Atorvastatin calcium selectively kills thyroid cancer cells by inhibiting the prenylation of HRAS proteins

Atorvastatin calcium (ATO), a small molecule inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, effectively reduces endogenous cholesterol synthesis, thus becoming the basic drug for cardiovascular and cerebrovascular diseases in clinical practice. It has been reported that the antineoplastic effect of ATO in breast cancer and pancreatic cancer; however, its efficacy in thyroid cancer remains largely unknown. Here, we demonstrated that ATO preferentially killed HRAS wild-type ( HRAS ^WT ) thyroid cancer cells by decreasing AKT phosphorylation but had little effect on HRAS - or PIK3CA -mutant thyroid cancer cells. Mechanistically, ATO impaired the localization of wild-type HRAS to cell membrane by blocking its prenylation, thereby inhibiting its activity. Further studies showed that the PI3K/AKT pathway was essential for the growth of HRAS ^WT thyroid cancer cells, but mutant HRAS mainly activated the MAPK/EKR signaling pathway in thyroid cancer cells, making them resistant to ATO. Combining ATO with MEK inhibitor produced a significant synergistic anti-tumor effect on HRAS -heterozygous mutant thyroid cancer cells by disrupting the membrane localization of HRAS via the inhibition of both prenylation and palmitoylation. Taken together, this study demonstrates that ATO selectively eradicates HRAS ^WT thyroid cancer cells by suppressing the prenylation of HRAS proteins and proposes a new therapeutic regimen for HRAS -mutant thyroid cancers by combining ATO and MEK inhibitor.