Anticancer Efficacy of Simvastatin on Prostate Cancer Cells and Tumor Xenografts Is Associated with Inhibition of Akt and Reduced Prostate-Specific Antigen Expression

Abstract

Prostate cancer is the second-leading cause of cancer-associated death among men in the United States. There has been renewed interest in the potential therapeutic benefits of statins for cancer. Simvastatin, a widely used generic drug for preventing cardiovascular events, is well known for its effects on cellular proliferation and inflammation, two key processes that also determine the rate of tumor growth. Although a growing body of evidence suggests that statins have the potential to reduce the risk of many cancers, there are discrepancies over the pro-and anticancer effects of statins. In the current study, we sought to investigate the effects of simvastatin on the Akt pathway in prostate cancer cells with respect to the regulation of various cell functions in vitro and tumor growth in vivo. Timeand dose-dependent effects of simvastatin on LNCaP (androgen-dependent) and PC3 (androgen-independent) cells indicate that treatment with simvastatin at concentrations as low as 25 M was sufficient to inhibit serum-stimulated Akt activity. Akin to this, treatment with simvastatin significantly inhibited serum-induced cell migration, invasion, colony formation, and proliferation. Simvastatin-mediated effects on colony formation were rescued by adenovirus-mediated expression of constitutively active Akt (myristoylated Akt) in PC3 cell lines. A PC3 xenograft model performed in nude mice exhibited reduced tumor growth with simvastatin treatment associated with decreased Akt activity and reduced prostate-specific antigen (PSA) levels. Our findings demonstrate the therapeutic benefits of simvastatin for prostate cancer and suggest a link between simvastatin, regulation of Akt activity, and PSA expression in prostate tumors.

HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation

“…In addition, our results showed that simvastatin decreased CCL17-induced HT-29 cell migration without any concomitant effects on cell proliferation of apoptosis, indicating a direct effect of simvastatin on colon cancer cell migration, which might be of beneficial value. Although this is the first report to show that simvastatin inhibits colon cancer cell migration in response to chemokine signaling, other investigations 11 have found that simvastatin can inhibit migration of breast [21], hepatic [22], renal [17] and prostate [23] cancer cells, supporting the concept that simvastatin is an effective inhibitor of tumor cell migration.…”

Anti-cancer potential of MAPK pathway inhibition in paragangliomas – effect of different statins on mouse pheochromocytoma cells

“…However, several new therapeutic strategies have been recently tested in model organisms [35][36][37][38], including lovastatin [1]. Previously, statins have been reported to decrease proliferation, survival, cell cycle progression, and migration in other cells including aggressive cancer models, amongst others by MAPK pathway inhibition [10,[25][26][27]29,30,[39][40][41]. However, currently evidence that statin treatment will be potent in the most aggressive type of PHEOs/PGLs, i.e.…”

P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion

“…Cells were resuspended in saline to a concentration of 1.7 ϫ 10 7 /ml. Cell suspension (100 l) was injected subcutaneously into 8-week-old nude mice (athymic nude mice; Harlan, Indianapolis, IN) (16). The respective controls were injected intraperitoneally with 0.9% saline.…”