An Endosomal Acid-Regulatory Feedback System Rewires Cytosolic cAMP Metabolism and Drives Tumor Progression.
Mol Cancer Res
; 22(5): 465-481, 2024 May 02.
Article
en En
| MEDLINE
| ID: mdl-38319300
ABSTRACT
Although suppressed cAMP levels have been linked to cancer for nearly five decades, the molecular basis remains uncertain. Here, we identify endosomal pH as a novel regulator of cytosolic cAMP homeostasis and a promoter of transformed phenotypic traits in colorectal cancer. Combining experiments and computational analysis, we show that the Na+/H+ exchanger NHE9 contributes to proton leak and causes luminal alkalinization, which induces resting [Ca2+], and in consequence, represses cAMP levels, creating a feedback loop that echoes nutrient deprivation or hypoxia. Higher NHE9 expression in cancer epithelia is associated with a hybrid epithelial-mesenchymal (E/M) state, poor prognosis, tumor budding, and invasive growth in vitro and in vivo. These findings point to NHE9-mediated cAMP suppression as a pseudostarvation-induced invasion state and potential therapeutic vulnerability in colorectal cancer. Our observations lay the groundwork for future research into the complexities of endosome-driven metabolic reprogramming and phenotype switching and the biology of cancer progression. IMPLICATIONS Endosomal pH regulator NHE9 actively controls cytosolic Ca2+ levels to downregulate the adenylate cyclase-cAMP system, enabling colorectal cancer cells to acquire hybrid E/M characteristics and promoting metastatic progression.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Endosomas
/
Intercambiadores de Sodio-Hidrógeno
/
AMP Cíclico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Cancer Res
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
País de afiliación:
India