Statins regulate kinase signaling by causing changes in phosphorylation, rather than through changes in gene expression or direct inhibition: evidence in colorectal cancer

Francisco Alejandro Lagunas-Rangel^1,2*Jörgen Jonsson¹Ludmila Jackevica²Robert Fredriksson¹Maija Dambrova²Helgi B Schiöth¹

• ¹Uppsala Universitet, Uppsala, Sweden
• ²Latvian Institute of Organic Synthesis (LAS), Riga, Latvia

Statins, widely used for hypercholesterolemia, have shown anticancer properties including induction of apoptosis and ferroptosis, modulation of autophagy, and reprogramming of the tumor microenvironment, making them potential candidates for repurposing in cancer therapy. There are increasing evidence that statins may affect kinase signaling, while the evidence is scattered and unconclusive. Given the central role of kinases in regulating cellular signaling pathways, we investigated how statins affect kinase activity. Integrating public RNA-seq and phosphoproteomic datasets with in vitro kinome inhibition profiles of atorvastatin, simvastatin, and cerivastatin on approximately 400 kinases, we found that statins predominantly modulate kinase signaling through changes in phosphorylation, rather than through transcriptional regulation or direct inhibition of kinases in these large-scale screening assays. The phosphoproteomics analyses suggested that most kinases exhibited reduced phosphorylation, although some showed increased activity. Importantly, the affected kinases were enriched in critical cancer-related pathways, including insulin signaling, EGF-EGFR signaling, PI3K/AKT signaling, and the PD-L1/PD-1 immune checkpoint axis. Notably, direct inhibition was observed for CAMK1G and TSSK1B, with IC50 values of 8.9 µM and 3.3 µM, respectively. Furthermore, in colorectal cancer cell lines, we demonstrated that reduced PI3K phosphorylation is at least partially due to mevalonate depletion, highlighting a key mechanism of statin action. These findings raised the possibility that the anticancer properties of statins could also be mediated, at least in part, through their capacity to modulate kinase phosphorylation and activity.