Accumulation of fructose 1,6-bisphosphate protects clear cell renal cell carcinoma from oxidative stress.

Clear cell renal cell carcinoma (ccRCC) is characterized by the activation of hypoxia-inducible factors and enhanced aerobic glycolysis. In our previous study, metabolic profiling revealed a threefold increase of fructose 1,6-bisphosphate (FBP) in ccRCC tissue compared with normal kidney tissue. As an important intermediate metabolite, its role in cancer development remains unknown. We found that high levels of FBP were required for cancer growth because of its ability to affect the redox status. Mechanistically, FBP regulated the redox status partially by suppressing NADPH oxidase isoform NOX4 activity in ccRCC cells. ccRCC maintained high levels of FBP through the downregulation of aldolase B (ALDOB). Reduction of FBP levels in cancer cells by the ectopic expression of ALDOB disrupted redox homeostasis, arrested cancer proliferation, and sensitized ccRCC cells to a chemotherapy agent (paclitaxel). Furthermore, low expression of ALDOB portended significantly worse disease-free survival and overall survival in ccRCC patients. In summary, the downregulation of ALDOB and accumulation of FBP promote ccRCC growth by counteracting oxidative stress.