Concomitant attenuation of HMGCR expression and activity enhances the growth inhibitory effect of atorvastatin on TGF-β-treated epithelial cancer cells

Epithelial-mesenchymal transition (EMT) in primary tumor cells is a key prerequisite for metastasis initiation. Statins, cholesterol-lowering drugs, can delay metastasis formation in vivo and attenuate the growth and proliferation of tumor cells in vitro. The latter effect is stronger in tumor cells with a mesenchymal-like phenotype than in those with an epithelial one. However, the effect of statins on epithelial cancer cells treated with EMT-inducing growth factors such as transforming growth factor-beta (TGF-beta) remains unclear. Here, we examined the effect of atorvastatin on two epithelial cancer cell lines following TGF-beta treatment. Atorvastatin-induced growth inhibition was stronger in TGF-beta -treated cells than in cells not thusly treated. Moreover, treatment of cells with atorvastatin prior to TGF-beta treatment enhanced this effect, which was further potentiated by the simultaneous reduction in the expression of the statin target enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Dual pharmacological targeting of HMGCR can thus strongly inhibit the growth and proliferation of epithelial cancer cells treated with TGF-beta and may also improve statin therapy-mediated attenuation of metastasis formation in vivo.

Automated summary

Statins, such as atorvastatin, can delay metastasis formation in vivo and attenuate the growth and proliferation of tumor cells, especially in those with a mesenchymal-like phenotype. In epithelial cancer cells treated with TGF-beta, atorvastatin-induced growth inhibition is stronger, and pre-treatment with atorvastatin can enhance this effect further by reducing HMGCR expression. Targeting HMGCR pharmacologically can strongly inhibit the growth of epithelial cancer cells treated with TGF-beta and potentially improve statin therapy-mediated attenuation of metastasis formation in vivo.