Stress-Induced Aggregation of pVHL in Renal Cell Carcinoma: Distinct Aggregate Phenotypes and Cellular Response

Protein aggregation has emerged as a dynamic regulatory mechanism extending far beyond its traditional association with pathogenesis. Within the tumor microenvironment, stress conditions such as hypoxia and acidosis promote reversible protein aggregation into a spectrum of assemblies ranging from dynamic condensates to amyloid-like structures. These physiological aggregates function as adaptive compartments that temporarily sequester proteins and facilitate cellular survival to stress. The von Hippel-Lindau tumor suppressor protein (pVHL) has been reported to aggregate under stress conditions. However, pVHL aggregation and its functional consequences in renal cell carcinoma (RCC) cells remain poorly understood. This thesis investigates stress-induced protein aggregation in the RCC cell lines Caki-1 and Caki-2, with particular focus on endogenous pVHL. The results demonstrate that acidic stress is the primary driver of pVHL aggregation, promoting its sequestration into reversible A-body-like nuclear structures. pVHL aggregation was also associated with increased expression of the HIF target GLUT-1, suggesting that stress-induced aggregation may impair pVHL function. Acidic stress also reduced cellular proliferation and increased the proportion of dormant cells while maintaining high cell viability, supporting a role for protein aggregation in cellular adaptation to stress conditions. Overall, these findings provide new insight into the aggregation behaviour of pVHL and suggest that stress-induced aggregates may contribute to cellular adaptation by promoting a cellular dormant state, thereby contributing to RCC progression.