Professor of Medicine University at Buffalo Buffalo, NY, United States
Background: Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal cell carcinoma (RCC) and have correlated mitochondrial activity with poor survival in a subset of patients. Lysosomes are intracellular Ca2+ hubs that are essential for membrane trafficking and signaling. The lysosomal purinergic receptor 4 (P2XR4), an ATP/Ca2+ pump, plays a key role in energy flux. Furthermore, dietary restrictions have been reported to potentially modulate tumor metabolism. In this study, we investigated the role of P2XR4 inhibition and amino acid (AA) restriction in metabolic and energy dynamics in clear cell (cc) and translocation (t) RCC models.
Methods: Seahorse experiments, immunofluorescence and fluorescence cell sorting, genetic silencing and pharmacological inhibition were utilized to assess the role of P2X4R and AA in regulating mitochondrial function. Patient-derived organoids and murine xenograft models were used to demonstrate the impact P2XR4 inhibition and AA restriction.
Results: Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells but in all the tRCC cells assessed. Mitochondrial function inhibition failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability. Amino acid restriction was associated in decreased oxidative phosphorylation in RCC models with baseline elevated mitochondrial function. The results from combining amino acid restriction and P2X4R inhibition are ongoing and will be presented.
Conclusions: Overall, our preliminary results suggest that the perturbed mitochondrial activity induced by P2XR4 inhibition and amino acid restriction may represent a new therapeutic strategy for a subset of RCC patients.
