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. Time- and 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 μM 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.
Footnotes
This research was funded by the University of Georgia Research Foundation (to P.R.S.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.174870.
-
ABBREVIATIONS:
- PSA
- prostate-specific antigen
- myrAkt
- myristoylated Akt
- DMEM
- Dulbecco's modified Eagle's medium
- GSK
- glycogen synthase kinase
- FBS
- fetal bovine serum
- ELISA
- enzyme-linked immunosorbent assay
- PBS
- phosphate-buffered saline
- DMSO
- dimethyl sulfoxide
- BrdU
- 5-bromo-2-deoxyuridine, bromodeoxyuridine
- EGF
- epidermal growth factor
- GFP
- green fluorescent protein.
- Received September 7, 2010.
- Accepted November 5, 2010.
- U.S. Government work not protected by U.S. copyright
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|