Lipophilic statins inhibit YAP nuclear localization, co-activator activity and colony formation in pancreatic cancer cells and prevent the initial stages of pancreatic ductal adenocarcinoma in KrasG12D mice

This study investigated how statins affect the localization, phosphorylation, and transcriptional activity of Yes-associated Protein (YAP) in both human and mouse pancreatic ductal adenocarcinoma (PDAC) cells. When PANC-1 and MiaPaCa-2 cell lines were treated with cerivastatin or simvastatin under low-density conditions, YAP was observed to shift from the nucleus to the cytoplasm. This shift was accompanied by a reduction in the expression of YAP/TEAD-regulated genes, including Connective Tissue Growth Factor (CTGF) and Cysteine-rich angiogenic inducer 61 (CYR61).

Statins also prevented YAP from entering the nucleus and suppressed CTGF and CYR61 expression in high-density cultures treated with insulin and neurotensin, a mitogenic stimulus. Furthermore, several lipophilic statins—including cerivastatin, simvastatin, atorvastatin, and fluvastatin—reduced the ability of PANC-1 and MiaPaCa-2 cells to form colonies in a dose-dependent manner. In contrast, the hydrophilic statin pravastatin showed no inhibitory effect even at a higher concentration.

Further analysis revealed that cerivastatin did not alter YAP phosphorylation at the Ser127 site, regardless of the presence of insulin and neurotensin, but it did interfere with the formation of actin stress fibers, which are important for YAP activity. These findings were extended using primary KC and KPC cells, derived from mice engineered to express oncogenic Kras alone or in combination with mutant p53. Lipophilic statins in these mouse-derived cells induced YAP translocation to the cytoplasm, reduced the expression of Ctgf, Cyr61, and Birc5, and markedly impaired colony formation.

In vivo experiments in KC mice fed a high-fat diet showed that simvastatin treatment prevented the early loss of pancreatic acinar cells and the formation of pancreatic intraepithelial neoplasias (PanINs), Super-TDU which are precursors to PDAC. Overall, the findings demonstrate that lipophilic statins suppress YAP activity and proliferation in PDAC models and may delay or prevent early pathological changes associated with pancreatic cancer.