Oxalate induces proliferation and mitochondrial metabolism in select clear cell renal cell carcinoma cell lines

Renal Cell Carcinoma (RCC) leads to over $3 billion in annual healthcare costs and reduces patients' quality of life. While the causes of RCC are not fully understood, studies suggest a link to kidney stone (KS) disease, particularly those containing calcium oxalate (CaOx). Oxalate is found in certain plant-derived foods and is known to cause oxidative stress, inflammation, and cancer-like properties in renal epithelial cells. However, its effect on RCC remains unclear. This study investigated the impact of oxalate on clear cell RCC (ccRCC), the most common RCC subtype, using two ccRCC cell lines: 786-O (ccB subtype) and 769-P (ccA subtype). We hypothesized that oxalate promotes tumor-like behavior in ccRCC cells. After exposing cells to both soluble and insoluble oxalate for 24 h, we measured cell proliferation, metabolism, oxidative stress, and DNA damage. In 786-O cells, oxalate increased proliferation, mitochondrial gene expression, and metabolism, while reducing oxidative stress. In contrast, oxalate had little effect on 769-P proliferation or metabolism but increased oxidative stress and DNA damage. To determine if these effects were subtype-specific, we treated Caki-1 cells (another ccB subtype) and observed similar responses to 786-O cells. Importantly, rapamycin, an mTOR inhibitor, prevented oxalate-induced responses in 786-O and Caki-1 cells. These findings suggest that oxalate enhances proliferation and metabolic activity in certain ccRCC subtypes and may contribute to the association between RCC and KS disease.