Statins and prostate cancer: role of cholesterol inhibition vs. prevention of small GTP-binding proteins.

Prostate cancer (PCa) is initially regulated by androgens, such as testosterone and dihydrotestosterone, which regulates cell proliferation and survival by activating the androgen receptor (AR), but later progresses to an aggressive, metastatic, androgen-independent stage for which, currently, there is no cure. Here, we argue that prevention of PCa progression is a better strategy compared to trying to cure the disease once it has already progressed. Statins inhibit the mevalonate pathway, thus preventing the synthesis of cholesterol, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. Multiple clinical studies have shown an inverse relationship between statin use and PCa risk, especially the risk for developing advanced metastatic cancer. Biochemical investigations have largely corroborated the positive effect of statins on PCa risk, showing that statins inhibited cell proliferation, induced apoptosis, and decreased cell migration and invasion in PCa cells in vitro. However, investigations of the biochemical mechanism of statin action in preventing advanced/high risk PCa remains inconclusive, as statins can act through cholesterol, geranylgeranyl, or farnesyl mediated signals. This review discusses the current clinical and biochemical findings on the use of statins in preventing PCa. Evidence of statin action through cholesterol as well as geranylgeranylation and farnesylation has been discussed. As cholesterol is a precursor of androgen production, it can reduce PCa risk by decreasing the levels of circulating testosterone, which in turn reduces the levels of interprostatic dihydrotestosterone, a strong ligand for the AR. Cholesterol was also shown to accumulate in lipid rafts and regulate the activation of the phosphatidylinositol 3-kinase/Akt pathway. However, clinical evidence from multiple studies also point to the existence of cholesterol-independent pathways mediating statin action in PCa patients. In particular, ligand-activated AR activation is seen in early stage PCa and activation of the cholesterol pathway did not indicate an effect on metastasis. Cell migration and invasion, on the other hand, is regulated strongly by members of the Ras superfamily of small GTPases, especially the Rho family, which is geranylgeranylated. This review, therefore, also compares the effects of statins on both cholesterol and geranylgeranylated and farnesylated small GTPases regulating tumor progression and metastasis in biochemical and clinical studies.