TP53 status is associated with differential stress-marker expression and APP maturation in colon cancer cells

The systemic influence of tumor-derived secretomes on the nervous system remains poorly understood. We investigated whether differences in TP53 status are associated with altered cellular stress-handling states and amyloid precursor protein (APP) processing in colon cancer cells.

APP maturation, intracellular localization, and stress-associated signaling were analyzed in TP53 wild-type and TP53-mutant colon cancer cells using immunoblotting, confocal microscopy, and ELISA. Functional associations between APP processing, GPX4-associated pathways, and neurotoxicity were further evaluated using pharmacological and genetic perturbation approaches, followed by conditioned-medium transfer experiments in HT22 neuronal and BV2 microglial cells.

Distinct patterns of APP maturation and intracellular localization were observed between colon cancer cells with different TP53 status. TP53-mutant cells preferentially processed APP into its mature form and displayed relatively higher GPX4 expression, whereas TP53 wild-type cells exhibited increased endoplasmic reticulum (ER) retention of immature APP, accompanied by reduced GPX4 and elevated ATF4 expression. Functional analyses further revealed that these distinct intracellular stress-associated states were accompanied by differential neurotoxic effects of tumor-derived conditioned media. Conditioned media derived from TP53 wild-type cells significantly reduced cell viability, decreased attached-cell density, and induced morphological deterioration in HT22 neuronal and BV2 microglial cells. In contrast, conditioned media derived from TP53-mutant cells exhibited comparatively reduced neurotoxicity. Conditioned media derived from isogenic TP53-null cells displayed similarly reduced neurotoxicity, further supporting an association between TP53 status and secretome-associated phenotypes.

Collectively, our findings suggest that differences in TP53 status are associated with distinct stress-associated signaling, APP maturation, and secretome-associated phenotypes, which may contribute to differential tumor-neural cross-talk mediated by tumor-derived secretomes.