Br J Cancer: Whole genome analysis reveals the role of statins in colorectal cancer

Colorectal cancer (CRC) is a major public health problem worldwide.
In 2018, CRC was the fourth leading cancer, with nearly 1.
8 million new cases and 881,000 deaths.
Although the current treatment of CRC has improved, there is still no cure for advanced CRC.
Colonoscopy isa basic strategy topreventCRC, but it cannot provide comprehensive preventive measures.

Past epidemiological studies and meta-analysis have shown that there is an association between the use of statins and the reduction in the incidence of CRC.
Previous studies have shown that statins can act on CRC by mediating the BMP (bone morphogenetic protein) signal transduction pathway.
However, their exact cellular targets and potential mechanisms remain to be studied.
In this study, the researchers assessed the effect of statins on the signal transduction of cancer cells through an array-based kinase assay.

Researchers performed kinetic analysis on CRC cells treated with or without Lovastatin.
And various CRC cell lines were immunized blot experiments, siRNA-mediated gene knockout experiments and specific inhibitor of BMP Noggin treated to further verify the discovery kinase array analysis.
And the correlation of the above findings was confirmed through the transplantation tumor experiment and Simvastatin treatment of CRC patients.

Changes of phosphorylated proteome in CRC cells after statin treatment

The results showed that the kinome analysis can distinguish the non-specific toxic effects caused by 10 μm lovastatin and the specific effects on cell signal transduction caused by 2 μm lovastatin.
Statins can induce the up-regulation of PTEN activity and lead to down-regulation of PI3K/Akt/mTOR signal.

Patient's statin treatment and transplanted tumor mouse model

When cells are treated with the specific BMP inhibitor Noggin, PTEN is knocked down, or AKT is transfected with sustained activity, all of them can eliminate the effect of lovastatin on mTOR phosphorylation.
In transplanted tumors and patients treated with simvastatin, it has also been confirmed that statins can mediate the activation of BMP pathway, the activation of PTEN, and the down-regulation of mTOR signaling.

All in all, the results of the study revealed that statins can induce BMP-specific activation of PTEN and inhibit the PI3K/Akt/mTOR signal transduction pathway in CRC.