novel insights into potential therapeutic targets for this deadly disease.
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Palabras Clave
Protein Kinase AMetabolismPancreatic Cancer