Molecular basis of 24-methyl cholesterol as an anti-renal clear cell carcinoma agent in the context of altered cellular glucose metabolism

Cancer is one of the leading causes of death as the World Health Organization estimates that one in six deaths is attributed to cancer globally. The American Cancer Society recorded over 400,000 new cases of kidney cancer developed globally with 80,000 new cases in the US in 2024. Of these renal carcinomas are the most common type. They are also associated with poor metabolic health. The Virginia Department of Health found that kidney cancer was the ninth most common cancer in Virginia with over 1,300 new cases of kidney cancer in 2021. Renal cell carcinomas (RCC) make up about 90% of kidney cancers and clear cell RCCs make up about 70% of kidney cancers. Due to their dependency on glucose as an energy substrate to promote cell division, one of the most promising avenues for inhibiting the growth of renal carcinomas is to inhibit glucose uptake. Our lab has demonstrated that 24-methyl cholesterol (24-MC) effectively inhibited glucose uptake in a dose-dependent manner (1, 10, 100 µM, and 1 mM) in 3T3-L1 adipocytes. AMP-activated protein kinase (AMPK) generally promotes increased energy substrate availability, which also leads to conditions conducive to increased cell proliferation. It is also an activator of the regulatory enzyme involved in NAD+ synthesis, which is a necessary co-substrate for glycolytic flux. Our lab found that 24MC inhibits NAMPT activity and further inhibits AMPK activity by promoting the phosphorylation of an inhibitory serine residue in clear cell RCCs. While these data suggest that 24-MC inhibits glucose uptake via an AMPK/NAMPT-dependent mechanism, further research is necessary to fully characterize the mechanism. Ongoing research in our lab is seeking to further characterize mechanism by which 24-MC inhibits glucose uptake. We are also seeking to compare the efficacy of 24-MC to other RCC therapeutics and explore the synergistic effects of 24-MC when combined with other chemotherapeutic agents.